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Sample records for rat mammary cancer

  1. Development and characterization of a novel rat model of estrogen-induced mammary cancer.

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    Dennison, Kirsten L; Samanas, Nyssa Becker; Harenda, Quincy Eckert; Hickman, Maureen Peters; Seiler, Nicole L; Ding, Lina; Shull, James D

    2015-04-01

    The ACI rat model of 17β-estradiol (E2)-induced mammary cancer is highly relevant for use in establishing the endocrine, genetic, and environmental bases of breast cancer etiology and identifying novel agents and strategies for preventing breast cancer. E2 treatment rapidly induces mammary cancer in female ACI rats and simultaneously induces pituitary lactotroph hyperplasia and adenoma. The pituitary tumors can result in undesired morbidity, which compromises long-term studies focused on mammary cancer etiology and prevention. We have defined the genetic bases of susceptibility to E2-induced mammary cancers and pituitary tumors and have utilized the knowledge gained in these studies to develop a novel inbred rat strain, designated ACWi, that retains the high degree of susceptibility to E2-induced mammary cancer exhibited by ACI rats, but lacks the treatment-related morbidity associated with pituitary lactotroph hyperplasia/adenoma. When treated with E2, female ACWi rats developed palpable mammary cancer at a median latency of 116 days, an incidence of 100% by 161 days and exhibited an average of 15.6 mammary tumors per rat following 196 days of treatment. These parameters did not differ from those observed for contemporaneously treated ACI rats. None of the E2-treated ACWi rats were killed before the intended experimental end point due to any treatment-related morbidity other than mammary cancer burden, whereas 20% of contemporaneously treated ACI rats exhibited treatment-related morbidity that necessitated premature killing. The ACWi rat strain is well suited for use by those in the research community, focusing on breast cancer etiology and prevention.

  2. Kinetics of mammary clonogenic cells and rat mammary cancer induction by X-rays or fission neutrons

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    Kamiya, Kenji [Hiroshima Univ. (Japan). Research Inst. for Radiation Biology and Medicine; Higgins, P.D.; Tanner, M.A.; Gould, M.N.; Clifton, K.H.

    1999-12-01

    Following the hormonal treatment of rats with high prolactin levels and glucocorticoid deficiency (Prl+/Glc-) for 48 days (Day +48), total recoverable mammary DNA was increased by more than sevenfold, tritiated thymidine uptake by nearly fourfold, and total mammary clonogens by about fivefold. Irradiation with 4, 40, and 80 cGy X-rays on Day +48 increased total mammary carcinomas per rat-day-at-risk linearly with dose, and 40 and 80 cGy significantly decreased first carcinoma latency. A dose of 40 cGy X-rays before hormone treatment (Day -1) yielded tumor latencies and frequencies insignificantly different from unirradiated controls but significantly different from those when the dose was given on Day +48. Total carcinomas per rat-day-at-risk were fitted better by a function of dose to the power 0.4 than by a linear function after exposure to 1, 10. and 20 cGy fission neutrons, and 10 and 20 cGy significantly shortened the time to appearance of the first cancer. In contrast to results with X-rays, 10 cGy neutrons on Day -1 yielded tumor frequencies and latencies insignificantly different from 10 cGy neutrons on Day +48. The carcinogenic action of X-rays, but not of neutrons, was thus influenced by total clonogen numbers and/or proliferation rates. (author)

  3. Resveratrol, but not EGCG, in the diet suppresses DMBA-induced mammary cancer in rats

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    Whitsett Timothy

    2006-05-01

    Full Text Available Abstract Despite the advent of new and aggressive therapeutics, breast cancer remains a leading killer among women; hence there is a need for the prevention of this disease. Several naturally occurring polyphenols have received much attention for their health benefits, including anti-carcinogenic properties. Two of these are resveratrol, a component of red grapes, and epigallocatechin-3-gallate (EGCG, the major catechin found in green tea. In this study, we tested the hypothesis that these two polyphenols protect against chemically-induced mammary cancer by modulating mammary gland architecture, cell proliferation, and apoptosis. Female Sprague-Dawley CD rats were exposed to either resveratrol (1 g/kg AIN-76A diet, EGCG (0.065% in the drinking water, or control diet (AIN-76A for the entirety of their life starting at birth. At 50 days postpartum, rats were treated with 60 mg dimethylbenz[a]anthracene (DMBA/kg body weight to induce mammary cancer. Resveratrol, but not EGCG, suppressed mammary carcinogenesis (fewer tumors per rat and longer tumor latency. Analysis of mammary whole mounts from 50-day-old rats revealed that resveratrol, but not EGCG, treatment resulted in more differentiated lobular structures. Bromodeoxyuridine (BrdU incorporation studies showed that resveratrol treatment caused a significant reduction in proliferative cells in mammary terminal ductal structures at 50 days postpartum, making them less susceptible to carcinogen insult. The epithelial cells of terminal end buds in the mammary glands of resveratrol-treated rats also showed an increase in apoptotic cells compared to the control or EGCG-treated rats as measured by a DNA fragmentation assay. At the given doses, resveratrol treatment resulted in a serum resveratrol concentration of 2.00 μM, while treatment with EGCG resulted in a serum EGCG concentration of 31.06 nM. 17β-Estradiol, progesterone, and prolactin concentrations in the serum were not significantly affected

  4. Mammary renin-angiotensin system-regulating aminopeptidase activities are modified in rats with breast cancer.

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    del Pilar Carrera, Maria; Ramírez-Expósito, Maria Jesus; Mayas, Maria Dolores; García, Maria Jesus; Martínez-Martos, Jose Manuel

    2010-12-01

    Angiotensin II in particular and/or the local renin-angiotensin system in general could have an important role in epithelial tissue growth and modelling; therefore, it is possible that it may be involved in breast cancer. In this sense, previous works of our group showed a predominating role of angiotensin II in tumoral tissue obtained from women with breast cancer. However, although classically angiotensin II has been considered the main effector peptide of the renin-angiotensin system cascade, several of its catabolism products such as angiotensin III and angiotensin IV also possess biological functions. These peptides are formed through the activity of several proteolytic regulatory enzymes of the aminopeptidase type, also called angiotensinases. The aim of this work was to analyse several specific angiotensinase activities involved in the renin-angiotensin system cascade in mammary tissue from control rats and from rats with mammary tumours induced by N-methyl-nitrosourea (NMU), which may reflect the functional status of their target peptides under the specific conditions brought about by the tumoural process. The results show that soluble and membrane-bound specific aspartyl aminopeptidase activities and membrane-bound glutamyl aminopeptidase activity increased in mammary tissue from NMU-treated animals and soluble aminopeptidase N and aminopeptidase B activities significantly decreased in mammary tissue from NMU-treated rats. These changes support the existence of a local mammary renin-angiotensin system and that this system and its putative functions in breast tissue could be altered by the tumour process, in which we suggest a predominant role of angiotensin III. All described data about the renin-angiotensin system in mammary tissue support the idea that it must be involved in normal breast tissue functions, and its disruption could be involved in one or more steps of the carcinogenesis process.

  5. Anticancer Potential of Nutraceutical Formulations in MNU-induced Mammary Cancer in Sprague Dawley Rats

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    Pitchaiah, Gummalla; Akula, Annapurna; Chandi, Vishala

    2017-01-01

    Background: Nutraceuticals help in combating some of the major health problems of the century including cancer, and ‘nutraceutical formulations’ have led to the new era of medicine and health. Objective: To develop different nutraceutical formulations and to assess the anticancer potential of nutraceutical formulations in N-methyl-N-nitrosourea (MNU)-induced mammary cancer in Sprague Dawley rats. Materials and Methods: Different nutraceutical formulations were prepared using fine powders of amla, apple, garlic, onion, papaya, turmeric, and wheat grass with and without cow urine distillate. Total phenolic content, acute oral toxicity, and microbial load of nutraceutical formulations were assessed. The anticancer potential of nutraceutical formulations was evaluated against MNU-induced mammary cancer in female Sprague Dawley rats. Results: Improvement in total phenolic content was significant (P amla, apple, garlic, onion, papaya, turmeric, and wheat grass with and without cow urine distillate. Total phenolic content, acute oral toxicity, and microbial load of nutraceutical formulations were assessed. The anticancer potential of nutraceutical formulations was evaluated against MNU-induced mammary cancer in female Sprague Dawley rats. Improvement in total phenolic content was observed after self-fortification process. Toxicity studies showed that the nutraceutical formulations were safe to use in animals. Microbial load was within the limits. Longer tumor-free days, lower tumor incidence, lower tumor multiplicity and tumor burden were observed for nutraceutical formulation-treated groups. This suggests that combination of whole food-based nutraceuticals acted synergistically in the prevention of mammary cancer. Further, the process of fortification enhanced the anticancer potential of nutraceutical formulations. Abbreviations used: HMNU: N-methyl-N-nitrosourea, CAM: Complementary and Alternative Medicine, NF: Nutraceutical Formulation, SFNF: Self

  6. Identification of rat mammary tumor-1 gene (RMT-1), which is highly expressed in rat mammary tumors.

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    Chiou, S; Yoo, J; Loh, K C; Guzman, R C; Gopinath, G R; Rajkumar, L; Chou, Y C; Yang, J; Popescu, N C; Nandi, S

    2001-12-10

    Full-term pregnancy early in life results in a permanent reduction in lifetime breast cancer risk in women. Parous rats and mice are also refractory to chemical carcinogenesis. Therefore, investigation of the differences between mammary glands from virgin and parous rats would provide valuable information regarding the protective effects of early full-term pregnancy. In this report, we examined the gene expression patterns in mammary glands from virgin and parous Lewis rats. Using differential display technology, a novel 4.2 kb cDNA, designated rat mammary tumor-1 (RMT-1) was isolated. Northern blot analysis of RMT-1 showed that RMT-1 expression was higher in the pre-pubertal and pubertal stages during rat mammary gland development while it was down-regulated in mammary glands from mature virgin and parous rats. RMT-1 expression was highest in rat mammary cancers compared with either the mammary glands of virgin or parous rats. At the Northern blot sensitivity level, RMT-1 expression was found only in the mammary gland. Northern blot analysis also showed that the expression of this gene was found in 74% of N-methyl-nitrosourea (MNU)-induced mammary cancers while it was not found in MNU-induced cancers from other organs. The examination of the RMT-1 gene structure revealed that it consists of five exons spanning 5.9 kb. Using fluorescence in situ hybridization, the gene was localized on rat chromosome 1 band q 43-51. The present data show that there is a correlation between high RMT-1 expression and rat mammary carcinogenesis or decreased RMT-1 expression and parity associated refractoriness to chemically induced mammary carcinogenesis. However, whether or not RMT-1 gene has a functional role in these processes remains to be investigated.

  7. Exposure to excess estradiol or leptin during pregnancy increases mammary cancer risk and prevents parity-induced protective genomic changes in rats.

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    de Assis, Sonia; Wang, Mingyue; Jin, Lu; Bouker, Kerrie B; Hilakivi-Clarke, Leena A

    2013-11-01

    Using a preclinical model, we investigated whether excess estradiol (E2) or leptin during pregnancy affects maternal mammary tumorigenesis in rats initiated by administering carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) on day 50. Two weeks later, rats were mated, and pregnant dams were treated daily with 10 μg of 17β-estradiol, 15 μg of leptin, or vehicle from gestation day 8 to 19. Tumor development was assessed separately during weeks 1 to 12 and 13 to 22 after DMBA administration, because pregnancy is known to induce a transient increase in breast cancer risk, followed by a persistent reduction. Parous rats developed less (32%) mammary tumors than nulliparous rats (59%, P tumors in the parous rats appeared before week 13 (vs. 41% in nulliparous rats), indicating that pregnancy induced a transient increase in breast cancer risk. Parous rats exposed to leptin (final tumor incidence 65%) or E2 (45%) during pregnancy developed mammary tumors throughout the tumor-monitoring period, similar to nulliparous control rats, and the incidence was significantly higher in both the leptin- and E2-exposed dams after week 12 than in the vehicle-exposed parous dams (P rats contained significantly more proliferating cells (P rats did not exhibit the protective genomic signature induced by pregnancy and seen in the parous control rats. Specifically, these rats exhibited downregulation of genes involved in differentiation and immune functions and upregulation of genes involved in angiogenesis, growth, and epithelial-to-mesenchymal transition.

  8. Molecular characterization of cancer reveals interactions between ionizing radiation and chemicals on rat mammary carcinogenesis.

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    Imaoka, Tatsuhiko; Nishimura, Mayumi; Doi, Kazutaka; Tani, Shusuke; Ishikawa, Ken-ichi; Yamashita, Satoshi; Ushijima, Toshikazu; Imai, Takashi; Shimada, Yoshiya

    2014-04-01

    Although various mechanisms have been inferred for combinatorial actions of multiple carcinogens, these mechanisms have not been well demonstrated in experimental carcinogenesis models. We evaluated mammary carcinogenesis initiated by combined exposure to various doses of radiation and chemical carcinogens. Female rats at 7 weeks of age were γ-irradiated (0.2-2 Gy) and/or exposed to 1-methyl-1-nitrosourea (MNU) (20 or 40 mg/kg, single intraperitoneal injection) or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) (40 mg/kg/day by gavage for 10 days) and were observed until 50 weeks of age. The incidence of mammary carcinoma increased steadily as a function of radiation dose in the absence of chemicals; mathematical analysis supported an additive increase when radiation was combined with a chemical carcinogen, irrespective of the chemical species and its dose. Hras mutations were characteristic of carcinomas that developed after chemical carcinogen treatments and were overrepresented in carcinomas induced by the combination of radiation and MNU (but not PhIP), indicating an interaction of radiation and MNU at the level of initiation. The expression profiles of seven classifier genes, previously shown to distinguish two classes of rat mammary carcinomas, categorized almost all examined carcinomas that developed after individual or combined treatments with radiation (1 Gy) and chemicals as belonging to a single class; more comprehensive screening using microarrays and a separate test sample set failed to identify differences in gene expression profiles among these carcinomas. These results suggest that a complex, multilevel interaction underlies the combinatorial action of radiation and chemical carcinogens in the experimental model.

  9. Characterization of mammary adenocarcinomas in male rats after N-methyl-N-nitrosourea exposure--Potential for human male breast cancer model.

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    Yoshizawa, Katsuhiko; Yuki, Michiko; Kinoshita, Yuichi; Emoto, Yuko; Yuri, Takashi; Shikata, Nobuaki; Elmore, Susan A; Tsubura, Airo

    2016-05-01

    The frequency of breast cancer in men is extremely rare, reported to be less than 1% and there is currently no available animal model for male mammary tumors. We compared the characteristics of various immunohistochemical markers in N-methyl-N-nitrosourea (MNU)-induced mammary adenocarcinomas in male and female Crj:CD(SD)IGS rats including: estrogen receptor α (ER), progesterone receptor (PgR), androgen receptor (AR), receptor tyrosine-protein kinase erbB-2 (HER2), GATA binding protein 3 (GATA3), and proliferating cell nuclear antigen (PCNA). Female mammary adenocarcinomas were strongly positive in the nuclei of tumor cells for PCNA and ER (100%) with only 60% and 53% expressing PgR and GATA3, respectively. 100% of male adenocarcinomas also exhibited strongly positive expression in the nuclei of tumor cells for PCNA, with 25% expressing AR and only 8% showing positivity for ER. Male carcinomas did not express PgR or GATA3 and none of the tumors, male or female, were positive for HER2. Based on the observed ER and PgR positivity and HER2 negativity within these tumors, MNU-induced mammary adenocarcinomas in female rats appear to be hormonally dependent, similar to human luminal A type breast cancer. In contrast, MNU-induced mammary adenocarcinomas in male rats showed no reactivity for ER, PgR, HER2 or GATA3, suggesting no hormonal dependency. Both male and female adenocarcinomas showed high proliferating activity by PCNA immunohistochemistry. Based on our literature review, human male breast cancers are mainly dependent on ER and/or PgR, therefore the biological pathogenesis of MNU-induced male mammary cancer in rats may differ from that of male breast cancer in humans.

  10. Genetic Susceptibility to Estrogen-Induced Mammary Cancers

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    2000-11-01

    mammary glands were reflected in mammary histology. (A and E) Thin sections from Fig. 3. E2 induced pituitary growth and hyperprolactinemia similarly in...with E2 5 (33%) exhibited a normal DNA profile where the great for 12 wk induced pituitary growth and hyperprolactinemia in majority of cells displayed...etal. , " terone, or PRL. Hyperprolactinemia has been shown to be sufficient to induce mammary cancer in certain strains of mouse 1 , (29-31) and rat

  11. Pathologic progression of mammary carcinomas in a C3(1)/SV40 T/t-antigen transgenic rat model of human triple-negative and Her2-positive breast cancer.

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    Hoenerhoff, M J; Shibata, M A; Bode, A; Green, J E

    2011-04-01

    The C3(1) component of the rat prostate steroid binding protein has been used to target expression of the SV40 T/t-antigen to the mammary epithelium of mice resulting in pre-neoplastic lesions that progress to invasive and metastatic cancer with molecular features of human basal-type breast cancer. However, there are major differences in the histologic architecture of the stromal and epithelial elements between the mouse and human mammary glands. The rat mammary gland is more enriched with epithelial and stromal components than the mouse and more closely resembles the cellular composition of the human gland. Additionally, existing rat models of mammary cancer are typically estrogen receptor positive and hormone responsive, unlike most genetically engineered mouse mammary cancer models. In an attempt to develop a mammary cancer model that might more closely resemble the pathology of human breast cancer, we generated a novel C3(1)/SV40 T/t-antigen transgenic rat model that developed progressive mammary lesions leading to highly invasive adenocarcinomas. However, aggressive tumor development prevented the establishment of transgenic lines. Characterization of the tumors revealed that they were primarily estrogen receptor and progesterone receptor negative, and either her2/neu positive or negative, resembling human triple-negative or Her2 positive breast cancer. Tumors expressed the basal marker K14, as well as the luminal marker K18, and were negative for smooth muscle actin. The triple negative phenotype has not been previously reported in a rat mammary cancer model. Further development of a C3(1)SV40 T/t-antigen based model could establish valuable transgenic rat lines that develop basal-type mammary tumors.

  12. Anticancer and Cancer Prevention Effects of Piperine-Free Piper nigrum Extract on N-nitrosomethylurea-Induced Mammary Tumorigenesis in Rats.

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    Sriwiriyajan, Somchai; Tedasen, Aman; Lailerd, Narissara; Boonyaphiphat, Pleumjit; Nitiruangjarat, Anupong; Deng, Yan; Graidist, Potchanapond

    2016-01-01

    Piper nigrum (P. nigrum) is commonly used in traditional medicine. This current study aimed to investigate the anticancer and cancer preventive activity of a piperine-free P. nigrum extract (PFPE) against breast cancer cells and N-nitrosomethylurea (NMU)-induced mammary tumorigenesis in rats. The cytotoxic effects and the mechanism of action were investigated in breast cancer cells using the MTT assay and Western blot analysis, respectively. An acute toxicity study was conducted according to the Organization for Economic Co-operation and Development guideline. Female Sprague-Dawley rats with NMU-induced mammary tumors were used in preventive and anticancer studies. The results showed that PFPE inhibited the growth of luminal-like breast cancer cells more so than the basal-like ones by induction of apoptosis. In addition, PFPE exhibited greater selectivity against breast cancer cells than colorectal cancer, lung cancer, and neuroblastoma cells. In an acute toxicity study, a single oral administration of PFPE at a dose of 5,000 mg/kg body weight resulted in no mortality and morbidity during a 14-day observation period. For the cancer preventive study, the incidence of tumor-bearing rats was 10% to 20% in rats treated with PFPE. For the anticancer activity study, the growth rate of tumors in the presence of PFPE-treated groups was much slower when compared with the control and vehicle groups. The extract itself caused no changes to the biochemical and hematologic parameters when compared with the control and vehicle groups. In conclusion, PFPE had a low toxicity and a potent antitumor effect on mammary tumorigenesis in rats.

  13. Pathologic progression of mammary carcinomas in a C3(1)/SV40 T/t-antigen transgenic rat model of human triple-negative and Her2-positive breast cancer

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    Hoenerhoff, M J; Shibata, M. A.; Bode, A.; Green, J. E.

    2010-01-01

    The C3(1) component of the rat prostate steroid binding protein has been used to target expression of the SV40 T/t-antigen to the mammary epithelium of mice resulting in pre-neoplastic lesions that progress to invasive and metastatic cancer with molecular features of human basal-type breast cancer. However, there are major differences in the histologic architecture of the stromal and epithelial elements between the mouse and human mammary glands. The rat mammary gland is more enriched with ep...

  14. Chemoprevention by grape seed extract and genistein in carcinogen-induced mammary cancer in rats is diet dependent.

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    Kim, Helen; Hall, Patti; Smith, Michelle; Kirk, Marion; Prasain, Jeevan K; Barnes, Stephen; Grubbs, Clinton

    2004-12-01

    Many popular dietary supplements are enriched in polyphenols such as the soy isoflavones, tea catechins, and resveratrol (from grape skins), each of which has been shown to have chemopreventive activity in cellular models of cancer. The proanthocyanidins, which are oligomers of the catechins, are enriched in grape seeds and form the basis of the dietary supplement grape seed extract (GSE). Evidence suggests that the proanthocyanidins may be metabolized to the monomeric catechins. This study was carried out to determine whether GSE added to rodent diets protected against carcinogen-induced mammary tumorigenesis in rats and whether this was affected by the composition of the whole diet. Female rats were begun on 5%, 1.25%, or 0% (control) GSE-supplemented diets at age 35 d. At age 50 d they were administered 7,12-dimethylbenz[a]anthracene (DMBA) in sesame oil at 80 mg/kg body weight. They were weighed and monitored weekly for tumor development until 120 d after DMBA administration. Administration of GSE in AIN-76A diet did not show any protective activity of GSE against DMBA-induced breast cancer. However, administration of GSE in a laboratory dry food diet (Teklad 4% rodent diet) resulted in a 50% reduction in tumor multiplicity. In similar experiments, genistein administered in AIN-76A diet also failed to show chemopreventive activity against the carcinogen N-methyl-N-nitrosourea; however, when administered at the same dose in the Teklad 4% rodent diet, genistein exhibited significant chemopreventive activity (44-61%). These results demonstrate that GSE is chemopreventive in an animal model of breast cancer; moreover, the diet dependency of the chemopreventive activity for both GSE and genistein suggests that whether or not a compound is chemopreventive may depend on the diet in which the agent is administered.

  15. Similarity of GATA-3 Expression between Rat and Human Mammary Glands

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    Kinoshita, Yuichi; Yoshizawa, Katsuhiko; Emoto, Yuko; Yuki, Michiko; Yuri, Takashi; Shikata, Nobuaki; Tsubura, Airo

    2014-01-01

    The GATA family members are zinc finger transcription factors involved in cell differentiation and proliferation. In particular, GATA-3 is necessary for mammary gland maturation and is a useful marker in the characterization of mammary carcinoma in humans. The expression of GATA-3 protein in normal mammary glands, fibroadenomas and carcinomas was immunohistochemically compared in female rats and humans. In normal mammary glands of rats and humans, scattered luminal cells in the acini and whole ductal epithelial cells were positive for GATA-3 in the nuclei. No positive cells were detected in rat or human fibroadenomas. In rat and human mammary carcinomas, the nuclei of proliferating luminal-derived cancer cells expressed GATA-3. Therefore, GATA-3 protein is a candidate marker for mammary carcinoma in rats as well as humans. PMID:25352719

  16. Site of iodination in rat mammary gland

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    Strum, J.M.

    1978-10-01

    The ability of the mammary gland to take up and organically bind radioiodide was studied in non-pregnant, pregnant, and lactating rats. Autoradiography was used to determine whether duct cells or alveolar cells are responsible for iodination in the rat mammary gland. Iodination was not detected in mammary glands from non-pregnant rats, but occurred late in the twelfth day of gestation and continued throughout pregnancy and lactation. Protein-containing vacuoles in alveolar cells and casein-like proteins in milk were the major sites where iodination occurred within the gland. Milk proteins in the lumens of ductules adjacent to alveoli were also iodinated. In contrast, ducts, myoepithelial cells, fat cells, blood vessels and other histological components of the gland did not show iodinating capability. Cytochemistry was also used to identify endogenous mammary peroxidase activity in the same glands, and it was found that the presence and location of this enzyme were correlated with the ability to iodinate.

  17. Physical Confirmation and Comparative Genomics of the Rat Mammary carcinoma susceptibility 3 Quantitative Trait Locus

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    Saasha Le

    2017-06-01

    Full Text Available Human breast and rat mammary cancer susceptibility are complex phenotypes where complete sets of risk associated loci remain to be identified for both species. We tested multiple congenic rat strains to physically confirm and positionally map rat Mammary carcinoma susceptibility 3 (Mcs3—a mammary cancer resistance allele previously predicted at Rattus norvegicus chromosome 1 (RNO1. The mammary cancer susceptible Wistar Furth (WF strain was the recipient, and the mammary cancer resistant Copenhagen (Cop strain was the RNO1-segment donor for congenics. Inbred WF females averaged 6.3 carcinogen-induced mammary carcinomas per rat. Two WF.Cop congenic strains averaged 2.8 and 3.4 mammary carcinomas per rat, which confirmed Mcs3 as an independently acting allele. Two other WF.Cop congenic strains averaged 6.6 and 8.1 mammary carcinomas per rat, and, thus, did not contain Mcs3. Rat Mcs3 was delimited to 27.8 Mb of RNO1 from rs8149408 to rs105131702 (RNO1:143700228-171517317 of RGSC 6.0/rn6. Human genetic variants with p values for association to breast cancer risk below 10−7 had not been reported for Mcs3 orthologous loci; however, human variants located in Mcs3-orthologous regions with potential association to risk (10−7 < p < 10−3 were listed in some population-based studies. Further, rat Mcs3 contains sequence orthologous to human 11q13/14—a region frequently amplified in female breast cancer. We conclude that Mcs3 is an independently acting mammary carcinoma resistance allele. Human population-based, genome-targeted association studies interrogating Mcs3 orthologous loci may yield novel breast cancer risk associated variants and genes.

  18. Physical Confirmation and Comparative Genomics of the Rat Mammary carcinoma susceptibility 3 Quantitative Trait Locus.

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    Le, Saasha; Martin, Zachary C; Samuelson, David J

    2017-06-07

    Human breast and rat mammary cancer susceptibility are complex phenotypes where complete sets of risk associated loci remain to be identified for both species. We tested multiple congenic rat strains to physically confirm and positionally map rat Mammary carcinoma susceptibility 3 (Mcs3)-a mammary cancer resistance allele previously predicted at Rattus norvegicus chromosome 1 (RNO1). The mammary cancer susceptible Wistar Furth (WF) strain was the recipient, and the mammary cancer resistant Copenhagen (Cop) strain was the RNO1-segment donor for congenics. Inbred WF females averaged 6.3 carcinogen-induced mammary carcinomas per rat. Two WF.Cop congenic strains averaged 2.8 and 3.4 mammary carcinomas per rat, which confirmed Mcs3 as an independently acting allele. Two other WF.Cop congenic strains averaged 6.6 and 8.1 mammary carcinomas per rat, and, thus, did not contain Mcs3 Rat Mcs3 was delimited to 27.8 Mb of RNO1 from rs8149408 to rs105131702 (RNO1:143700228-171517317 of RGSC 6.0/rn6). Human genetic variants with p values for association to breast cancer risk below 10(-7) had not been reported for Mcs3 orthologous loci; however, human variants located in Mcs3-orthologous regions with potential association to risk (10(-7) < p < 10(-3)) were listed in some population-based studies. Further, rat Mcs3 contains sequence orthologous to human 11q13/14-a region frequently amplified in female breast cancer. We conclude that Mcs3 is an independently acting mammary carcinoma resistance allele. Human population-based, genome-targeted association studies interrogating Mcs3 orthologous loci may yield novel breast cancer risk associated variants and genes. Copyright © 2017 Le et al.

  19. Mammary Cancer and Activation of Transposable Elements

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    2015-03-01

    transcriptionally activated during pregnancy and lactation , and the mice are predisposed to develop mammary cancer after a minimum of 3 pregnancies and...pregnancy and lactation . After 3 pregnancies and lactations , but not after 1 pregnancy and lactation , females develop mammary cancers at an average...mated females per experimental condition (1 or 3 pregnancies/ lactations . 5 breeding strategy to develop triple transgenic cancer -prone and control

  20. Perinatal ethinyl oestradiol alters mammary gland development in male and female Wistar rats

    DEFF Research Database (Denmark)

    Mandrup, Karen; Hass, Ulla; Christiansen, Sofie

    2012-01-01

    Increased attention is being paid to human mammary gland development because of concerns for environmental influences on puberty onset and breast cancer development. Studies in rodents have showed a variety of changes in the mammary glands after perinatal exposure to endocrine disrupting chemical...... exposures may alter mammary gland development, disrupt lactation and alter susceptibility to breast cancer.......Increased attention is being paid to human mammary gland development because of concerns for environmental influences on puberty onset and breast cancer development. Studies in rodents have showed a variety of changes in the mammary glands after perinatal exposure to endocrine disrupting chemicals......, Wistar rats were exposed to 0, 5, 15 or 50 μg/kg of ethinyl oestradiol per day during gestation and lactation. A wide range of morphological parameters were evaluated in whole mounts of mammary glands from male and female offspring PD21–22. This study showed that in both male and female pre...

  1. Prepubertal exposure to cow's milk reduces susceptibility to carcinogen-induced mammary tumorigenesis in rats

    DEFF Research Database (Denmark)

    Nielsen, Tina Skau; Khan, Galam; Davis, Jennifer

    2011-01-01

    Cow's milk contains high levels of estrogens, progesterone and insulin-like growth factor 1 (IGF-1), all of which are associated with breast cancer. We investigated whether prepubertal milk exposure affects mammary gland development and carcinogenesis in rats. Sprague-Dawley rats were given either...... whole milk or tap water to drink from postnatal day (PND) 14 to PND 35, and thereafter normal tap water. Mammary tumorigenesis was induced by administering 7,12-dimethylbenz[a]anthracene on PND 50. Milk exposure increased circulating E2 levels on PND 25 by 10-fold (p vaginal...... or apoptosis were seen. IGF-1 mRNA levels were reduced on PND 50 in the mammary glands of rats exposed to milk at puberty. Our results suggest that drinking milk before puberty reduces later risk of developing mammary cancer in rats. This might be mediated by a reduction in the number of TEBs and lower...

  2. Mammary Cancer and Activation of Transposable Elements

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    2012-09-01

    SV40Tag is transcriptionally activated during pregnancy and lactation , and the mice are predisposed to develop mammary cancer after 3 pregnancies...and lactations . Using this model, populations of marked cells can be collected for integrated analysis of gene expression, promoter usage, and DNA...completed over the first 6 months on the job . Training included mouse husbandry and colony management, mammary cell isolations in preparation for

  3. Folic acid supplementation promotes mammary tumor progression in a rat model.

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    Deghan Manshadi, Shaidah; Ishiguro, Lisa; Sohn, Kyoung-Jin; Medline, Alan; Renlund, Richard; Croxford, Ruth; Kim, Young-In

    2014-01-01

    Folic acid supplementation may prevent the development of cancer in normal tissues but may promote the progression of established (pre)neoplastic lesions. However, whether or not folic acid supplementation can promote the progression of established (pre)neoplastic mammary lesions is unknown. This is a critically important issue because breast cancer patients and survivors in North America are likely exposed to high levels of folic acid owing to folic acid fortification and widespread supplemental use after cancer diagnosis. We investigated whether folic acid supplementation can promote the progression of established mammary tumors. Female Sprague-Dawley rats were placed on a control diet and mammary tumors were initiated with 7,12-dimethylbenza[a]anthracene at puberty. When the sentinel tumor reached a predefined size, rats were randomized to receive a diet containing the control, 2.5x, 4x, or 5x supplemental levels of folic acid for up to 12 weeks. The sentinel mammary tumor growth was monitored weekly. At necropsy, the sentinel and all other mammary tumors were analyzed histologically. The effect of folic acid supplementation on the expression of proteins involved in proliferation, apoptosis, and mammary tumorigenesis was determined in representative sentinel adenocarcinomas. Although no clear dose-response relationship was observed, folic acid supplementation significantly promoted the progression of the sentinel mammary tumors and was associated with significantly higher sentinel mammary tumor weight and volume compared with the control diet. Furthermore, folic acid supplementation was associated with significantly higher weight and volume of all mammary tumors. The most significant and consistent mammary tumor-promoting effect was observed with the 2.5x supplemental level of folic acid. Folic acid supplementation was also associated with an increased expression of BAX, PARP, and HER2. Our data suggest that folic acid supplementation may promote the progression

  4. The mammary cellular hierarchy and breast cancer.

    Science.gov (United States)

    Oakes, Samantha R; Gallego-Ortega, David; Ormandy, Christopher J

    2014-11-01

    Advances in the study of hematopoietic cell maturation have paved the way to a deeper understanding the stem and progenitor cellular hierarchy in the mammary gland. The mammary epithelium, unlike the hematopoietic cellular hierarchy, sits in a complex niche where communication between epithelial cells and signals from the systemic hormonal milieu, as well as from extra-cellular matrix, influence cell fate decisions and contribute to tissue homeostasis. We review the discovery, definition and regulation of the mammary cellular hierarchy and we describe the development of the concepts that have guided our investigations. We outline recent advances in in vivo lineage tracing that is now challenging many of our assumptions regarding the behavior of mammary stem cells, and we show how understanding these cellular lineages has altered our view of breast cancer.

  5. Relationship between histology, development and tumorigenesis of mammary gland in female rat

    Science.gov (United States)

    LÍŠKA, Ján; BRTKO, Július; DUBOVICKÝ, Michal; MACEJOVÁ, Dana; KISSOVÁ, Viktória; POLÁK, Štefan; UJHÁZY, Eduard

    2015-01-01

    The mammary gland is a dynamic organ that undergoes structural and functional changes associated with growth, reproduction, and post-menopausal regression. The postnatal transformations of the epithelium and stromal cells of the mammary gland may contribute to its susceptibility to carcinogenesis. The increased cancer incidence in mammary glands of humans and similarly of rodents in association with their development is believed to be partly explained by proliferative activity together with lesser degree of differentiation, but it is not completely understood how the virgin gland retains its higher susceptibility to carcinogenesis. During its developmental cycle, the mammary gland displays many of the properties associated with breast cancer. An early first full-term pregnancy may have a protective effect. Rodent models are useful for investigating potential breast carcinogens. The purpose of this review is to help recognizing histological appearance of the epithelium and the stroma of the normal mammary gland in rats, and throughout its development in relation to tumorigenic potential. PMID:26424555

  6. A Cytogenetic Footprint for Mammary Carcinomas Induced by PhIP in Rats

    Energy Technology Data Exchange (ETDEWEB)

    Christian, A T

    2001-04-01

    PhIP (2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine), a mutagen/carcinogen belonging to the class of heterocyclic amines (HCAs) found in cooked meats, is a mammary gland carcinogen in rats and has been implicated in the etiology of certain human cancers including breast cancer. To gain insight into the genomic alterations associated with PhIP-induced mammary gland carcinogenesis, we used comparative genomic hybridization (CGH) to examine chromosomal abnormalities in rat mammary carcinomas induced by PhIP, and for comparison, by DMBA (7,12-dimethylbenz[a]anthracene), a potent experimental mammary carcinogen. There was a consistent and characteristic pattern of chromosome-region loss in PhIP-induced carcinomas that clearly distinguished them from carcinomas induced by DMBA.

  7. Effect of Cu supplementation on genomic instability in chemically-induced mammary carcinogenesis in the rat

    Directory of Open Access Journals (Sweden)

    Bobrowska Barbara

    2011-12-01

    Full Text Available Abstract Backround The aim of the present study was to assess the effect of dietary supplementation (copper or copper and resveratrol on the intensity of carcinogenesis and the frequency of microsatellite instability in a widely used model of mammary carcinogenesis induced in the rat by treatment with 7,12-dimethylbenz[a]anthracene (DMBA. Methods DNA was extracted from rat mammary cancers and normal tisues, amplified by PCR, using different polymorphic DNA markers and the reaction products were analyzed for microsatellite instability. Results It was found that irrespectively of the applied diet there was no inhibition of mammary carcinogenesis in the rats due to DMBA. Besides, in the groups supplemented with Cu (II or Cu (II and resveratrol the tumor formation was clearly accelerated. Unlike the animals that were fed with standard diet, the supplemented rats were characterized by the loss of heterozygosity of microsatellite D3Mgh9 in cancer tumors (by respectively 50 and 40%. When the animals received Cu (II and resveratrol supplemented diet the occurrence of genomic instability was additionally found in their livers in the case of microsatellite D1Mgh6 (which was stable in the animals without dietary supplementation. Conclusions Identification of the underlying mechanisms by which dietary factors affect genomic stability might prove useful in the treatment of mammary cancer as well as in the incorporation of dietary factors into mammary cancer prevention strategies.

  8. Tocopherols inhibit oxidative and nitrosative stress in estrogen-induced early mammary hyperplasia in ACI rats.

    Science.gov (United States)

    Das Gupta, Soumyasri; So, Jae Young; Wall, Brian; Wahler, Joseph; Smolarek, Amanda K; Sae-Tan, Sudathip; Soewono, Kelvin Y; Yu, Haixiang; Lee, Mao-Jung; Thomas, Paul E; Yang, Chung S; Suh, Nanjoo

    2015-09-01

    Oxidative stress is known to play a key role in estrogen-induced breast cancer. This study assessed the chemopreventive activity of the naturally occurring γ-tocopherol-rich mixture of tocopherols (γ-TmT) in early stages of estrogen-induced mammary hyperplasia in ACI rats. ACI rats provide an established model of rodent mammary carcinogenesis due to their high sensitivity to estrogen. Female rats were implanted with 9 mg of 17β-estradiol (E2) in silastic tubings and fed with control or 0.3% γ-TmT diet for 1, 3, 7, and 14 d. γ-TmT increased the levels of tocopherols and their metabolites in the serum and mammary glands of the rats. Histological analysis revealed mammary hyperplasia in the E2 treated rats fed with control or γ-TmT diet. γ-TmT decreased the levels of E2-induced nitrosative and oxidative stress markers, nitrotyrosine, and 8-oxo-dG, respectively, in the hyperplastic mammary tissues. 8-Isoprostane, a marker of oxidative stress in the serum, was also reduced by γ-TmT. Noticeably, γ-TmT stimulated Nrf2-dependent antioxidant response in the mammary glands of E2 treated rats, evident from the induced mRNA levels of Nrf2 and its downstream antioxidant enzymes, superoxide dismutase, catalase, and glutathione peroxidase. Therefore, inhibition of nitrosative/oxidative stress through induction of antioxidant response is the primary effect of γ-TmT in early stages of E2-induced mammary hyperplasia. Due to its cytoprotective activity, γ-TmT could be a potential natural agent for the chemoprevention of estrogen-induced breast cancer.

  9. Chemoprevention of Radiation Induced Rat Mammary Neoplasms

    Science.gov (United States)

    Huso, David L.

    1999-01-01

    Radiations encountered in space include protons and heavy ions such as iron as well as their secondaries. The relative biological effect (RBE) of these ions is not known, particularly at the doses and dose-rates expected for planetary missions. Neutrons, are not particularly relevant to space travel, but have been found experimentally to have an increase in their RBE with decreasing dose. If a similar trend of increasing RBE with decreasing dose is present for heavy ions and protons during irradiation in space, the small doses received during space travel could potentially have substantial carcinogenic risk. Clearly more investigation of the effects of heavy ions and protons is needed before accurate risk assessment for prolonged travel in space can be done. One means to mitigate the increased risk of cancer due to radiation exposure in space is by developing effective countermeasures that can reduce the incidence of tumor development. Tamoxifen has recently been shown to be an effective chemopreventive agent in both animal models and humans for the prevention of mammary tumors. Tamoxifen is a unique drug, with a highly specific mechanism of action affecting a specific radiation-sensitive population of epithelial cells in the mammary gland. In human studies, the annual incidence of a primary tumor in the contralateral breast of women with previous breast cancer is about 8 per 1000, making them an exceedingly high-risk group for the development of breast cancer. In this high risk group, treated with tamoxifen, daily, for 2 years, the incidence of a new primary tumor in the contralateral breast was approximately one third of that noted in the non-tamoxifen treatment group. Tamoxifen antagonizes the action of estrogen by competing for the nuclear receptor complex thereby altering the association of the receptor complex and nuclear binding sites. Its effects in reducing the development of breast cancer could be accomplished by controlling clinically undetectable

  10. Chemoprevention of Radiation Induced Rat Mammary Neoplasms

    Science.gov (United States)

    Huso, David L.

    1999-01-01

    Radiations encountered in space include protons and heavy ions such as iron as well as their secondaries. The relative biological effect (RBE) of these ions is not known, particularly at the doses and dose-rates expected for planetary missions. Neutrons, are not particularly relevant to space travel, but have been found experimentally to have an increase in their RBE with decreasing dose. If a similar trend of increasing RBE with decreasing dose is present for heavy ions and protons during irradiation in space, the small doses received during space travel could potentially have substantial carcinogenic risk. Clearly more investigation of the effects of heavy ions and protons is needed before accurate risk assessment for prolonged travel in space can be done. One means to mitigate the increased risk of cancer due to radiation exposure in space is by developing effective countermeasures that can reduce the incidence of tumor development. Tamoxifen has recently been shown to be an effective chemopreventive agent in both animal models and humans for the prevention of mammary tumors. Tamoxifen is a unique drug, with a highly specific mechanism of action affecting a specific radiation-sensitive population of epithelial cells in the mammary gland. In human studies, the annual incidence of a primary tumor in the contralateral breast of women with previous breast cancer is about 8 per 1000, making them an exceedingly high-risk group for the development of breast cancer. In this high risk group, treated with tamoxifen, daily, for 2 years, the incidence of a new primary tumor in the contralateral breast was approximately one third of that noted in the non-tamoxifen treatment group. Tamoxifen antagonizes the action of estrogen by competing for the nuclear receptor complex thereby altering the association of the receptor complex and nuclear binding sites. Its effects in reducing the development of breast cancer could be accomplished by controlling clinically undetectable

  11. Prepubertal exposure to cow’s milk reduces susceptibility to carcinogen-induced mammary tumorigenesis in rats

    OpenAIRE

    Nielsen, Tina S.; Khan, Galam; Davis, Jennifer; Michels, Karin B; Hilakivi-Clarke, Leena

    2011-01-01

    Cow’s milk contains high levels of estrogens, progesterone and insulin-like growth factor 1 (IGF-1), all of which are associated with breast cancer. We investigated whether prepubertal milk exposure affects mammary gland development and carcinogenesis in rats. Sprague Dawley rats were given either whole milk or tap water to drink from postnatal day (PND) 14 to PND 35, and thereafter normal tap water. Mammary tumorigenesis was induced by administering 7,12-dimethylbenz[a]anthracene (DMBA) on P...

  12. The rat ErbB2 tyrosine kinase receptor produced in plants is immunogenic in mice and confers protective immunity against ErbB2(+) mammary cancer.

    Science.gov (United States)

    Matić, Slavica; Quaglino, Elena; Arata, Lucia; Riccardo, Federica; Pegoraro, Mattia; Vallino, Marta; Cavallo, Federica; Noris, Emanuela

    2016-01-01

    The rat ErbB2 (rErbB2) protein is a 185-kDa glycoprotein belonging to the epidermal growth factor-related proteins (ErbB) of receptor tyrosine kinases. Overexpression and mutations of ErbB proteins lead to several malignancies including breast, lung, pancreatic, bladder and ovary carcinomas. ErbB2 is immunogenic and is an ideal candidate for cancer immunotherapy. We investigated the possibility of expressing the extracellular (EC) domain of rErbB2 (653 amino acids, aa) in Nicotiana benthamiana plants, testing the influence of the 23 aa transmembrane (TM) sequence on protein accumulation. Synthetic variants of the rErbB2 gene portion encoding the EC domain, optimized with a human codon usage and either linked to the full TM domain (rErbB2_TM, 676 aa), to a portion of it (rErbB2-pTM, 662 aa), or deprived of it (rErbB2_noTM, 653 aa) were cloned in the pEAQ-HT expression vector as 6X His tag fusions. All rErbB2 variants (72-74.5 kDa) were transiently expressed, but the TM was detrimental for rErbB2 EC accumulation. rERbB2_noTM was the most expressed protein; it was solubilized and purified with Nickel affinity resin. When crude soluble extracts expressing rErbB2_noTM were administered to BALB/c mice, specific rErbB2 immune responses were triggered. A potent antitumour activity was induced when vaccinated mice were challenged with syngeneic transplantable ErbB2(+) mammary carcinoma cells. To our knowledge, this is the first report of expression of rErbB2 in plants and of its efficacy in inducing a protective antitumour immune response, opening interesting perspectives for further immunological testing.

  13. Stem cells in normal mammary gland and breast cancer.

    Science.gov (United States)

    Luo, Jie; Yin, Xin; Ma, Tao; Lu, Jun

    2010-04-01

    The mammary gland is a structurally dynamic organ that undergoes dramatic alterations with age, menstrual cycle, and reproductive status. Mammary gland stem cells, the minor cell population within the mature organ, are thought to have multiple functions in regulating mammary gland development, tissue maintenance, major growth, and structural remodeling. In addition, accumulative evidence suggests that breast cancers are initiated and maintained by a subpopulation of tumor cells with stem cell features (called cancer stem cells). A variety of methods have been developed to identify and characterize mammary stem cells, and several signal transduction pathways have been identified to be essential for the self-renewal and differentiation of mammary gland stem cells. Understanding the origin of breast cancer stem cells, their relationship to breast cancer development, and the differences between normal and cancer stem cells may lead to novel approaches to breast cancer diagnosis, prevention, and treatment.

  14. Mapping Mammary Carcinoma Suppressor Genes in the Laboratory Rat

    Science.gov (United States)

    1997-07-01

    AD GRANT NUMBER DAMDI7-94-J-4040 TITLE: Mapping Mammary Carcinoma Suppressor Genes in the Laboratory Rat PRINCIPAL INVESTIGATOR: Michael Gould, Ph.D...Carcinoma Suppressor Genes in the Laboratory Rat DAMDI7-94-J-4040 6. AUTHOR(S) Michael Gould, Ph.D. Hong Lan, Ph.D. 7. PERFORMING ORGANIZATION NAME(S) AND

  15. Morphological changes induced by testosterone in the mammary glands of female Wistar rats

    Directory of Open Access Journals (Sweden)

    Chambô-Filho A.

    2005-01-01

    Full Text Available Increased levels of androgens in postmenopausal women are considered to be a risk factor for breast cancer. Testosterone, alone or in combination with estrogen, induces epithelial dysplasia and mammary tumors in Noble rats. Since this model of hormone-induced neoplasia has not been reported in other rat strains, we studied the effect of testosterone on the mammary gland morphology of female Wistar rats. Sixty adult, non-castrated, female Wistar rats were implanted in the dorsum midline with a silicone tube containing 50 mg testosterone (testosterone propionate in 30 animals and non-esterified testosterone in the remaining 30 animals and 20 additional animals were implanted with empty tubes and used as control. Five animals per group were killed 30, 60, 90, 120, 150, and 180 days after implantation, and the mammary glands were dissected, fixed and embedded in paraffin. Histological sections were then stained with hematoxylin and eosin and picrosyrius red for collagen visualization. Morphological and morphometric analysis demonstrated ductal proliferation and acinotubular differentiation with secretory activity in all treated animals, peaking at 90 days of androgen exposure. After 90 days the proliferation of acinar epithelial cells was evident, but there was a progressive reduction of secretory differentiation and an increase in intralobular collagen fibers. There was no morphological evidence of dysplastic changes or other pre-neoplastic lesions. Testosterone treatment applied to adult, non-castrated female Wistar rats induced a mammary gland hyperplasia resembling the lactating differentiation, with progressive reduction in secretory differentiation.

  16. Mammary development and breast cancer: the role of stem cells.

    Science.gov (United States)

    Ercan, C; van Diest, P J; Vooijs, M

    2011-06-01

    The mammary gland is a highly regenerative organ that can undergo multiple cycles of proliferation, lactation and involution, a process controlled by stem cells. The last decade much progress has been made in the identification of signaling pathways that function in these stem cells to control self-renewal, lineage commitment and epithelial differentiation in the normal mammary gland. The same signaling pathways that control physiological mammary development and homeostasis are also often found deregulated in breast cancer. Here we provide an overview on the functional and molecular identification of mammary stem cells in the context of both normal breast development and breast cancer. We discuss the contribution of some key signaling pathways with an emphasis on Notch receptor signaling, a cell fate determination pathway often deregulated in breast cancer. A further understanding of the biological roles of the Notch pathway in mammary stem cell behavior and carcinogenesis might be relevant for the development of future therapies.

  17. Research on the Changes of Endocrine Hormones in Mammary Cancer and Hyperplasia of Mammary Glands

    Institute of Scientific and Technical Information of China (English)

    CHEN Chengqi

    2002-01-01

    Objective Based on a comparison of endocrine hormones between patients of mammary cancer and those of hyperplasia of mammary glands, a preliminary analysis of the interaction between endocrine hormones and the immune system was oonducted. Methods The experiment involved 50 cases of mammary cancer and hyperplasia of mammary glands each.Blood samples were taken from pre - menopausal and menopausal patients; six kinds of hypophyseal hommones(PRL, GH, TSH,ACTH, FSH and LH) and three kinds of sex hormones ( E2,P and T) were subjected to RIA tests.Results Wilcoxon matchpaired assay and normal approximation of the experiment indicated that the FSH level before pre - menopause and the ACTH level during menopause in patients with mammary canoer were higher that those of patients suffering hyperplasia of mamary glands. Conclusion Statistics show the the normal rhythm between endocrine hormones and the immune system is disrupted in mammary cancer patients, the feedback mechanism of the hypothalamo- hypophyseal- adrenal system is maladjusted,resulting in inhibition of the immune function. Female hormones induce the gene mutation and the sensitivity of the cells is increased, resulting in a significant acceleration of the hyperplasia of cancer cells.

  18. Mammary cancer promotion by ovarian hormones involves IGFR/AKT/mTOR signaling.

    Science.gov (United States)

    Arumugam, Arunkumar; Parada, Jacqueline; Rajkumar, Lakshmanaswamy

    2012-06-01

    In a previous study, we observed that N-methyl-N-nitrosourea (MNU)-induced mammary lesions are promoted to overt mammary cancers by exogenous administration of estradiol (E) and progesterone (P). The purpose of the present study was to identify the early molecular events occurring during the hormonal promotion of mammary carcinogenesis and persistent activation of molecular pathways responsible for tumor growth. Seven-week-old female Copenhagen (COP) rats, which are resistant to MNU-induced mammary carcinogenesis, were intraperitoneally administered a single dose of MNU (50 mg/kg body weight). Six weeks after carcinogen administration, the rats were treated with E+P, killed at 15th week and 43rd week to obtain mammary lesions and tumor tissues and the molecular analysis were performed. Quantitative RT-PCR experiments showed increased mRNA expression of Igfr, Grb2, Sos1, and Shc1 in mammary lesions and tumors. Immunoblot data also showed increased protein levels of IGFR, GRB2 and SHC1 in mammary lesions and tumors, which is in correlation with their respective RT-PCR data. Activation of AKT and ERK1/2 were up regulated in E+P treated mammary lesions and tumors. Molecular analysis of mTOR pathway proteins revealed increased phosphorylation of p70S6K and 4EBP1 in the hormone treated tumors indicating the activation of mTOR signaling. E+P treatment reduced the protein expression of BAX and increased BCL2 expression along with down regulation of active caspase 3 and 8. Together, these data demonstrate that ovarian hormones promote the lesions to mammary tumors by enhancing IGFR and Akt/mTOR signaling along with inhibition of apoptotic stimuli.

  19. Quantification of epithelial cell differentiation in mammary glands and carcinomas from DMBA- and MNU-exposed rats.

    Directory of Open Access Journals (Sweden)

    Deepak Sharma

    Full Text Available Rat mammary carcinogenesis models have been used extensively to study breast cancer initiation, progression, prevention, and intervention. Nevertheless, quantitative molecular data on epithelial cell differentiation in mammary glands of untreated and carcinogen-exposed rats is limited. Here, we describe the characterization of rat mammary epithelial cells (RMECs by multicolor flow cytometry using antibodies against cell surface proteins CD24, CD29, CD31, CD45, CD49f, CD61, Peanut Lectin, and Thy-1, intracellular proteins CK14, CK19, and FAK, along with phalloidin and Hoechst staining. We identified the luminal and basal/myoepithelial populations and actively dividing RMECs. In inbred rats susceptible to mammary carcinoma development, we quantified the changes in differentiation of the RMEC populations at 1, 2, and 4 weeks after exposure to mammary carcinogens DMBA and MNU. DMBA exposure did not alter the percentage of basal or luminal cells, but upregulated CD49f (Integrin α6 expression and increased cell cycle activity. MNU exposure resulted in a temporary disruption of the luminal/basal ratio and no CD49f upregulation. When comparing DMBA- or MNU-induced mammary carcinomas, the RMEC differentiation profiles are indistinguishable. The carcinomas compared with mammary glands from untreated rats, showed upregulation of CD29 (Integrin β1 and CD49f expression, increased FAK (focal adhesion kinase activation especially in the CD29hi population, and decreased CD61 (Integrin β3 expression. This study provides quantitative insight into the protein expression phenotypes underlying RMEC differentiation. The results highlight distinct RMEC differentiation etiologies of DMBA and MNU exposure, while the resulting carcinomas have similar RMEC differentiation profiles. The methodology and data will enhance rat mammary carcinogenesis models in the study of the role of epithelial cell differentiation in breast cancer.

  20. Hippo pathway in mammary gland development and breast cancer.

    Science.gov (United States)

    Shi, Peiguo; Feng, Jing; Chen, Ceshi

    2015-01-01

    Accumulated evidence suggests that the Hippo signaling pathway plays crucial roles in mammary gland development and breast cancer. Key components of the Hippo pathway regulate breast epithelial cell proliferation, migration, invasion, and stemness. Additionally, the Hippo pathway regulates breast tumor growth, metastasis, and drug resistance. It is expected that the Hippo pathway will provide novel therapeutic targets for breast cancer. This review will discuss and summarize the roles of several core components of the Hippo pathway in mammary gland development and breast cancer.

  1. Evaluation of mammary cancer in 7,12-dimethylbenz(a)anthracene-induced Wister rats by asymmetrical temperature distribution analysis using thermography: a comparison with serum CEA levels and histopathology.

    Science.gov (United States)

    Angeline Kirubha, S P; Anburajan, M; Venkataraman, B; Akila, R; Sharath, D; Raj, Baldev

    2012-01-01

    Animal surface temperature profile captured using infrared camera is helpful for the assessment of physiological responses associated with the regulation of body temperature. Diagnosing breast cancer in early stage itself has a greater effect on the prognosis. In this work, asymmetrical temperature distribution analysis of chemical carcinogen 7,12-dimethyl benz(a)anthracene-induced in the lower right flank region of Wistar rats (n = 6) was carried out to test the potential of thermography in diagnosing mammary cancer and tumor growth over a period of nine weeks in comparison with histopathology results as standard. Temperature difference between the tumor induced lower right and left side of flank region was significant (with P value induced lower flank region was 0.5 to 2%, whereas in the other regions it was induced lower flank region. Temperature reduction was observed in the tumor induced region after the seventh day of carcinogen induction. Asymmetrical thermogram analysis is the best method of diagnosing mammary cancer and for studying tumor development.

  2. Flor-Essence? Herbal Tonic Promotes Mammary Tumor Development in Sprague Dawley Rats

    Energy Technology Data Exchange (ETDEWEB)

    Bennett, L; Montgomery, J; Steinberg, S; Kulp, K

    2004-01-28

    Background: Women who are diagnosed with breast cancer often self-administer complementary and alternative medicines to augment their conventional treatments, improve health, or prevent recurrence. Flor-Essence{reg_sign} Tonic is a complex mixture of herbal extracts used by cancer patients because of anecdotal evidence that it can treat or prevent disease. Methods: Female Sprague Dawley rats were given water or exposed to 3% or 6% Flor-Essence{reg_sign} beginning at one day of age. Mammary tumors were induced with a single oral 40 mg/kg/bw dose of dimethylbenz(a)anthracene at 50 days of age and sacrificed at 23 weeks. Rats were maintained on AIN-76A diet. Results: Control rats had palpable mammary tumor incidence of 51.0% at 19 weeks of age compared to 65.0% and 59.4% for the 3% and 6% Flor-Essence{reg_sign} groups respectively. Overall, no significant difference in time until first palpable tumor was detected among any of the groups. At necropsy, mammary tumor incidence was 82.5% for controls compared to 90.0% and 97.3% for rats consuming 3% and 6% Flor-Essence{reg_sign}, respectively. Mean mammary tumor multiplicity ({+-}SES) for the controls was 2.8 ({+-} 0.5) and statistically different from the 3% or 6% Flor- Essence{reg_sign} groups with 5.2 ({+-} 0.7), and 4.8 ({+-} 0.6), respectively (p{<=}0.01). As expected, the majority of isolated tumors were diagnosed as adenocarcinomas. Conclusions: Flor-Essence{reg_sign} can promote mammary tumor development in the Sprague Dawley rat model. This observation is contrary to widely available anecdotal evidence as well as the desire of the consumer that this commercially available herbal tonic will suppress and/or inhibit tumor growth.

  3. Breast cancer detection using mammary ductoscopy.

    Science.gov (United States)

    Sauter, Edward

    2005-06-01

    Mammary ductoscopy (MD) has been used as a tool to evaluate the breast for cancer for over 10 years. MD allows the direct visualization of the duct lumen, providing a more targeted approach to the diagnosis of disease arising in the ductal system, since the lesion can be visualized and samples collected in the area of interest. Initial studies of MD evaluated women with pathologic spontaneous nipple discharge (PND), while more recent reports are also using MD to assess women without PND for the presence of breast cancer. Cytologic assessment of MD is highly specific but less sensitive in the detection of breast cancer. Nonetheless, a MD sample from a breast with PND may rarely undergo cytologic review and be interpreted as consistent with malignancy, only later to undergo surgical resection demonstrating benign pathology. For this reason, PND specimens interpreted as malignant on cytologic review require histopathologic confirmation prior to instituting therapy. Additional sample evaluation using image or molecular analysis may improve the sensitivity and specificity of MD in breast cancer detection.

  4. Imbalance between apoptosis and cell proliferation during early stages of mammary gland carcinogenesis in ACI rats

    Energy Technology Data Exchange (ETDEWEB)

    Kutanzi, Kristy R.; Koturbash, Igor [Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, T1K3M4 (Canada); Bronson, Roderick T. [Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115 (United States); Pogribny, Igor P., E-mail: igor.pogribny@fda.hhs.gov [Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Kovalchuk, Olga, E-mail: olga.kovalchuk@uleth.ca [Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, T1K3M4 (Canada)

    2010-12-10

    Estrogen and ionizing radiation are well-documented human breast carcinogens, yet the exact mechanisms of their deleterious effects on mammary gland remain to be discerned. Here we analyze the balance between cellular proliferation and apoptosis in the mammary glands of rats exposed to estrogen and X-ray radiation and the combined action of these carcinogenic agents. For the first time, we show that combined exposure to estrogen and radiation has a synergistic effect on cell proliferation in the mammary glands of ACI rats, as evidenced by a substantially greater magnitude of cell proliferation, especially after 12 and 18 weeks of treatment, when compared to mammary glands of rats exposed to estrogen or radiation alone. We also demonstrate that an imbalance between cell proliferation and apoptosis, rather than enhanced cell proliferation or apoptosis suppression alone, may be a driving force for carcinogenesis. Our studies further suggest that compromised functional activity of p53 may be one of the mechanisms responsible for the proliferation/apoptosis imbalance. In sum, the results of our study indicate that evaluation of the extent of cell proliferation and apoptosis before the onset of preneoplastic lesions may be a potential biomarker of breast cancer risk after exposure to breast carcinogens.

  5. HORMONAL INFLUENCES ON MAMMARY TUMORS OF THE RAT

    Science.gov (United States)

    Huggins, Charles; Torralba, Yolanda; Mainzer, Klaus

    1956-01-01

    A transplanted mammary fibroadenoma was found to grow in 95 per cent of intact adult female rats and the increment of tumor weights was progressive and logarithmic. The growth of the tumor was retarded by ovariectomy and still more when this was combined with adrenalectomy. In ovariectomized rats the growth of the tumor was stimulated by phenolic estrogens, this increase being enhanced when progesterone was added. In these responses to hormonal changes the mammary gland and the tumor resembled each other. Yet there are many differences between the growth of the fibroadenoma and that of the mammary gland. In contrast to the progressive growth which occurred in intact adult females there was a prolonged period of indolent growth of transplants in hypophysectomized rats; but after many weeks active growth began and the tumors eventually reached large size. During the period of quiescent growth the tumor was cytologically atrophic but after the growth spurt had started the microscopic appearance of the fibroadenoma resembled that of tumors growing in normal adult females. The mammary gland remained atrophic during both the slow and the accelerated phases of tumor growth, and so too with the other secondary sex expressions. In hypophysectomized rats estrone and progesterone, when combined, stimulated the growth of the tumor, and this growth was accelerated by the additional administration of lactogenic or growth hormones. None of these hormones, separately, stimulated the growth of the tumor. In ovariectomized rats other differences were demonstrated between the growth of the mammary gland and the fibroadenoma. Progesterone, injected alone, accelerated the growth of the tumor but not that of the mammary glands. The administration of phenolic estrogens exerted a biphasic effect on the growth of the tumor whilst that on the breast of its hosts was monophasic. With progressively increasing doses of these phenols there occurred primarily an augmentation of the rate of

  6. Dietary extra-virgin olive oil and corn oil differentially modulate the mRNA expression of xenobiotic-metabolizing enzymes in the liver and in the mammary gland in a rat chemically induced breast cancer model.

    Science.gov (United States)

    Manzanares, Miguel Á; Solanas, Montserrat; Moral, Raquel; Escrich, Raquel; Vela, Elena; Costa, Irmgard; Escrich, Eduard

    2015-05-01

    High extra-virgin olive oil (EVOO) and corn oil diets differentially modulate experimental mammary carcinogenesis. We have investigated their influence on the initiation stage through the modulation of the expression of xenobiotic-metabolizing enzymes (XMEs) in the liver and the mammary gland. Female Sprague-Dawley rats were fed a low-fat (LF), high corn oil (HCO), or high EVOO (HOO) diet from weaning and gavaged with 7,12-dimethylbenz(a)anthracene (DMBA). The HCO diet increased the mRNA levels of the phase I enzymes CYP1A1, CYP1A2 and, to a lesser extent, CYP1B1, in the liver. The Aryl hydrocarbon receptor (AhR) seemed to be involved in this upregulated CYP1 expression. However, a slight trend toward an increase in the mRNA levels of the phase II enzymes GSTP1 and NQO1 was observed with the HOO diet. At least in the case of GSTP1, this effect was linked to an increased Nrf2 transactivation activity. This different regulation of the XMEs expression led, in the case of the HCO diet, to a balance between the production of active carcinogenic compounds and their inactivation tilted toward phase I, which would stimulate DMBA-induced cancer initiation, whereas the HOO diet was associated with a slower phase I metabolism accompanied by a faster phase II detoxification, thus reducing the output of the active compounds to the target tissues. In the mammary gland, the differential effects of diets may be conditioned by the state of cell differentiation, sexual maturity, and hormone metabolism.

  7. A review of mammary ductoscopy in breast cancer.

    Science.gov (United States)

    Yamamoto, Daigo; Tanaka, Kanji

    2004-01-01

    Breast carcinoma and hyperplasia are thought to start in the lining of the breast duct. Mammary ductoscopy is an emerging technique allowing direct visual access of the ductal system of the breast through the nipple. This article reviews and discusses the utility of mammary ductoscopy. Abnormalities can be identified successfully by mammary ductoscopy, and intraductal biopsy can be used when the tumor is a polypoid type. Ductal lavage using microcatheters is effective in identifying malignant cells in high-risk women and this has stimulated interest in exploring the role of mammary ductoscopy in breast cancer screening. Mammary ductoscopy combined with ductal lavage may have a role in the management of patients with nipple discharge, the guiding of breast-conserving surgery for cancer, and in screening for high-risk women. The addition of molecular and genetic analysis of cells obtained by mammary ductoscopy are likely to enhance the use of this technique. Mammary ductoscopy techniques are safe and appear useful for detecting abnormalities in the breast. The additional molecular biologic study or ductal lavage may enhance the ability to direct and limit subsequent surgery when removing the offending lesions.

  8. Quercetin attenuates oxidative stress in the blood plasma of rats bearing DMBA-induced mammary cancer and treated with a combination of doxorubicin and docetaxel.

    Science.gov (United States)

    Tabaczar, Sabina; Pieniążek, Anna; Czepas, Jan; Piasecka-Zelga, Joanna; Gwoździński, Krzysztof; Koceva-Chyła, Aneta

    2013-12-01

    The development of side-effects during doxorubicin-docetaxel (DOX-DTX) chemotherapy is considered as related to generation of oxidative stress by DOX. The addition of docetaxel potentiates this effect. Thus, antioxidants are assumed as a promising remedy for neutralizing deteriorating effects of reactive oxygen species (ROS) in pathological conditions and polyphenolic antioxidants are suitable candidates for such a therapeutic approach. We evaluated the ability of quercetin to attenuate oxidative stress developed during the process of DMBA carcinogenesis and DOX-DTX chemotherapy in the blood plasma of rats bearing mammary tumors. We have found that quercetin significantly improved the plasma nonenzymatic antioxidant capacity (NEAC) and reduced lipid peroxidation, which suggest the beneficial effect of flavonoid. The inclusion of quercetin to the DOX-DTX chemotherapy was also advantageous. A considerable decrease of carbonyls and lipid peroxidation products (TBARS) and improvement of the endogenous antioxidant defense system (an increase of NEAC, thiols and SOD activity) were observed compared to rats treated with DOX-DTX chemotherapy. These results suggest that quercetin could protect blood plasma constituents against oxidative damage evoked by DOX and DTX.

  9. Notch in mammary gland development and breast cancer.

    Science.gov (United States)

    Politi, Katerina; Feirt, Nikki; Kitajewski, Jan

    2004-10-01

    Notch signaling has been implicated in many processes including cell fate determination and oncogenesis. In mice, the Notch1 and Notch4 genes are both targets for insertion and rearrangement by the mouse mammary tumor virus and these mutations promote epithelial mammary tumorigenesis. Moreover, expression of a constitutively active form of Notch4 in mammary epithelial cells inhibits epithelial differentiation and leads to tumor formation in this organ. These data implicate the Notch pathway in breast tumorigenesis and provide the foundation for future experiments that will aid in our understanding of the role of Notch in human breast cancer development. Here, we review studies of mammary tumorigenesis induced by Notch in mouse and in vitro culture models providing evidence that Notch activation is a causal factor in human breast cancer.

  10. Integrin Signaling in Mammary Epithelial Cells and Breast Cancer

    OpenAIRE

    Lambert, Arthur W.; Sait Ozturk; Sam Thiagalingam

    2012-01-01

    Cells sense and respond to the extracellular matrix (ECM) by way of integrin receptors, which facilitate cell adhesion and intracellular signaling. Advances in understanding the mammary epithelial cell hierarchy are converging with new developments that reveal how integrins regulate the normal mammary gland. But in breast cancer, integrin signaling contributes to the development and progression of tumors. This paper highlights recent studies which examine the role of integrin signaling in mam...

  11. Epidermal growth factor in mammary glands and milk from rats

    DEFF Research Database (Denmark)

    Thulesen, J; Raaberg, Lasse; Nexø, Ebba

    1993-01-01

    Epidermal growth factor (EGF) is one of the major growth-promoting agents in milk. Using immunohistochemistry we localized EGF in the mammary glands of lactating rats to the luminal border of the secretory cells. Following proteolytic pretreatment of the histological sections, the EGF-immunoreact......Epidermal growth factor (EGF) is one of the major growth-promoting agents in milk. Using immunohistochemistry we localized EGF in the mammary glands of lactating rats to the luminal border of the secretory cells. Following proteolytic pretreatment of the histological sections, the EGF......-immunoreactivity was revealed homogeneously in the cytoplasm of the secretory cells, which might suggest that EGF is present as a precursor molecule in the mammary glands. Altered glucose metabolism during lactation results in secondary hypoinsulinaemia in the lactating rat. As insulin is also known to affect lactation...... in several species, we treated normal lactating rats daily with insulin and studied the effect on the composition of milk. A significant increase in the content of total protein and milk fat was observed after a few days of insulin-treatment, as compared to a control group [total protein: 50 (36-97) g/l vs...

  12. Influence of DMBA-induced mammary cancer on the liver CPT I, mit HMG-CoA synthase and PPARalpha mRNA expression in rats fed a low or high corn oil diet.

    Science.gov (United States)

    Moral, Raquel; Solanas, Montserrat; Manzanares, Eva Mónica; Haro, Diego; Escrich, Eduard

    2004-08-01

    Hepatic mitochondrial outer membrane carnitine palmitoyltransferase I (CPT I) and mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase) enzymes play a key role in regulation of fatty acid oxidation and in ketogenic pathways, respectively. Their expression are regulated by fatty acids mainly by the peroxisome proliferator-activated receptor alpha (PPARalpha). To investigate possible mechanisms through which cancer alters the lipid metabolism, we analyzed by Northern blot, the mRNA relative abundance of these proteins in liver from healthy and DMBA-induced mammary tumor-bearing rats fed a low or high corn oil diet. Serum levels of lipids, body weight and mass were also determined. Whereas mRNA steady-state levels of CPT I and mit HMG-CoA synthase were unaffected by the presence of the extra-hepatic tumor, the cancer state seemed to modify the regulation of the expression of these genes by high fat diet. We hypothesize that putative changes in PPARalpha mRNA levels could have contributed to such alterations. These results, together with changes in serum lipid profiles, body weight and mass, indicate fat mobilization and non-enhanced oxidation rates despite a high-fat feeding. This effect of the cancer state could be related to tumor aggressiveness and suggest a preferential redirection of long-chain fatty acids into energetic and specific pathways of the cancer cells.

  13. Effect of bisphenol A on morphology, apoptosis and proliferation in the resting mammary gland of the adult albino rat.

    Science.gov (United States)

    Ibrahim, Marwa A A; Elbakry, Reda H; Bayomy, Naglaa A

    2016-02-01

    Bisphenol A (BPA) is a synthetic oestrogen that is extensively used in a wide range of daily used plastic products. This makes it one of the environmental chemicals that may have impact on human health. Due to its oestrogenic effect, BPA might affect the mammary gland. This study aimed to investigate the influence of BPA on the histological structure of the mammary gland of the adult female albino rat and its effect on epithelial cell proliferation and apoptosis status, in addition to its possible modulating effect on estrogen receptor expression. Thirty female adult albino rats were divided into control and experimental groups. The rats in the experimental group were gavaged with 5 mg/kg BPA daily for 8 weeks. The mammary glands were dissected and processed for histological and immunohistochemical stains for Ki-67, activated caspase-3 and estrogen receptor alpha (ER-α). BPA induced an increase in the number and size of the acini and ducts in the mammary gland of treated rats with hyperplasia of their lining epithelial cells. The collagen fibre content was significantly increased in the connective tissue stroma separating the ducts. Immunohistochemical results showed a significant increase in Ki-67 and caspase-3, but a non-significant increase in ER-α expression. Bisphenol A induced structural changes and affected the proliferation rate of mammary glands, so it might be one of the predisposing factors for breast cancer.

  14. Development of Hyperplasias, Preneoplasias, and Mammary Tumors in MMTV-c-erbB-2 and MMTV-TGFα Transgenic Rats

    Science.gov (United States)

    Davies, Barry R.; Platt-Higgins, Angela M.; Schmidt, Gunter; Rudland, Philip S.

    1999-01-01

    Human cDNAs corresponding to two epidermal growth factor-related products that are overexpressed in human breast cancers, that for c-erbB-2 (HER-2) and for transforming growth factor α (TGFα), have been cloned downstream of the mouse mammary tumor virus (MMTV) long terminal repeat promoter and injected into the pronucleus of fertilized oocytes of Sprague-Dawley rats to produce transgenic offspring. Expression of the transgenic mRNAs is not detectable in mammary tissue from virgin transgenic rats but is detected in mammary tissue from certain lines of mid-pregnant transgenic rats. When two such lines of either type of transgenic rat are subjected to repeated cycles of pregnancy and lactation, they produce, primarily in the mammary glands, extensive pathologies, whereas virgin transgenic rats produce no such abnormalities. Multiparous transgenic female offspring from c-erbB-2-expressing lines develop a variety of focal hyperplastic and benign lesions that resemble lesions commonly found in human breasts. These lesions include lobular and ductal hyperplasia, fibroadenoma, cystic expansions, and papillary adenomas. More malignant lesions, including ductal carcinoma in situ and carcinoma, also develop stochastically at low frequency. The mammary glands of transgenic females invariably fail to involute fully after lactation. Similar phenotypes are observed in female MMTV-TGFα transgenic rats. In addition, multiparous TGFα-expressing female transgenics frequently develop severe pregnancy-dependent lactating hyperplasias as well as residual lobules of hyperplastic secretory epithelium and genuine lactating adenomas after weaning. These transgenic rat models confirm the conclusions reached in transgenic mice that overexpression of the c-erbB-2 and TGFα genes predisposes the mammary gland to stochastic tumor development. PMID:10393862

  15. Multiple susceptibility loci for radiation-induced mammary tumorigenesis in F2[Dahl S x R]-intercross rats.

    Directory of Open Access Journals (Sweden)

    Victoria L Herrera

    Full Text Available Although two major breast cancer susceptibility genes, BRCA1 and BRCA2, have been identified accounting for 20% of breast cancer genetic risk, identification of other susceptibility genes accounting for 80% risk remains a challenge due to the complex, multi-factorial nature of breast cancer. Complexity derives from multiple genetic determinants, permutations of gene-environment interactions, along with presumptive low-penetrance of breast cancer predisposing genes, and genetic heterogeneity of human populations. As with other complex diseases, dissection of genetic determinants in animal models provides key insight since genetic heterogeneity and environmental factors can be experimentally controlled, thus facilitating the detection of quantitative trait loci (QTL. We therefore, performed the first genome-wide scan for loci contributing to radiation-induced mammary tumorigenesis in female F2-(Dahl S x R-intercross rats. Tumorigenesis was measured as tumor burden index (TBI after induction of rat mammary tumors at forty days of age via ¹²⁷Cs-radiation. We observed a spectrum of tumor latency, size-progression, and pathology from poorly differentiated ductal adenocarcinoma to fibroadenoma, indicating major effects of gene-environment interactions. We identified two mammary tumorigenesis susceptibility quantitative trait loci (Mts-QTLs with significant linkage: Mts-1 on chromosome-9 (LOD-2.98 and Mts-2 on chromosome-1 (LOD-2.61, as well as two Mts-QTLs with suggestive linkage: Mts-3 on chromosome-5 (LOD-1.93 and Mts-4 on chromosome-18 (LOD-1.54. Interestingly, Chr9-Mts-1, Chr5-Mts-3 and Chr18-Mts-4 QTLs are unique to irradiation-induced mammary tumorigenesis, while Chr1-Mts-2 QTL overlaps with a mammary cancer susceptibility QTL (Mcs 3 reported for 7,12-dimethylbenz-[α]antracene (DMBA-induced mammary tumorigenesis in F2[COP x Wistar-Furth]-intercross rats. Altogether, our results suggest at least three distinct susceptibility QTLs for

  16. Multiple susceptibility loci for radiation-induced mammary tumorigenesis in F2[Dahl S x R]-intercross rats.

    Science.gov (United States)

    Herrera, Victoria L; Ponce, Lorenz R; Ruiz-Opazo, Nelson

    2013-01-01

    Although two major breast cancer susceptibility genes, BRCA1 and BRCA2, have been identified accounting for 20% of breast cancer genetic risk, identification of other susceptibility genes accounting for 80% risk remains a challenge due to the complex, multi-factorial nature of breast cancer. Complexity derives from multiple genetic determinants, permutations of gene-environment interactions, along with presumptive low-penetrance of breast cancer predisposing genes, and genetic heterogeneity of human populations. As with other complex diseases, dissection of genetic determinants in animal models provides key insight since genetic heterogeneity and environmental factors can be experimentally controlled, thus facilitating the detection of quantitative trait loci (QTL). We therefore, performed the first genome-wide scan for loci contributing to radiation-induced mammary tumorigenesis in female F2-(Dahl S x R)-intercross rats. Tumorigenesis was measured as tumor burden index (TBI) after induction of rat mammary tumors at forty days of age via ¹²⁷Cs-radiation. We observed a spectrum of tumor latency, size-progression, and pathology from poorly differentiated ductal adenocarcinoma to fibroadenoma, indicating major effects of gene-environment interactions. We identified two mammary tumorigenesis susceptibility quantitative trait loci (Mts-QTLs) with significant linkage: Mts-1 on chromosome-9 (LOD-2.98) and Mts-2 on chromosome-1 (LOD-2.61), as well as two Mts-QTLs with suggestive linkage: Mts-3 on chromosome-5 (LOD-1.93) and Mts-4 on chromosome-18 (LOD-1.54). Interestingly, Chr9-Mts-1, Chr5-Mts-3 and Chr18-Mts-4 QTLs are unique to irradiation-induced mammary tumorigenesis, while Chr1-Mts-2 QTL overlaps with a mammary cancer susceptibility QTL (Mcs 3) reported for 7,12-dimethylbenz-[α]antracene (DMBA)-induced mammary tumorigenesis in F2[COP x Wistar-Furth]-intercross rats. Altogether, our results suggest at least three distinct susceptibility QTLs for irradiation

  17. Multiple Susceptibility Loci for Radiation-Induced Mammary Tumorigenesis in F2[Dahl S x R]-Intercross Rats

    Science.gov (United States)

    Herrera, Victoria L.; Ponce, Lorenz R.; Ruiz-Opazo, Nelson

    2013-01-01

    Although two major breast cancer susceptibility genes, BRCA1 and BRCA2, have been identified accounting for 20% of breast cancer genetic risk, identification of other susceptibility genes accounting for 80% risk remains a challenge due to the complex, multi-factorial nature of breast cancer. Complexity derives from multiple genetic determinants, permutations of gene-environment interactions, along with presumptive low-penetrance of breast cancer predisposing genes, and genetic heterogeneity of human populations. As with other complex diseases, dissection of genetic determinants in animal models provides key insight since genetic heterogeneity and environmental factors can be experimentally controlled, thus facilitating the detection of quantitative trait loci (QTL). We therefore, performed the first genome-wide scan for loci contributing to radiation-induced mammary tumorigenesis in female F2-(Dahl S x R)-intercross rats. Tumorigenesis was measured as tumor burden index (TBI) after induction of rat mammary tumors at forty days of age via 127Cs-radiation. We observed a spectrum of tumor latency, size-progression, and pathology from poorly differentiated ductal adenocarcinoma to fibroadenoma, indicating major effects of gene-environment interactions. We identified two mammary tumorigenesis susceptibility quantitative trait loci (Mts-QTLs) with significant linkage: Mts-1 on chromosome-9 (LOD-2.98) and Mts-2 on chromosome-1 (LOD-2.61), as well as two Mts-QTLs with suggestive linkage: Mts-3 on chromosome-5 (LOD-1.93) and Mts-4 on chromosome-18 (LOD-1.54). Interestingly, Chr9-Mts-1, Chr5-Mts-3 and Chr18-Mts-4 QTLs are unique to irradiation-induced mammary tumorigenesis, while Chr1-Mts-2 QTL overlaps with a mammary cancer susceptibility QTL (Mcs 3) reported for 7,12-dimethylbenz-[α]antracene (DMBA)-induced mammary tumorigenesis in F2[COP x Wistar-Furth]-intercross rats. Altogether, our results suggest at least three distinct susceptibility QTLs for irradiation

  18. Cadherin Cell Adhesion System in Canine Mammary Cancer: A Review

    Directory of Open Access Journals (Sweden)

    Adelina Gama

    2012-01-01

    Full Text Available Cadherin-catenin adhesion complexes play important roles by providing cell-cell adhesion and communication in different organ systems. Abnormal expression of cadherin adhesion molecules constitutes a common phenomenon in canine mammary cancer and has been frequently implicated in tumour progression. This paper summarizes the current knowledge on cadherin/catenin adhesion molecules (E-cadherin, β-catenin, and P-cadherin in canine mammary cancer, focusing on the putative biological functions and clinical significance of these molecules in this disease. This paper highlights the need for further research studies in this setting in order to elucidate the role of these adhesion molecules during tumour progression and metastasis.

  19. Mammary gland density predicts the cancer inhibitory activity of the N-3 to N-6 ratio of dietary fat.

    Science.gov (United States)

    Zhu, Zongjian; Jiang, Weiqin; McGinley, John N; Prokopczyk, Bogden; Richie, John P; El Bayoumy, Karam; Manni, Andrea; Thompson, Henry J

    2011-10-01

    This study investigated the effect of a broad range of dietary ratios of n-3:n-6 fatty acids on mammary gland density and mammary cancer risk. Cancer was induced in female rats by N-methyl-N-nitrosourea. Purified diet that provided 30% of dietary kilocalories from fat was formulated to contain ratios of n-3:n-6 fatty acids from 25:1 to 1:25. Mammary gland density was determined by digital analysis, fatty acids by gas chromatography/flame ionization detection, and other plasma analytes via ELISA. Mammary gland density was reduced dose dependently at n-3:n-6 ratios from 1:1 to 25:1 (r = -0.477, P = 0.038), with a 20.3% decrease of mammary gland density between n-3:n-6 of 1:1 versus 25:1, P effect of the n-3:n-6 ratio on plasma leptin (decreased, P = 0.005) and adiponectin (increased, P tissue function was modulated. However, neither cytokine was predictive of mammary gland density. Plasma insulin-like growth factor I (IGF-I) decreased with increasing dietary n-3:n-6 ratio (P = 0.004) and was predictive of the changes in mammary gland density (r = 0.362, P effects in the presence or absence of hormonal regulation of carcinogenesis, and (iii) signaling pathways regulated by IGF-I are potential targets for further mechanistic investigation.

  20. The effect of dietary zinc - and polyphenols intake on DMBA-induced mammary tumorigenesis in rats

    Directory of Open Access Journals (Sweden)

    Bobrowska-Korczak Barbara

    2012-04-01

    Full Text Available Abstract Background The aim of the study was to investigate the effect of dietary supplementation with zinc and polyphenol compounds, i.e. resveratrol and genistein, on the effectiveness of chemically induced mammary cancer and the changes in the content of selected elements (Zn, Cu, Mg, Fe, Ca in tumors as compared with normal tissue of the mammary gland. Methods Female Sprague-Dawley rats were divided into study groups which, apart from the standard diet and DMBA (7,12-dimethyl-1,2- benz[a]anthracene, were treated with zinc ions (Zn or zinc ions + resveratrol (Zn + resveratrol or zinc ions + genistein (Zn + genistein via gavage for a period from 40 days until 20 weeks of age. The ICP-OES (inductively coupled plasma optical emission spectrometry technique was used to analyze the following elements: magnesium, iron, zinc and calcium. Copper content in samples was estimated in an atomic absorption spectrophotometer. Results Regardless of the diet (standard; Zn; Zn + resveratrol; Zn + genistein, DMBA-induced breast carcinogenesis was not inhibited. On the contrary, in the Zn + resveratrol supplemented group, tumorigenesis developed at a considerably faster rate. On the basis of quantitative analysis of selected elements we found - irrespectively of the diet applied - great accumulation of copper and iron, which are strongly prooxidative, with a simultaneous considerable decrease of the magnesium content in DMBA-induced mammary tumors. The combination of zinc supplementation with resveratrol resulted in particularly large differences in the amount of the investigated elements in tumors as compared with their content in normal tissue. Conclusions Diet supplementation with zinc and polyphenol compounds, i.e. resveratrol and genistein had no effect on the decreased copper level in tumor tissue and inhibited mammary carcinogenesis in the rat. Irrespectively of the applied diet, the development of the neoplastic process in rats resulted in changes of

  1. Significance of rat mammary tumors for human risk assessment.

    Science.gov (United States)

    Russo, Jose

    2015-02-01

    We have previously indicated that the ideal animal tumor model should mimic the human disease. This means that the investigator should be able to ascertain the influence of host factors on the initiation of tumorigenesis, mimic the susceptibility of tumor response based on age and reproductive history, and determine the response of the tumors induced to chemotherapy. The utilization of experimental models of mammary carcinogenesis in risk assessment requires that the influence of ovarian, pituitary, and placental hormones, among others, as well as overall reproductive events are taken into consideration, since they are important modifiers of the susceptibility of the organ to neoplastic development. Several species, such as rodents, dogs, cats, and monkeys, have been evaluated for these purposes; however, none of them fulfills all the criteria specified previously. Rodents, however, are the most widely used models; therefore, this work will concentrate on discussing the rat rodent model of mammary carcinogenesis. © 2014 by The Author(s).

  2. Development of Hyperplasias, Preneoplasias, and Mammary Tumors in MMTV-c-erbB-2 and MMTV-TGFα Transgenic Rats

    OpenAIRE

    Davies, Barry R.; Platt-Higgins, Angela M.; Schmidt, Gunter; Rudland, Philip S.

    1999-01-01

    Human cDNAs corresponding to two epidermal growth factor-related products that are overexpressed in human breast cancers, that for c-erbB-2 (HER-2) and for transforming growth factor α (TGFα), have been cloned downstream of the mouse mammary tumor virus (MMTV) long terminal repeat promoter and injected into the pronucleus of fertilized oocytes of Sprague-Dawley rats to produce transgenic offspring. Expression of the transgenic mRNAs is not detectable in mammary tissue from virgin transgenic r...

  3. Migrastatin analogues inhibit canine mammary cancer cell migration and invasion.

    Directory of Open Access Journals (Sweden)

    Kinga Majchrzak

    Full Text Available BACKGROUND: Cancer spread to other organs is the main cause of death of oncological patients. Migration of cancer cells from a primary tumour is the crucial step in the complex process of metastasis, therefore blocking this process is currently the main treatment strategy. Metastasis inhibitors derived from natural products, such as, migrastatin, are very promising anticancer agents. Thus, the aim of our study was to investigate the effect of six migrastatin analogues (MGSTA-1 to 6 on migration and invasion of canine mammary adenocarcinoma cell lines isolated from primary tumours and their metastases to the lungs. Canine mammary tumours constitute a valuable tool for studying multiple aspect of human cancer. RESULTS: OUR RESULTS SHOWED THAT TWO OF SIX FULLY SYNTHETIC ANALOGUES OF MIGRASTATIN: MGSTA-5 and MGSTA-6 were potent inhibitors of canine mammary cancer cells migration and invasion. These data were obtained using the wound healing test, as well as trans-well migration and invasion assays. Furthermore, the treatment of cancer cells with the most effective compound (MGSTA-6 disturbed binding between filamentous F-actin and fascin1. Confocal microscopy analyses revealed that treatment with MGSTA-6 increased the presence of unbound fascin1 and reduced co-localization of F-actin and fascin1 in canine cancer cells. Most likely, actin filaments were not cross-linked by fascin1 and did not generate the typical filopodial architecture of actin filaments in response to the activity of MGSTA-6. Thus, administration of MGSTA-6 results in decreased formation of filopodia protrusions and stress fibres in canine mammary cancer cells, causing inhibition of cancer migration and invasion. CONCLUSION: Two synthetic migrastatin analogues (MGSTA-5 and MGSTA-6 were shown to be promising compounds for inhibition of cancer metastasis. They may have beneficial therapeutic effects in cancer therapy in dogs, especially in combination with other anticancer drugs

  4. Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer

    NARCIS (Netherlands)

    Poortmans, P.M.P.; Collette, S.; Kirkove, C.; Limbergen, E. van; Budach, V.; Struikmans, H.; Collette, L.; Fourquet, A.; Maingon, P.; Valli, M.; Winter, K. De; Marnitz, S.; Barillot, I.; Scandolaro, L.; Vonk, E.; Rodenhuis, C.; Marsiglia, H.; Weidner, N.; Tienhoven, G. van; Glanzmann, C.; Kuten, A.; Arriagada, R.; Bartelink, H.; Bogaert, W. Van den

    2015-01-01

    BACKGROUND: The effect of internal mammary and medial supraclavicular lymph-node irradiation (regional nodal irradiation) added to whole-breast or thoracic-wall irradiation after surgery on survival among women with early-stage breast cancer is unknown. METHODS: We randomly assigned women who had a

  5. Culture and characterization of mammary cancer stem cells in mammospheres.

    Science.gov (United States)

    Piscitelli, Eleonora; Cocola, Cinzia; Thaden, Frank Rüdiger; Pelucchi, Paride; Gray, Brian; Bertalot, Giovanni; Albertini, Alberto; Reinbold, Rolland; Zucchi, Ileana

    2015-01-01

    Mammospheres (MMs) are a model for culturing and maintaining mammary gland stem cells (SCs) or cancer stem cells (CSCs) ex situ. As MMs recapitulate the micro-niche of the mammary gland or a tumor, MMs are a model for studying the properties of SCs or CSCs, and for mapping, isolating, and characterizing the SC/CSC generated lineages. Cancer stem cells share with normal SCs the properties of self-renewal and the capacity to generate all cell types and organ structures of the mammary gland. Analysis of human tumor samples suggests that CSCs are heterogeneous in terms of proliferation and differentiation potential. Mammospheres from CSCs likewise display heterogeneity. This heterogeneity makes analysis of CSC generated MMs challenging. To identify the unique and diverse properties of MM derived CSCs, comparative analysis with MMs obtained from normal SCs is required. Here we present protocols for identifying and enriching cells with SC features from a cancer cell line using the LA7CSCs as a model. A comprehensive and comparative approach for identifying, isolating, and characterizing MMs from SCs and CSCs from human breast is also introduced. In addition, we describe detailed procedures for identifying, isolating, and characterizing mammary gland specific cell types, generated during MM formation.

  6. Copper and resveratrol attenuates serum catalase, glutathione peroxidase, and element values in rats with DMBA-induced mammary carcinogenesis.

    Science.gov (United States)

    Skrajnowska, Dorota; Bobrowska-Korczak, Barbara; Tokarz, Andrzej; Bialek, Slawomir; Jezierska, Ewelina; Makowska, Justyna

    2013-12-01

    In this paper, a hypothesis was assessed whether or not the intoxication with copper and supplementation with copper plus resveratrol would result in changes in the activities of catalase and glutathione peroxidase and moreover if the characteristic changes would appear in concentrations of copper, iron, calcium, magnesium, and zinc in the serum of rats with chemically induced carcinogenesis. Female Sprague-Dawley rats were divided into study groups which, apart from the standard diet, were treated with copper (42.6 mg Cu/kg food as CuSO4·5H2O) or copper plus resveratrol (0.2 mg/kg body) via gavage for a period from 40 days until 20 weeks of age. In cancer groups, the rats were treated with a dose of 80 mg/body weight of 7,12-dimethyl-1,2-benz[a]anthracene (DMBA) given in rapeseed oil at 50 and 80 days of age to induce mammary carcinogenesis. The control groups included the rats kept in the same conditions and fed with the same diet as the animals from the study groups, but not DMBA-treated. The activity of catalase significantly decreased in groups of rats with mammary carcinogenesis that were supplemented with copper (p copper plus resveratrol (p cancer groups of nonsupplemented rats, the increase of glutathione peroxidase activity was observed. The process of carcinogenesis and the applied supplementation significantly altered the concentrations of trace elements in serum, in particular as concerns iron and copper. The mean serum iron levels in rats with breast cancer were significantly lower than those in the control groups (p copper levels significantly decreased in the groups of rats with mammary carcinogenesis that were supplemented with copper or copper plus resveratrol in comparison with the control groups that received the same diets (p copper and zinc/iron ratios in blood may be used as one of the prognostic factors in breast cancer research.

  7. Chemoprevention of Rat Mammary Carcinogenesis by Apiaceae Spices

    Science.gov (United States)

    Aqil, Farrukh; Jeyabalan, Jeyaprakash; Munagala, Radha; Ravoori, Srivani; Vadhanam, Manicka V.; Schultz, David J.; Gupta, Ramesh C.

    2017-01-01

    Scientific evidence suggests that many herbs and spices have medicinal properties that alleviate symptoms or prevent disease. In this study, we examined the chemopreventive effects of the Apiaceae spices, anise, caraway, and celery seeds against 17β-estrogen (E2)-mediated mammary tumorigenesis in an ACI (August-Copenhagen Irish) rat model. Female ACI rats were given either control diet (AIN 93M) or diet supplemented with 7.5% (w/w) of anise, caraway, or celery seed powder. Two weeks later, one half of the animals in each group received subcutaneous silastic implants of E2. Diet intake and body weight were recorded weekly, and animals were euthanized after 3 and 12 weeks. E2-treatment showed significantly (2.1- and 3.4-fold) enhanced growth of pituitary gland at 3 and 12 weeks, respectively. All test spices significantly offset the pituitary growth by 12 weeks, except celery which was effective as early as three weeks. Immunohistochemical analysis for proliferative cell nuclear antigen (PCNA) in mammary tissues showed significant reduction in E2-mediated mammary cell proliferation. Test spices reduced the circulating levels of both E2 and prolactin at three weeks. This protection was more pronounced at 12 weeks, with celery eliciting the highest effect. RT-PCR and western blot analysis were performed to determine the potential molecular targets of the spices. Anise and caraway diets significantly offset estrogen-mediated overexpression of both cyclin D1 and estrogen receptor α (ERα). The effect of anise was modest. Likewise, expression of CYP1B1 and CYP1A1 was inhibited by all test spices. Based on short-term molecular markers, caraway was selected over other spices based on its enhanced effect on estrogen-associated pathway. Therefore, a tumor-end point study in ACI rats was conducted with dietary caraway. Tumor palpation from 12 weeks onwards revealed tumor latency of 29 days in caraway-treated animals compared with first tumor appearance at 92 days in control

  8. Chemoprevention of Rat Mammary Carcinogenesis by Apiaceae Spices

    Directory of Open Access Journals (Sweden)

    Farrukh Aqil

    2017-02-01

    Full Text Available Scientific evidence suggests that many herbs and spices have medicinal properties that alleviate symptoms or prevent disease. In this study, we examined the chemopreventive effects of the Apiaceae spices, anise, caraway, and celery seeds against 17β-estrogen (E2-mediated mammary tumorigenesis in an ACI (August-Copenhagen Irish rat model. Female ACI rats were given either control diet (AIN 93M or diet supplemented with 7.5% (w/w of anise, caraway, or celery seed powder. Two weeks later, one half of the animals in each group received subcutaneous silastic implants of E2. Diet intake and body weight were recorded weekly, and animals were euthanized after 3 and 12 weeks. E2-treatment showed significantly (2.1- and 3.4-fold enhanced growth of pituitary gland at 3 and 12 weeks, respectively. All test spices significantly offset the pituitary growth by 12 weeks, except celery which was effective as early as three weeks. Immunohistochemical analysis for proliferative cell nuclear antigen (PCNA in mammary tissues showed significant reduction in E2-mediated mammary cell proliferation. Test spices reduced the circulating levels of both E2 and prolactin at three weeks. This protection was more pronounced at 12 weeks, with celery eliciting the highest effect. RT-PCR and western blot analysis were performed to determine the potential molecular targets of the spices. Anise and caraway diets significantly offset estrogen-mediated overexpression of both cyclin D1 and estrogen receptor α (ERα. The effect of anise was modest. Likewise, expression of CYP1B1 and CYP1A1 was inhibited by all test spices. Based on short-term molecular markers, caraway was selected over other spices based on its enhanced effect on estrogen-associated pathway. Therefore, a tumor-end point study in ACI rats was conducted with dietary caraway. Tumor palpation from 12 weeks onwards revealed tumor latency of 29 days in caraway-treated animals compared with first tumor appearance at 92

  9. RUNX2 in mammary gland development and breast cancer.

    Science.gov (United States)

    Ferrari, Nicola; McDonald, Laura; Morris, Joanna S; Cameron, Ewan R; Blyth, Karen

    2013-06-01

    Runx2 is best known as an essential factor in osteoblast differentiation and bone development but, like many other transcription factors involved in development, is known to operate over a much wider tissue range. Our understanding of these other aspects of Runx2 function is still at a relatively early stage and the importance of its role in cell fate decisions and lineage maintenance in non-osseous tissues is only beginning to emerge. One such tissue is the mammary gland, where Runx2 is known to be expressed and participate in the regulation of mammary specific genes. Furthermore, differential and temporal expression of this gene is observed during mammary epithelial differentiation in vivo, strongly indicative of an important functional role. Although the precise nature of that role remains elusive, preliminary evidence hints at possible involvement in the regulation of mammary stem and/or progenitor cells. As with many genes important in regulating cell fate, RUNX2 has also been linked to metastatic cancer where in some established breast cell lines, retention of expression is associated with a more invasive phenotype. More recently, expression analysis has been extended to primary breast cancers where high levels of RUNX2 align with a specific subtype of the disease. That RUNX2 expression correlates with the so called "Triple Negative" subtype is particularly interesting given the known cross talk between Runx2 and estrogen receptor signaling pathways. This review summaries our current understanding of Runx2 in mammary gland development and cancer, and postulates a role that may link both these processes.

  10. BAC CGH-array identified specific small-scale genomic imbalances in diploid DMBA-induced rat mammary tumors

    Directory of Open Access Journals (Sweden)

    Samuelson Emma

    2012-08-01

    Full Text Available Abstract Background Development of breast cancer is a multistage process influenced by hormonal and environmental factors as well as by genetic background. The search for genes underlying this malignancy has recently been highly productive, but the etiology behind this complex disease is still not understood. In studies using animal cancer models, heterogeneity of the genetic background and environmental factors is reduced and thus analysis and identification of genetic aberrations in tumors may become easier. To identify chromosomal regions potentially involved in the initiation and progression of mammary cancer, in the present work we subjected a subset of experimental mammary tumors to cytogenetic and molecular genetic analysis. Methods Mammary tumors were induced with DMBA (7,12-dimethylbenz[a]anthrazene in female rats from the susceptible SPRD-Cu3 strain and from crosses and backcrosses between this strain and the resistant WKY strain. We first produced a general overview of chromosomal aberrations in the tumors using conventional kartyotyping (G-banding and Comparative Genome Hybridization (CGH analyses. Particular chromosomal changes were then analyzed in more details using an in-house developed BAC (bacterial artificial chromosome CGH-array platform. Results Tumors appeared to be diploid by conventional karyotyping, however several sub-microscopic chromosome gains or losses in the tumor material were identified by BAC CGH-array analysis. An oncogenetic tree analysis based on the BAC CGH-array data suggested gain of rat chromosome (RNO band 12q11, loss of RNO5q32 or RNO6q21 as the earliest events in the development of these mammary tumors. Conclusions Some of the identified changes appear to be more specific for DMBA-induced mammary tumors and some are similar to those previously reported in ACI rat model for estradiol-induced mammary tumors. The later group of changes is more interesting, since they may represent anomalies that involve

  11. Mammary Cancer and Activation of Transposable Elements

    Science.gov (United States)

    2015-03-01

    derived adipo- cytes and ADS-derived induced pluripotent stem cells (ADS-iPSCs) (19) and primary mouse ES cells to isolated sperm and oocytes (20). We...Mesendoderm 2353 765 051 59 5 92% H9-IMR90 5875 7 669 782 605 58 91% oocyte - ES cell (mouse) 4727 1 204 883 334 25 93% sperm - ES cell (mouse) 4580 4 364 748...engineered mouse model in which a specific mammary cell population is fluorescently marked upon initial transcriptional activation of the SV40 large T

  12. Social isolation induces autophagy in the mouse mammary gland: link to increased mammary cancer risk.

    Science.gov (United States)

    Sumis, Allison; Cook, Katherine L; Andrade, Fabia O; Hu, Rong; Kidney, Emma; Zhang, Xiyuan; Kim, Dominic; Carney, Elissa; Nguyen, Nguyen; Yu, Wei; Bouker, Kerrie B; Cruz, Idalia; Clarke, Robert; Hilakivi-Clarke, Leena

    2016-10-01

    Social isolation is a strong predictor of early all-cause mortality and consistently increases breast cancer risk in both women and animal models. Because social isolation increases body weight, we compared its effects to those caused by a consumption of obesity-inducing diet (OID) in C57BL/6 mice. Social isolation and OID impaired insulin and glucose sensitivity. In socially isolated, OID-fed mice (I-OID), insulin resistance was linked to reduced Pparg expression and increased neuropeptide Y levels, but in group-housed OID fed mice (G-OID), it was linked to increased leptin and reduced adiponectin levels, indicating that the pathways leading to insulin resistance are different. Carcinogen-induced mammary tumorigenesis was significantly higher in I-OID mice than in the other groups, but cancer risk was also increased in socially isolated, control diet-fed mice (I-C) and G-OID mice compared with that in controls. Unfolded protein response (UPR) signaling (GRP78; IRE1) was upregulated in the mammary glands of OID-fed mice, but not in control diet-fed, socially isolated I-C mice. In contrast, expression of BECLIN1, ATG7 and LC3II were increased, and p62 was downregulated by social isolation, indicating increased autophagy. In the mammary glands of socially isolated mice, but not in G-OID mice, mRNA expressions of p53 and the p53-regulated autophagy inducer Dram1 were upregulated, and nuclear p53 staining was strong. Our findings further indicated that autophagy and tumorigenesis were not increased in Atg7(+/-) mice kept in social isolation and fed OID. Thus, social isolation may increase breast cancer risk by inducing autophagy, independent of changes in body weight.

  13. Pueraria mirifica Exerts Estrogenic Effects in the Mammary Gland and Uterus and Promotes Mammary Carcinogenesis in Donryu Rats

    Science.gov (United States)

    Kakehashi, Anna; Yoshida, Midori; Tago, Yoshiyuki; Ishii, Naomi; Okuno, Takahiro; Gi, Min; Wanibuchi, Hideki

    2016-01-01

    Pueraria mirifica (PM), a plant whose dried and powdered tuberous roots are now widely used in rejuvenating preparations to promote youthfulness in both men and women, may have major estrogenic influence. In this study, we investigated modifying effects of PM at various doses on mammary and endometrial carcinogenesis in female Donryu rats. Firstly, PM administered to ovariectomized animals at doses of 0.03%, 0.3%, and 3% in a phytoestrogen-low diet for 2 weeks caused significant increase in uterus weight. Secondly, a 4 week PM application to non-operated rats at a dose of 3% after 7,12-dimethylbenz[a]anthracene (DMBA) initiation resulted in significant elevation of cell proliferation in the mammary glands. In a third experiment, postpubertal administration of 0.3% (200 mg/kg body weight (b.w.)/day) PM to 5-week-old non-operated animals for 36 weeks following initiation of mammary and endometrial carcinogenesis with DMBA and N-ethyl-N′-nitro-N-nitrosoguanidine (ENNG), respectively, resulted in significant increase of mammary adenocarcinoma incidence. A significant increase of endometrial atypical hyperplasia multiplicity was also observed. Furthermore, PM at doses of 0.3%, and more pronouncedly, at 1% induced dilatation, hemorrhage and inflammation of the uterine wall. In conclusion, postpubertal long-term PM administration to Donryu rats exerts estrogenic effects in the mammary gland and uterus, and at a dose of 200 mg/kg b.w./day was found to promote mammary carcinogenesis initiated by DMBA. PMID:27827907

  14. Pueraria mirifica Exerts Estrogenic Effects in the Mammary Gland and Uterus and Promotes Mammary Carcinogenesis in Donryu Rats

    Directory of Open Access Journals (Sweden)

    Anna Kakehashi

    2016-11-01

    Full Text Available Pueraria mirifica (PM, a plant whose dried and powdered tuberous roots are now widely used in rejuvenating preparations to promote youthfulness in both men and women, may have major estrogenic influence. In this study, we investigated modifying effects of PM at various doses on mammary and endometrial carcinogenesis in female Donryu rats. Firstly, PM administered to ovariectomized animals at doses of 0.03%, 0.3%, and 3% in a phytoestrogen-low diet for 2 weeks caused significant increase in uterus weight. Secondly, a 4 week PM application to non-operated rats at a dose of 3% after 7,12-dimethylbenz[a]anthracene (DMBA initiation resulted in significant elevation of cell proliferation in the mammary glands. In a third experiment, postpubertal administration of 0.3% (200 mg/kg body weight (b.w./day PM to 5-week-old non-operated animals for 36 weeks following initiation of mammary and endometrial carcinogenesis with DMBA and N-ethyl-N′-nitro-N-nitrosoguanidine (ENNG, respectively, resulted in significant increase of mammary adenocarcinoma incidence. A significant increase of endometrial atypical hyperplasia multiplicity was also observed. Furthermore, PM at doses of 0.3%, and more pronouncedly, at 1% induced dilatation, hemorrhage and inflammation of the uterine wall. In conclusion, postpubertal long-term PM administration to Donryu rats exerts estrogenic effects in the mammary gland and uterus, and at a dose of 200 mg/kg b.w./day was found to promote mammary carcinogenesis initiated by DMBA.

  15. Enzymes of the taurine biosynthetic pathway are expressed in rat mammary gland.

    Science.gov (United States)

    Ueki, Iori; Stipanuk, Martha H

    2007-08-01

    Taurine is the most abundant free amino acid in the body and is present at high concentrations during development and in the early milk. It is synthesized from cysteine via oxidation of cysteine to cysteinesulfinate by the enzyme cysteine dioxygenase (CDO), followed by the decarboxylation of cysteinesulfinate to hypotaurine, catalyzed by cysteine sulfinic acid decarboxylase (CSAD). To determine whether the taurine biosynthetic pathway is present in mammary gland and whether it is differentially expressed during pregnancy and lactation, and also to further explore the possible regulation of hepatic taurine synthesis during pregnancy and lactation, we measured mammary and hepatic CDO and CSAD mRNA and protein concentrations and tissue, plasma and milk taurine concentrations. CDO and CSAD mRNA and protein were expressed in mammary gland and liver regardless of physiological state. Immunohistochemistry demonstrated the expression of CDO in ductal cells of pregnant rats, but not in other mammary epithelial cells or in ductal cells of nonpregnant rats. CDO was also present in stromal adipocytes in mammary glands of both pregnant and nonpregnant rats. Our findings support an upregulation of taurine synthetic capacity in the mammary gland of pregnant rats, based on mammary taurine and hypotaurine concentrations and the intense immunohistochemical staining for CDO in ductal cells of pregnant rats. Hepatic taurine synthetic capacity, particularly CSAD, and taurine concentrations were highest in rats during the early stages of lactation, suggesting the liver may also play a role in the synthesis of taurine to support lactation or repletion of maternal reserves.

  16. Trypanosoma cruzi extracts elicit protective immune response against chemically induced colon and mammary cancers.

    Science.gov (United States)

    Ubillos, Luis; Freire, Teresa; Berriel, Edgardo; Chiribao, María Laura; Chiale, Carolina; Festari, María Florencia; Medeiros, Andrea; Mazal, Daniel; Rondán, Mariella; Bollati-Fogolín, Mariela; Rabinovich, Gabriel A; Robello, Carlos; Osinaga, Eduardo

    2016-04-01

    Trypanosoma cruzi, the protozoan parasite that causes Chagas' disease, has anticancer effects mediated, at least in part, by parasite-derived products which inhibit growth of tumor cells. We investigated whether immunity to T. cruzi antigens could induce antitumor activity, using two rat models which reproduce human carcinogenesis: colon cancer induced by 1,2-dimethylhydrazine (DMH), and mammary cancer induced by N-nitroso-N-methylurea (NMU). We found that vaccination with T. cruzi epimastigote lysates strongly inhibits tumor development in both animal models. Rats immunized with T. cruzi antigens induce activation of both CD4(+) and CD8(+) T cells and splenocytes from these animals showed higher cytotoxic responses against tumors as compared to rats receiving adjuvant alone. Tumor-associated immune responses included increasing number of CD11b/c(+) His48(-) MHC II(+) cells corresponding to macrophages and/or dendritic cells, which exhibited augmented NADPH-oxidase activity. We also found that T. cruzi lysate vaccination developed antibodies specific for colon and mammary rat cancer cells, which were capable of mediating antibody-dependent cellular cytotoxicity (ADCC) in vitro. Anti-T. cruzi antibodies cross-reacted with human colon and breast cancer cell lines and recognized 41/60 (68%) colon cancer and 38/63 (60%) breast cancer samples in a series of 123 human tumors. Our results suggest that T. cruzi antigens can evoke an integrated antitumor response involving both the cellular and humoral components of the immune response and provide novel insights into the understanding of the intricate relationship between parasite infection and tumor growth.

  17. [Controversy about internal mammary chain irradiation in breast cancer].

    Science.gov (United States)

    Hennequin, C; Fourquet, A

    2014-10-01

    Irradiation of lymph nodes areas after surgery of breast cancer, and specifically of the internal mammary chain, is an open question, frequently discussed. Three randomised trials (French, European-EORTC, Canadian) have been recently published or presented. The French trial did not show any benefit for internal mammary chain irradiation, but it was probably underpowered. The EORTC and Canadian trials demonstrated an improvement in overall survival after lymph nodes irradiation, including the internal mammary chain. The absolute benefit is 1.6% (hazard ratio-0.88 in a recent meta-analysis). Because this benefit is limited, it is important to define the characteristics of the patients who may benefit from this irradiation. Analyses of the randomized trials are not complete, and it is difficult at this moment to accurately define this population. However, cardiac and pulmonary toxicity of lymph nodes irradiation is well known. For each patient, evaluation of the potential late toxicity must be evaluated and so an accurate dosimetry for critical organs must be performed: the indication of internal mammary chain irradiation depends of the benefit/risk ratio. Copyright © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

  18. Trianthema portulacastrum Linn. exerts chemoprevention of 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis in rats

    Energy Technology Data Exchange (ETDEWEB)

    Bishayee, Anupam, E-mail: abishayee@auhs.edu [Department of Pharmaceutical Sciences, School of Pharmacy, American University of Health Sciences, Signal Hill, CA 90755 (United States); Mandal, Animesh [Cancer Therapeutics and Chemoprevention Group, Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272 (United States)

    2014-10-15

    Highlights: • Dietary administration of an ethanolic extract of aerial parts of T. portulacastrum (TPE) exhibits a striking chemopreventive effect in an experimentally induced classical animal model of breast cancer. • The mammary tumor-inhibitory effect of TPE could be achieved, at least in part, though intervention of key hallmark capabilities of tumor cells, such as abnormal cell proliferation and evasion of apoptosis. • TPE is capable of diminishing activated canonical Wnt/β-catenin signaling to exhibit antiproliferative, proapoptotic and oncostatic effects during this early-stage mammary carcinoma. • These results coupled with a safety profile of T. portulacastrum may encourage further studies to understand the full potential of this dietary plant for chemoprevention of breast cancer. - Abstract: Due to limited treatment options for advanced-stage metastatic breast cancer, a high priority should be given to develop non-toxic chemopreventive drugs. The value of various natural and dietary agents to reduce the risk of developing breast cancer is well established. Trianthema portulacastrum Linn. (Aizoaceae), a dietary and medicinal plant, has been found to exert antihepatotoxic and antihepatocarcinogenic properties in rodents. This study was initiated to investigate mechanism-based chemopreventive potential of an ethanolic extract of T. portulacastrum (TPE) against 7,12-dimethylbenz(a)anthracene (DMBA)-initiated rat mammary gland carcinogenesis, an experimental tumor model that closely resembles human breast cancer. Rats had access to a basal diet supplemented with TPE to yield three dietary doses of the extract, i.e., 50, 100 and 200 mg/kg body weight. Following two weeks of TPE treatment, mammary tumorigenesis was initiated by oral administration of DMBA (50 mg/kg body weight). At the end of the study (16 weeks after DMBA exposure), TPE exhibited a striking reduction of DMBA-induced mammary tumor incidence, total tumor burden and average tumor weight

  19. Trianthema portulacastrum Linn. exerts chemoprevention of 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis in rats.

    Science.gov (United States)

    Bishayee, Anupam; Mandal, Animesh

    2014-10-01

    Due to limited treatment options for advanced-stage metastatic breast cancer, a high priority should be given to develop non-toxic chemopreventive drugs. The value of various natural and dietary agents to reduce the risk of developing breast cancer is well established. Trianthema portulacastrum Linn. (Aizoaceae), a dietary and medicinal plant, has been found to exert antihepatotoxic and antihepatocarcinogenic properties in rodents. This study was initiated to investigate mechanism-based chemopreventive potential of an ethanolic extract of T. portulacastrum (TPE) against 7,12-dimethylbenz(a)anthracene (DMBA)-initiated rat mammary gland carcinogenesis, an experimental tumor model that closely resembles human breast cancer. Rats had access to a basal diet supplemented with TPE to yield three dietary doses of the extract, i.e., 50, 100 and 200 mg/kg body weight. Following two weeks of TPE treatment, mammary tumorigenesis was initiated by oral administration of DMBA (50 mg/kg body weight). At the end of the study (16 weeks after DMBA exposure), TPE exhibited a striking reduction of DMBA-induced mammary tumor incidence, total tumor burden and average tumor weight and reversed intratumor histopathological alterations. TPE dose-dependently suppressed proliferating cell nuclear antigen and cyclin D1 expression, induced apoptosis, upregulated proapoptotic protein Bax, downregulated antiapoptotic protein Bcl-2 and diminished the expression of nuclear and cytosolic β-catenin in mammary tumors. Our results clearly provide the first experimental evidence that TPE exerts chemopreventive effect in the classical DMBA model of breast cancer by suppressing abnormal cell proliferation and inducing apoptosis mediated through alteration of Bax/Bcl-2 ratio. Mechanistically, TPE is capable of diminishing activated canonical Wnt/β-catenin signaling to exhibit antiproliferative, proapoptotic and oncostatic effects during an early-stage breast cancer. These results may encourage further

  20. /sup 20/neon ion- and x-ray-induced mammary carcinogenesis in female rats

    Energy Technology Data Exchange (ETDEWEB)

    Shellabarger, C.J.; Baum, J.W.; Holtzman, S.; Stone, J.P.

    1983-01-01

    One of the proposed uses of heavy ion irradiation is to image lesions of the human female breast. The rat model system was chosen to assess the carcinogenic potential of heavy ion irradiation in the belief that data obtained from rat studies would have a qualitatively predictive value for the human female. Accordingly, female rats were exposed to /sup 20/Ne ions at the BEVALAC and studied for the development of mammary neoplasia for 312 +- 2 days at Brookhaven along with rats exposed concurrently to x-irradiation or to no irradiation. As the dose of either type of radiation was increased the percent of rats with mammary adenocarcinomas, and the percent of rats with mammary fibroadenomas, tended to increase. At a prevalence of 20%, the RBE for /sup 20/Neon ions for mammary adenocarcinomas was estimated to be larger than 5 and for mammary fibroadenomas the RBE was estimated to be less than 2. No conclusion was reached concerning whether or not the RBE might vary with dose. We suggest that /sup 20/Ne ions do have a carcinogenic potential for rat mammary tissue and that this carcinogenic potential is likely to be greater than for x-irradiation. (DT)

  1. Simulation of the pentose cycle in lactating rat mammary gland

    Science.gov (United States)

    Haut, Michael J.; London, Jack W.; Garfinkel, David

    1974-01-01

    A computer model representing the pentose cycle, the tricarboxylic acid cycle and glycolysis in slices of lactating rat mammary glands has been constructed. This model is based primarily on the studies, with radioactive chemicals, of Abraham & Chaikoff (1959) [although some of the discrepant data of Katz & Wals (1972) could be accommodated by changing one enzyme activity]. Data obtained by using [1-14C]-, [6-14C]- and [3,4-14C]-glucose were simulated, as well as data obtained by using unlabelled glucose (for which some new experimental data are presented). Much past work on the pentose cycle has been mainly concerned with the division of glucose flow between the pentose cycle and glycolysis, and has relied on the assumption that the system is in steady state (both labelled and unlabelled). This assumption may not apply to lactating rat mammary glands, since the model shows that the percentage flow through the shunt progressively decreased for the first 2h of a 3h experiment, and we were unable to construct a completely steady-state model. The model allows examination of many quantitative features of the system, especially the amount of material passing through key enzymes, some of which appear to be regulated by NADP+ concentrations as proposed by McLean (1960). Supplementary information for this paper has been deposited as Supplementary Publication SUP 50023 at the British Museum (Lending Division) (formerly the National Lending Library for Science and Technology), Boston Spa, Yorks. LS23 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1973) 131, 5. PMID:4154746

  2. MicroRNA expression in canine mammary cancer.

    Science.gov (United States)

    Boggs, R Michelle; Wright, Zachary M; Stickney, Mark J; Porter, Weston W; Murphy, Keith E

    2008-08-01

    MicroRNAs (miRNAs) are 18-22-nt noncoding RNAs that are involved in post-transcriptional regulation of genes. Oncomirs, a subclass of miRNAs, include genes whose expression, or lack thereof, are associated with cancers. Until the last decade, the domestic dog was an underused model for the study of various human diseases that have genetic components. The dog exhibits marked genetic and physiologic similarity to the human, thereby making it an excellent model for study and treatment of various hereditary diseases. Furthermore, because the dog presents with distinct, spontaneously occurring mammary tumors, it may serve as a model for genetic analysis and treatments of humans with malignant breast tumors. Because miRNAs have been found to act as both tumor suppressors and oncogenes in several different cancers, expression patterns of ten miRNAs (miR-15a, miR-16, miR-17-5p, miR-21, miR-29b, miR-125b, miR-145, miR-155, miR-181b, let-7f) known to be associated with human breast cancers were compared to malignant canine mammary tumors (n = 6) and normal canine mammary tissue (n = 10). Resulting data revealed miR-29b and miR-21 to have a statistically significant (p pattern of expression as in the human, except for miR-145 which does not show a difference in expression between the normal and cancerous canine samples. In addition, when analyzed according to specific cancer phenotypes, miR-15a and miR-16 show a significant downregulation in canine ductal carcinomas while miRsR-181b, -21, -29b, and let-7f show a significant upregulation in canine tubular papillary carcinomas.

  3. Effects of metformin, buformin, and phenformin on the post-initiation stage of chemically induced mammary carcinogenesis in the rat.

    Science.gov (United States)

    Zhu, Zongjian; Jiang, Weiqin; Thompson, Matthew D; Echeverria, Dimas; McGinley, John N; Thompson, Henry J

    2015-06-01

    Metformin is a widely prescribed drug for the treatment of type II diabetes. Although epidemiologic data have provided a strong rationale for investigating the potential of this biguanide for use in cancer prevention and control, uncertainty exists whether metformin should be expected to have an impact in nondiabetic patients. Furthermore, little attention has been given to the possibility that other biguanides may have anticancer activity. In this study, the effects of clinically relevant doses of metformin (9.3 mmol/kg diet), buformin (7.6 mmol/kg diet), and phenformin (5.0 mmol/kg diet) were compared with rats fed control diet (AIN93-G) during the post-initiation stage of 1-methyl-1-nitrosourea-induced (50 mg/kg body weight) mammary carcinogenesis (n = 30/group). Plasma, liver, skeletal muscle, visceral fat, mammary gland, and mammary carcinoma concentrations of the biguanides were determined. In comparison with the control group, buformin decreased cancer incidence, multiplicity, and burden, whereas metformin and phenformin had no statistically significant effect on the carcinogenic process relative to the control group. Buformin did not alter fasting plasma glucose or insulin. Within mammary carcinomas, evidence was obtained that buformin treatment perturbed signaling pathways related to energy sensing. However, further investigation is needed to determine the relative contributions of host systemic and cell autonomous mechanisms to the anticancer activity of biguanides such as buformin.

  4. Genotype x diet interactions in mice predisposed to mammary cancer: II. Tumors and metastasis

    DEFF Research Database (Denmark)

    Gordon, Ryan R; Hunter, Kent W; Merrill, Michele La

    2008-01-01

    effects of diet on mammary tumor and metastases phenotypes, mapping of tumor/metastasis modifier genes, and the interaction between dietary fat levels and effects of cancer modifiers. Results demonstrate that animals fed a high-fat diet are not only more likely to experience decreased mammary cancer...

  5. Pueraria mirifica Exerts Estrogenic Effects in the Mammary Gland and Uterus and Promotes Mammary Carcinogenesis in Donryu Rats

    OpenAIRE

    Anna Kakehashi; Midori Yoshida; Yoshiyuki Tago; Naomi Ishii; Takahiro Okuno; Min Gi; Hideki Wanibuchi

    2016-01-01

    Pueraria mirifica (PM), a plant whose dried and powdered tuberous roots are now widely used in rejuvenating preparations to promote youthfulness in both men and women, may have major estrogenic influence. In this study, we investigated modifying effects of PM at various doses on mammary and endometrial carcinogenesis in female Donryu rats. Firstly, PM administered to ovariectomized animals at doses of 0.03%, 0.3%, and 3% in a phytoestrogen-low diet for 2 weeks caused significant increase in u...

  6. Intraductal approach to breast cancer: the role of mammary ductoscopy.

    Science.gov (United States)

    Deshmane, Vinay

    2010-09-01

    Mammary ductoscopy is a recent advance enabling direct visualisation and sampling of human mammary ducts using a micro endoscope. The majority of pre malignant and malignant changes in the breast arise from the epithelium lining the duct lobular unit, and access to this region by ductoscopy has the potential to revolutionise breast cancer diagnosis and treatment. The ability to sample ductal epithelium may allow identification of early malignant and pre-malignant cytological changes and assist surgical excision, facilitating diagnosis of non palpable cancer before detection on current imaging modalities. Presently, there are three main indications for ductoscopy in clinical practice viz. determining extent of resection for breast cancer, assessment of high risk individuals and in the management of patients with pathological nipple discharge. Our initial experience with ductoscopy in patients with nipple discharge undergoing surgery has been rewarding. Ductoscopy was feasible in 92% of patients. Abnormal findings on ductoscopy were associated with DCIS in 37% and DCIS with early invasive breast cancer in 21%, while normal ductoscopy correlated with a normal pathological assessment.

  7. Modulation of lipid peroxidation and antioxidant status upon administration of 'Shemamruthaa' in 7,12-dimethylbenz[a]anthracene induced mammary carcinoma bearing rats

    Institute of Scientific and Technical Information of China (English)

    Ayyakkannu Purushothaman; Elumalai Nandhakumar; Panchanatham Sachdanandam

    2012-01-01

    Objective: To investigate the therapeutic efficacy of a Shemamruthaa (SM), (combination of Hibiscus rosasinensis (H. rosasinensis) flowers, fruits of Phyllanthus emblica (P. emblica) and pure honey in definite ratio), against lipid peroxidation (LPO) and antioxidant status in experimentally induced mammary carcinoma rats. Methods: Adult female Sprague-Dawley rats were used for the study and were divided into four groups. Group I control animals received standard pellet diet and water ad libitum. Group II rats were induced with 7,12-dimethyl benz[a]anthracene (DMBA) (25 mg in 1 mL olive oil) by gastric intubation, whereas another set of DMBA-induced rats were treated with SM (400 mg/kg body weight/d) in olive oil orally by gastric intubation for 14 d after 3 months of induction period (group III). Group IV rats served as SM-treated control animals. At the end of the experimental period, the rats were anaesthetised and sacrificed and used for biochemical measures and histology studies. Results: The LPO was increased and antioxidant levels were decreased in the serum, liver and mammary tissues of cancer-induced rats. The administration of SM drug significantly (P<0.05) decreased LPO and reversed the status of antioxidants to near normal level in cancer-bearing animals. Conclusions: The results obtained indicate the additive and synergistic action of constituents’ plants in the SM drug against oxidative damage and its protective role in DMBA induced mammary cancer.

  8. Mixtures of environmentally relevant endocrine disrupting chemicals affect mammary gland development in female and male rats.

    Science.gov (United States)

    Mandrup, Karen Riiber; Johansson, Hanna Katarina Lilith; Boberg, Julie; Pedersen, Anne Stilling; Mortensen, Mette Sidsel; Jørgensen, Jennifer Solgaard; Vinggaard, Anne Marie; Hass, Ulla

    2015-07-01

    Estrogenic chemicals are able to alter mammary gland development in female rodents, but little is known on the effects of anti-androgens and mixtures of endocrine disrupting chemicals (EDCs) with dissimilar modes of action. Pregnant rat dams were exposed during gestation and lactation to mixtures of environmentally relevant EDCs with estrogenic, anti-androgenic or dissimilar modes of action (TotalMix) of 100-, 200- or 450-fold high end human intake estimates. Mammary glands of prepubertal and adult female and male offspring were examined. Oestrogens increased mammary outgrowth in prepubertal females and the mRNA level of matrix metalloproteinase-3, which may be a potential biomarker for increased outgrowth. Mixtures of EDCs gave rise to ductal hyperplasia in adult males. Adult female mammary glands of the TotalMix group showed morphological changes possibly reflecting increased prolactin levels. In conclusion both estrogenic and anti-androgenic chemicals given during foetal life and lactation affected mammary glands in the offspring.

  9. Pesticide chlorpyrifos acts as an endocrine disruptor in adult rats causing changes in mammary gland and hormonal balance.

    Science.gov (United States)

    Ventura, Clara; Nieto, María Rosa Ramos; Bourguignon, Nadia; Lux-Lantos, Victoria; Rodriguez, Horacio; Cao, Gabriel; Randi, Andrea; Cocca, Claudia; Núñez, Mariel

    2016-02-01

    Endocrine disruptors (EDs) are compounds that interfere with hormone regulation and influence mammary carcinogenesis. We have previously demonstrated that the pesticide chlorpyrifos (CPF) acts as an ED in vitro, since it induces human breast cancer cells proliferation through estrogen receptor alpha (ERα) pathway. In this work, we studied the effects of CPF at environmental doses (0.01 and 1mg/kg/day) on mammary gland, steroid hormone receptors expression and serum steroid hormone levels. It was carried out using female Sprague-Dawley 40-days-old rats exposed to the pesticide during 100 days. We observed a proliferating ductal network with a higher number of ducts and alveolar structures. We also found an increased number of benign breast diseases, such as hyperplasia and adenosis. CPF enhanced progesterone receptor (PgR) along with the proliferating cell nuclear antigen (PCNA) in epithelial ductal cells. On the other hand, the pesticide reduced the expression of co-repressors of estrogen receptor activity REA and SMRT and it decreased serum estradiol (E2), progesterone (Pg) and luteinizing hormone (LH) levels. Finally, we found a persistent decrease in LH levels among ovariectomized rats exposed to CPF. Therefore, CPF alters the endocrine balance acting as an ED in vivo. These findings warn about the harmful effects that CPF exerts on mammary gland, suggesting that this compound may act as a risk factor for breast cancer.

  10. Remodeling of endogenous mammary epithelium by breast cancer stem cells.

    Science.gov (United States)

    Parashurama, Natesh; Lobo, Neethan A; Ito, Ken; Mosley, Adriane R; Habte, Frezghi G; Zabala, Maider; Smith, Bryan R; Lam, Jessica; Weissman, Irving L; Clarke, Michael F; Gambhir, Sanjiv S

    2012-10-01

    Poorly regulated tissue remodeling results in increased breast cancer risk, yet how breast cancer stem cells (CSC) participate in remodeling is unknown. We performed in vivo imaging of changes in fluorescent, endogenous duct architecture as a metric for remodeling. First, we quantitatively imaged physiologic remodeling of primary branches of the developing and regenerating mammary tree. To assess CSC-specific remodeling events, we isolated CSC from MMTV-Wnt1 (mouse mammary tumor virus long-term repeat enhancer driving Wnt1 oncogene) breast tumors, a well studied model in which tissue remodeling affects tumorigenesis. We confirm that CSC drive tumorigenesis, suggesting a link between CSC and remodeling. We find that normal, regenerating, and developing gland maintain a specific branching pattern. In contrast, transplantation of CSC results in changes in the branching patterns of endogenous ducts while non-CSC do not. Specifically, in the presence of CSC, we identified an increased number of branches, branch points, ducts which have greater than 40 branches (5/33 for CSC and 0/39 for non-CSC), and histological evidence of increased branching. Moreover, we demonstrate that only CSC implants invade into surrounding stroma with structures similar to developing mammary ducts (nine for CSC and one for non-CSC). Overall, we demonstrate a novel approach for imaging physiologic and pathological remodeling. Furthermore, we identify unique, CSC-specific, remodeling events. Our data suggest that CSC interact with the microenvironment differently than non-CSC, and that this could eventually be a therapeutic approach for targeting CSC.

  11. Unplanned irradiation of internal mammary lymph nodes in breast cancer.

    Science.gov (United States)

    Kanyilmaz, Gul; Aktan, Meryem; Koc, Mehmet; Demir, Hikmettin; Demir, Lütfi Saltuk

    2017-06-01

    To evaluate the incidental dose to the internal mammary chain (IMC) in patients treated with three-dimensional conformal radiotherapy, to estimate the predictors affecting the magnitude of IMC receiving dose and to determine the predictive role of clinical parameters on survival. Between 2009 and 2015, 348 patients undergoing RT for breast cancer were retrospectively analyzed. All patients underwent our department's routine procedure for breast cancer. The internal mammary lymph nodes were contoured according to Radiation Therapy Oncology Group (RTOG) concensus. Based on each patient's dose-volume histograms, the mean doses (D mean) to internal mammary gland were analyzed. Overall survival and disease-free survival were also evaluated. The median follow-up time was 38 (range 3-80) months. The D mean to IMC was 32.8 Gy and the dose delivered to IMC showed a greater coverage in modified radical mastectomy (MRM) group compared with breast conserving surgery (34.6 vs 26.7 Gy). The T-stage of tumor and the N-stage of tumor affected the incidental dose to IMC. The tumor size, the number of involved lymph nodes, the percentage of involved lymph nodes, hormonal status, advanced T-stage and advanced N-stage were the prognostic factors that affect survival. The IMC received meaningful incidental irradiation dose when treated with two opposite tangential fields and ipsilateral supraclavicular fossa with a single anterior field. The real effect of incidental dose on survival and the hypothesis about the benefit of incidental irradiation of IMC should be examined in clinical studies.

  12. Unique expression pattern of the three insulin receptor family members in the rat mammary gland

    DEFF Research Database (Denmark)

    Hvid, Henning; Klopfleisch, Robert; Vienberg, Sara Gry

    2011-01-01

    Supra-pharmacological doses of the insulin analog X10 (AspB10) increased the incidence of mammary tumors in female Sprague-Dawley rats in chronic toxicity studies, most likely via receptor-mediated mechanisms. However, little is known about the expression of the insulin receptor family in the rat...

  13. Granulocytic subset of myeloid derived suppressor cells in rats with mammary carcinoma

    NARCIS (Netherlands)

    Dolen, Y.; Gunaydin, G.; Esendagli, G.; Guc, D.

    2015-01-01

    Limited knowledge is available on myeloid derived suppressor cells (MDSCs) of rat origin. We examined the myeloid cells from peripheral blood, bone marrow and spleens of healthy and mammary tumor bearing rats employing a novel immunophenotyping strategy with CD172a, HIS48, and Rp-1 antibodies. We ad

  14. ANTICANCER EFFECTS OF CARICA PAPAYA IN EXPERIMENTAL INDUCED MAMMARY TUMORS IN RATS

    Directory of Open Access Journals (Sweden)

    Gurudatta M, Deshmukh YA, Naikwadi A A

    2015-07-01

    Full Text Available Objective: To evaluate the anticancer effect of Carica papaya in DMBA induced mammary tumors in rats. Methods: Wistar rats were divided in to five groups (n=6, Group-I (Normal control administered vehicle olive oil, Group-II, Group-III ,Group-IV and V induced mammary tumors by administering single dose of DMBA (7,12 Dimethyl benz(Aanthracene orally 65 mg/kg. Group-III was administered aqueous leaf extract of Carica papaya (ALQECP in a dose of 200 mg/kg body wt for a period of 3 months, group-IV has given ALQECP 200 mg/kg body wt for a period of 21 days post 3 months of tumor induction, group-V rats were administered a small dose of Carica papaya extract intra tumor locally in the region of tumor. Results: Values of CA15-3 were increased in group-II rats (tumor control significantly, whereas in group-III (prevention group the levels of CA15-3 were found to be reduced substantially and the P value < 0.001. Similarly, CA-15-3 levels were reduced significantly in group-IV (treatment groupand P<0.005. The levels of LDH were seen to be increased in group-II, where as in group-III LDH levels were decreased and P<0.001.similarly group-IV LDH levels also reduced significantly but not to the level of group-III. Conclusion: Among the various markers for the detection of cancer antigen-15(CA15-3 and lactate dehydrogenase (LDH are important biochemical parameters that give a clear understanding of the progression and proliferation of cancer cells. In this study it was found that there is increase in the levels of markers such as CA15-3 and LDH and also the tumor volume in tumor control, these marker levels were decreased by the administration of aqueous leaf extract of Carica papaya in a dose of 200 mg/kg body wt. ALQECP not only prevented the progression of cancer growth but also has significant effect in reducing the both CA15-3 and LDH levels in treatment group.

  15. Interplay between progesterone and prolactin in mammary development and implications for breast cancer.

    Science.gov (United States)

    Lee, Heather J; Ormandy, Christopher J

    2012-06-24

    Progesterone and prolactin remodel mammary morphology during pregnancy by acting on the mammary epithelial cell hierarchy. The roles of each hormone in mammary development have been well studied, but evidence of signalling cross-talk between progesterone and prolactin is still emerging. Factors such as receptor activator of NFkB ligand (RANKL) may integrate signals from both hormones to orchestrate their joint actions on the epithelial cell hierarchy. Common targets of progesterone and prolactin signalling are also likely to integrate their pro-proliferative actions in breast cancer. Therefore, a thorough understanding of the interplay between progesterone and prolactin in mammary development may reveal therapeutic targets for breast cancer. This review summarises our understanding of Pg and PRL action in mammary gland development before focusing on molecular mechanisms of signalling cross-talk and the implications for breast cancer. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  16. Developmental signaling pathways regulating mammary stem cells and contributing to the etiology of triple-negative breast cancer

    OpenAIRE

    Rangel,Maria Cristina; Bertolette, Daniel; Castro, Nadia P.; Klauzinska, Malgorzata; Cuttitta, Frank; Salomon, David S

    2016-01-01

    Cancer has been considered as temporal and spatial aberrations of normal development in tissues. Similarities between mammary embryonic development and cell transformation suggest that the underlying processes required for mammary gland development are also those perturbed during various stages of mammary tumorigenesis and breast cancer (BC) development. The master regulators of embryonic development Cripto-1, Notch/CSL, and Wnt/β-catenin play key roles in modulating mammary gland morphogenes...

  17. Identification of genes differentially expressed between benign and osteopontin transformed rat mammary epithelial cells

    Directory of Open Access Journals (Sweden)

    Rudland Philip S

    2009-02-01

    Full Text Available Abstract Background Osteopontin is a secreted, integrin-binding and phosphorylated acidic glycoprotein which has an important role in tumor progression. Findings In this study, we have utilized suppressive subtractive hybridization (SSH to evaluate OPN regulated gene expression, using the Rama 37 benign non-invasive rat mammary cell line and a subclone, Rama 37-OPN. Rama 37-OPN was produced by stably transfecting Rama 37 with an OPN expression vector and it demonstrates increased malignant properties in vitro. Sequence and expression array analysis of the respective cDNA libraries of over 1600 subtracted cDNA fragments revealed 982 ESTs, 45 novel sequences and 659 known genes. The known up-regulated genes in the Rama 37-OPN library code for proteins with a variety of functions including those involved in metabolism, cell adhesion and migration, signal transduction and in apoptosis. Four of the most differentially expressed genes between the benign and in vitro malignant rat mammary cell lines are tumor protein translationally controlled I (TPTI, aryl hydrocarbon receptor nuclear translocator (ARNT, ataxia telangiectasia mutated (ATM and RAN GTPase (RAN. The largest difference (ca 10,000 fold between the less aggressively (MCF-7, ZR-75 and more aggressively malignant (MDA MB 231, MDA MB 435S human breast cancer cell lines is that due to RAN, the next is that due to osteopontin itself. Conclusion The results suggest that enhanced properties associated with the malignant state in vitro induced by osteopontin may be due to, in part, overexpression of RAN GTPase and these biological results are the subject of a subsequent publication 1.

  18. Chemopreventive potential of fungal taxol against 7, 12-dimethylbenz[a]anthracene induced mammary gland carcinogenesis in Sprague Dawley rats.

    Science.gov (United States)

    Gokul Raj, Kathamuthu; Chidambaram, Ranganathan; Varunkumar, Krishnamoorthy; Ravikumar, Vilwanathan; Pandi, Mohan

    2015-11-15

    Breast cancer is the second most prevalent cancer and foremost global public health problem. The present study was designed to appraise the chemopreventive potential of fungal taxol against 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary gland carcinogenesis in Sprague Dawley rats. After 90 days of tumor induction, fungal and authentic taxol were given intraperitoneally once in a week for four weeks. Infrared thermal imaging analysis, serum biochemical parameters such as lipid peroxidase (LPO), creatinine, enzymic and non enzymic antioxidants, liver markers tests such as alanine transaminase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglycerides (TG) and lipoproteins was analysed. In addition, histopathological observation (breast, kidney and liver), immunohistochemical analysis (p53 and Her2/neu) and western blotting experiments (bcl-2, bax and caspase-9) were performed both in control and experimental animals. In thermal imaging, decreased temperature was observed in rat treated with fungal and authentic taxol when compared to tumor induced rats. The significant decrease in LPO, creatinine, ALT, AST, TC, TG, lipoproteins and increase in enzymic, non-enzymic antioxidants were exemplified in serum of treated groups. Further histopathology, immunohistochemical and western blot analysis (bax, cas-9 and bcl-2) of apoptotic markers in breast tissues clearly showed the anti-carcinogenic property of fungal taxol. Our findings implement that fungal taxol is a potential chemo preventive agent against DMBA induced mammary gland carcinogenesis.

  19. Influence of dietary menhaden oil on 7,12-dimethylbenzanthracene induced mammary tumorigenesis in rats

    Energy Technology Data Exchange (ETDEWEB)

    O' Connor, T.P.; Peterson, F.; Campbell, T.C.

    1986-03-05

    The effect of dietary menhaden oil on 7,12-dimethylbenzanthracene (DMBA) induced mammary tumorigenesis was examined in female Sprague-Dawley rats. Rats were obtained at age 28 days and acclimated until age 50 days when they received a single i.g. dose of 5 mg DMBA dissolved in 1 ml corn oil. Rats were then randomly assigned to one of four treatment groups with 25 rats per group. One group was fed a diet based on fish protein (freeze-dried cod) and corn oil (F/C). The second group received a diet based on fish protein and menhaden oil (F/M). The third group received a casein based diet with corn oil as the lipid source (C/C). The fourth group was fed a casein based diet with menhaden oil as the lipid source (C/M). Both the protein and lipid sources were fed at a level of 20% by weight of the diets. Rats were palpated weekly to check for mammary tumor development and the experiment was terminated 24 weeks after DMBA administration. Rats fed menhaden oil as a lipid source (F/M and C/M groups) developed significantly fewer mammary tumors than animals on the corn oil based diets (F/C and C/C groups, respectively). Thus, menhaden oil, rich in omega-3 fatty acids, significantly inhibited the development of DMBA induced mammary tumors in this experiment.

  20. Modulatory effect of Pleurotus ostreatus on oxidant/antioxidant status in 7, 12-dimethylbenz (a) anthracene induced mammary carcinoma in experimental rats--A dose-response study.

    Science.gov (United States)

    Krishnamoorthy, Deepalakshmi; Sankaran, Mirunalini

    2016-01-01

    Worldwide, breast cancer is the second most prevalent cancer among women and its incidence is increasing alarmingly. To determine a dose-response effect of Pleurotus ostreatus on oxidant/antioxidant status in 7,12-dimethylbenz. (a) antheracene induced. (DMBA) mammary carcinoma in experimental rats. Cancer bearing female Sprague Dawley rats were orally treated with Pleurotus ostreatus ethanolic extract (POEet) (150, 300 and 600 mg/kg body weight) for 16 weeks. By means of high performance liquid chromatography (HPLC) analysis, ergosterol (48.82%) were identified and quantified in POEet. Body weight of experimental rats in each groups and the biochemical parameters of plasma, liver and mammary tissues were carried out. Histopathological analyses were also determined. Results were analyzed using SPSS software package, version 16.0. The values were analyzed by one way analysis of variance (ANOVA) followed by Duncan's multiple range test (DMRT). The result showed that depleted activities of enzymatic and non-enzymatic antioxidant level and significant elevated TBARS level were observed in DMBA group of plasma, mammary and liver tissues of experimental rats. The effects were dose.dependent and the above noted parameters were renovated to near normal after supplementation with different dose of POEet (150 mg, 300 mg and 600 mg/kg bwt). The data obtained from the study indicate that POEet at a dose of 600 mg/kg bwt possesses optimum anticancer effects against DMBA induced mammary carcinogenesis. Based on the scientific appraisal, we conclude that the POEet is having a potent antioxidant capacity; thereby it offers maximum protection against DMBA-induced mammary carcinogenesis.

  1. Does cancer start in the womb? altered mammary gland development and predisposition to breast cancer due to in utero exposure to endocrine disruptors.

    Science.gov (United States)

    Soto, Ana M; Brisken, Cathrin; Schaeberle, Cheryl; Sonnenschein, Carlos

    2013-06-01

    We are now witnessing a resurgence of theories of development and carcinogenesis in which the environment is again being accepted as a major player in phenotype determination. Perturbations in the fetal environment predispose an individual to disease that only becomes apparent in adulthood. For example, gestational exposure to diethylstilbestrol resulted in clear cell carcinoma of the vagina and breast cancer. In this review the effects of the endocrine disruptor bisphenol-A (BPA) on mammary development and tumorigenesis in rodents is used as a paradigmatic example of how altered prenatal mammary development may lead to breast cancer in humans who are also widely exposed to it through plastic goods, food and drink packaging, and thermal paper receipts. Changes in the stroma and its extracellular matrix led to altered ductal morphogenesis. Additionally, gestational and lactational exposure to BPA increased the sensitivity of rats and mice to mammotropic hormones during puberty and beyond, thus suggesting a plausible explanation for the increased incidence of breast cancer.

  2. Exposure to estrogen and ionizing radiation causes epigenetic dysregulation, activation of mitogen-activated protein kinase pathways, and genome instability in the mammary gland of ACI rats.

    Science.gov (United States)

    Kutanzi, Kristy; Kovalchuk, Olga

    2013-07-01

    The impact of environmental mutagens and carcinogens on the mammary gland has recently received a lot of attention. Among the most generally accepted carcinogenic agents identified as factors that may increase breast cancer incidence are ionizing radiation and elevated estrogen levels. However, the molecular mechanisms of mammary gland aberrations associated with radiation and estrogen exposure still need to be further elucidated, especially the interplay between elevated hormone levels and radiation. Therefore, in the present study, we investigated molecular changes induced in rat mammary gland tissue by estrogen, ionizing radiation, and the combined action of these two carcinogens using a well-established ACI rat model. We found that continuous exposure of intact female ACI rats to elevated levels of estrogen or to both estrogen and radiation resulted in significant hyperproliferative changes in rat mammary glands. In contrast, radiation exposure alone did not induce hyperplasia. Interestingly, despite the obvious disparity in mammary gland morphology, we did not detect significant differences in the levels of genomic methylation among animals exposed to estrogen, radiation, or both agents together. Specifically, we observed a significant global genomic hypomethylation at 6 weeks of exposure. However, by 12 and 18 weeks, the levels of global DNA methylation returned to those of age-matched controls. We also found that combined exposure to radiation and estrogen significantly altered the levels of histone H3 and H4 methylation and acetylation. Most importantly, we for the first time demonstrated that estrogen and radiation exposure caused a significant induction of p42/44 MAPK and p38 pathways that was paralleled by elevated levels of H3S10 phosphorylation, a well-established biomarker of genome and chromosome instability. The precise role of MAPK pathways and their inter-relationship with H3S10 phosphorylation and genome instability in mammary gland tissues needs

  3. Low-dose effects of bisphenol A on mammary gland development in rats.

    Science.gov (United States)

    Mandrup, K; Boberg, J; Isling, L K; Christiansen, S; Hass, U

    2016-07-01

    Bisphenol A (BPA) is widely used in food contact materials, toys, and other products. Several studies have indicated that effects observed at doses near human exposure levels may not be observed at higher doses. Many studies have shown effects on mammary glands at low doses of BPA, however, because of small number of animals or few doses investigated these data have not been used by EFSA as point of departure for the newly assessed tolerable daily intake (TDI). We performed a study with perinatal exposure to BPA (0, 0.025, 0.25, 5, and 50 mg/kg bw/day) in rats (n = 22 mated/group). One of the aims was to perform a study robust enough to contribute to the risk assessment of BPA and to elucidate possible biphasic dose-response relationships. We investigated mammary gland effects in the offspring at 22, 100, and 400 days of age. Male offspring showed increased mammary outgrowth on pup day (PD) 22 at 0.025 mg/kg BPA, indicating an increased mammary development at this low dose only. Increased prevalence of intraductal hyperplasia was observed in BPA females exposed to 0.25 mg/kg at PD 400, but not at PD 100, and not at higher or lower doses. The present findings support data from the published literature showing that perinatal exposure to BPA can induce increased mammary growth and proliferative lesions in rodents. Our results indicate that low-dose exposure to BPA can affect mammary gland development in male and female rats, although higher doses show a different pattern of effects. The observed intraductal hyperplasia in female rats could be associated with an increased risk for developing hyperplastic lesions, which are parallels to early signs of breast neoplasia in women. Collectively, current knowledge on effects of BPA on mammary gland at low doses indicates that highly exposed humans may not be sufficiently protected.

  4. Detection of differentially expressed genes in methylnitrosourea-induced rat mammary adenocarcinomas.

    Science.gov (United States)

    Hu, L; Lin, L; Crist, K A; Kelloff, G J; Steele, V E; Lubet, R A; You, M; Wang, Y

    1997-01-01

    In this study, altered gene expression in five methylnitrosourea (MNU)-induced rat mammary adenocarcinomas was investigated using a newly developed competitive cDNA library screening assay. In order to detect the differentially expressed cDNA transcripts, three cDNA libraries (rat mammary, rat liver, and rat kidney) with over 18,000 clones were differentially screened with competing normal and neoplastic mammary cDNA probes. Ninety-eight clones indicated by competitive hybridization to be differentially expressed in tumors were verified by dot-blot hybridization analysis. Of these clones, 45 were found to be overexpressed while 53 were underexpressed in tumors. Forty-five of the confirmed clones were further analyzed by single-pass cDNA sequence determination. Four clones showed homology with cytochrome oxidase subunit I, polyoma virus PTA noncoding region, cytoplasmic beta-actin, and mouse secretory protein containing thrombospondin motifs. Further investigation into the potential roles of these identified genes should contribute significantly to our understanding of the molecular mechanism(s) of rat mammary tumorigenesis.

  5. Human mammary microenvironment better regulates the biology of human breast cancer in humanized mouse model.

    Science.gov (United States)

    Zheng, Ming-Jie; Wang, Jue; Xu, Lu; Zha, Xiao-Ming; Zhao, Yi; Ling, Li-Jun; Wang, Shui

    2015-02-01

    During the past decades, many efforts have been made in mimicking the clinical progress of human cancer in mouse models. Previously, we developed a human breast tissue-derived (HB) mouse model. Theoretically, it may mimic the interactions between "species-specific" mammary microenvironment of human origin and human breast cancer cells. However, detailed evidences are absent. The present study (in vivo, cellular, and molecular experiments) was designed to explore the regulatory role of human mammary microenvironment in the progress of human breast cancer cells. Subcutaneous (SUB), mammary fat pad (MFP), and HB mouse models were developed for in vivo comparisons. Then, the orthotopic tumor masses from three different mouse models were collected for primary culture. Finally, the biology of primary cultured human breast cancer cells was compared by cellular and molecular experiments. Results of in vivo mouse models indicated that human breast cancer cells grew better in human mammary microenvironment. Cellular and molecular experiments confirmed that primary cultured human breast cancer cells from HB mouse model showed a better proliferative and anti-apoptotic biology than those from SUB to MFP mouse models. Meanwhile, primary cultured human breast cancer cells from HB mouse model also obtained the migratory and invasive biology for "species-specific" tissue metastasis to human tissues. Comprehensive analyses suggest that "species-specific" mammary microenvironment of human origin better regulates the biology of human breast cancer cells in our humanized mouse model of breast cancer, which is more consistent with the clinical progress of human breast cancer.

  6. Calcitonin gene-related peptide (CGRP) in the nipple of the rat mammary gland

    DEFF Research Database (Denmark)

    Thulesen, J; Rasmussen, T N; Schmidt, P;

    1994-01-01

    The distribution of nerve fibres immunoreactive to calcitonin gene-related peptide (CGRP) was investigated by immunohistochemistry in nipples and mammary glands from lactating and non-lactating rats and compared to the immunoreactivity of other neuropeptides including substance P (SP), neuropeptide...... Y (NPY), vasoactive intestinal peptide (VIP) and somatostatin (SOM). The study revealed an extensive innervation of the mammary nipples, in which CGRP-immunoreactive (IR) nerve fibres were abundantly present in the epidermis, dermal connective tissue and intralobular connective tissue of the mammary...... gland parenchyma. Several of the dermal CGRP-IR fibres seemed to follow blood vessels, or formed "ringlet-like" structures. The latter were mostly observed in the dermal connective tissue of the nipple from the lactating rat and may have a mechanoreceptive function, e.g. for the suckling stimuli...

  7. Chemoprevention of Breast Cancer by Transdermal Delivery of α-Santalol through Breast Skin and Mammary Papilla (Nipple).

    Science.gov (United States)

    Dave, Kaushalkumar; Alsharif, Fahd M; Islam, Saiful; Dwivedi, Chandradhar; Perumal, Omathanu

    2017-09-01

    Almost all breast cancers originate from epithelial cells lining the milk ducts in the breast. To this end, the study investigated the feasibility of localized transdermal delivery of α-santalol, a natural chemopreventive agent to the breast. Different α-santalol formulations (cream, solution and microemulsion) were developed and the in vitro permeability was studied using excised animal (porcine and rat) and human breast skin/mammary papilla (nipple). The in vivo biodistribution and efficacy studies were conducted in female rats. A chemical carcinogenesis model of breast cancer was used for the efficacy studies. Phospholipid based α-santalol microemulsion showed the highest penetration through the nipple and breast skin. Delivery of α-santalol through the entire breast (breast skin and nipple) in vivo in rats resulted in significantly higher concentration in the mammary gland compared to transdermal delivery through the breast skin or nipple. There was no measurable α-santalol concentration in the blood. Transdermal delivery of α-santalol reduced the tumor incidence and tumor multiplicity. Furthermore, the tumor size was significantly reduced with α-santalol treatment. The findings from this study demonstrate the feasibility of localized transdermal delivery of α-santalol for chemoprevention of breast cancer.

  8. Chemotherapeutic effect of tangeretin, a polymethoxylated flavone studied in 7, 12-dimethylbenz(a)anthracene induced mammary carcinoma in experimental rats.

    Science.gov (United States)

    Lakshmi, A; Subramanian, S

    2014-04-01

    Globally, breast cancer is the second most prevalent cancer among women and its incidence is amplifying alarmingly. Since genetics is believed to account for only 10% of the reported cases, the environmental factors including diet are thought to play a significant role in predisposing breast cancer. Many bioactive compounds of plant origin have been reported for their anticancer potential. Tangeretin, a pentamethoxy flavone, is a naturally occurring phytoconstituent found to be present in significant amounts in the peel of citrus fruits. Tangeretin possess a wide array of pharmacological activities such as cytostatic, anti-proliferative and antioxidant properties. In the absence of systemic studies in the literature, the present study was aimed to evaluate the chemotherapeutic potential of tangeretin in 7, 12-dimethyl benz(a)anthracene (DMBA) induced mammary carcinoma in rats. Oral treatment of tangeretin (50 mg/kg BW) to breast tumor bearing rats daily for four weeks was found to be effective against DMBA induced mammary gland carcinogenesis in female Wistar rats. The increased activities of AST, ALT, ALP, ACP, 5'-ND, γ-GT and LDH in serum of control and experimental breast cancer rats were significantly (p induced breast cancer in rats.

  9. Redirection of Human Cancer Cells upon the Interaction with the Regenerating Mouse Mammary Gland Microenvironment

    Directory of Open Access Journals (Sweden)

    Sonia M. Rosenfield

    2013-01-01

    Full Text Available Tumorigenesis is often described as a result of accumulated mutations that lead to growth advantage and clonal expansion of mutated cells. There is evidence in the literature that cancer cells are influenced by the microenvironment. Our previous studies demonstrated that the mouse mammary gland is capable of redirecting mouse cells of non-mammary origins as well as Mouse Mammary Tumor Virus (MMTV-neu transformed cells toward normal mammary epithelial cell fate during gland regeneration. Interestingly, the malignant phenotype of MMTV-neu transformed cells was suppressed during serial transplantation experiments. Here, we discuss our studies that demonstrated the potential of the regenerating mouse mammary gland to redirect cancer cells of different species into a functional tumor-free mammary epithelial cell progeny. Immunochemistry for human specific CD133, mitochondria, cytokeratins as well as milk proteins and FISH for human specific probe identified human epithelial cell progeny in ducts, lobules, and secretory acini. Fluorescent In Situ Hybridization (FISH for human centromeric DNA and FACS analysis of propidium iodine staining excluded the possibility of mouse-human cell fusion. To our knowledge this is the first evidence that human cancer cells of embryonic or somatic origins respond to developmental signals generated by the mouse mammary gland microenvironment during gland regeneration in vivo.

  10. Automatic Tracing and Segmentation of Rat Mammary Fat Pads in MRI Image Sequences Based on Cartoon-Texture Model

    Institute of Scientific and Technical Information of China (English)

    TU Shengxian; ZHANG Su; CHEN Yazhu; Freedman Matthew T; WANG Bin; XUAN Jason; WANG Yue

    2009-01-01

    The growth patterns of mammary fat pads and glandular tissues inside the fat pads may be related with the risk factors of breast cancer.Quantitative measurements of this relationship are available after segmentation of mammary pads and glandular tissues.Rat fat pads may lose continuity along image sequences or adjoin similar intensity areas like epidermis and subcutaneous regions.A new approach for automatic tracing and segmentation of fat pads in magnetic resonance imaging (MRI) image sequences is presented,which does not require that the number of pads be constant or the spatial location of pads be adjacent among image slices.First,each image is decomposed into cartoon image and texture image based on cartoon-texture model.They will be used as smooth image and feature image for segmentation and for targeting pad seeds,respectively.Then,two-phase direct energy segmentation based on Chan-Vese active contour model is applied to partitioning the cartoon image into a set of regions,from which the pad boundary is traced iteratively from the pad seed.A tracing algorithm based on scanning order is proposed to accurately trace the pad boundary,which effectively removes the epidermis attached to the pad without any post processing as well as solves the problem of over-segmentation of some small holes inside the pad.The experimental results demonstrate the utility of this approach in accurate delineation of various numbers of mammary pads from several sets of MRI images.

  11. Use of a Novel Embryonic Mammary Stem Cell Gene Signature to Improve Human Breast Cancer Diagnostics and Therapeutic Decision Making

    Science.gov (United States)

    2014-10-01

    SUBTITLE Use of a Novel Embryonic Mammary Stem Cell Gene Signature to Improve Human Breast Cancer Diagnostics and Therapeutic Decision Making Improve...to determine whether Fetal Mammary Stem Cell (fMaSC) signatures correlate with response to chemotherapy and metastasis in different breast cancer...positioned to achieve its aims. 15. SUBJECT TERMS Breast Cancer Prognosis, Mammary Stem Cells, Embryonic Development, Single Cell Transcriptomics 16

  12. Effects of maternal exposure to cow's milk high or low in isoflavones on carcinogen-induced mammary tumorigenesis among rat offspring.

    Science.gov (United States)

    Nielsen, Tina Skau; Purup, Stig; Wärri, Anni; Godschalk, Roger W; Hilakivi-Clarke, Leena

    2011-05-01

    We investigated whether maternal exposure during pregnancy to cow's milk containing endogenous estrogens and insulin-like growth factor 1 (IGF-1) and either high or low levels of isoflavones from dietary legumes (HIM and LIM, respectively) affected carcinogen-induced mammary carcinogenesis in female rat offspring. Pregnant Sprague-Dawley rats were given HIM, LIM, or tap water (control) from gestational day (GD) 11 until birth; hereafter all rats received tap water. Mammary tumorigenesis was induced by administrating 7,12-dimethylbenz[a]anthracene (DMBA) on postnatal day 50. No differences in maternal serum estradiol (P = 0.19) and IGF-1 levels (P = 0.15) at GD 19 or birth weight among the milk and water groups were seen, but estradiol, and IGF-1 levels and birth weight were numerically higher in the LIM group than in the HIM group. Puberty onset occurred earlier in the LIM offspring than in controls (P = 0.03). Although the high isoflavone content seemed to prevent the effect on circulating estradiol and IGF-1 levels and advanced puberty onset seen in the LIM group, HIM increased DMBA-DNA adducts in the mammary gland and tended to increase mammary tumorigenesis. In contrast, offspring exposed to LIM in utero, did not exhibit increased breast cancer risk, despite having higher estradiol and IGF-1 environment and consequently earlier puberty onset. These results indicate that the phytochemical content in the cow's milk, consumed by a pregnant dam, determines how milk affects the offspring.

  13. Comparative activities of p-nonylphenol and diethylstilbestrol in noble rat mammary gland and uterotrophic assays.

    Science.gov (United States)

    Odum, J; Pyrah, I T; Foster, J R; Van Miller, J P; Joiner, R L; Ashby, J

    1999-04-01

    Colerangle and Roy (1996, Endocrine 4, 115-122) have described the apparent ability of both diethylstilbestrol (DES) and p-nonylphenol (NP) to cause extensive cell proliferation and lobular development in the mammary glands of young adult Noble rats. The chemicals were administered over 11 days via subcutaneously implanted minipumps. The dose level of DES used (0.076 mg/kg/day) was about 70 times higher than its minimum detection level in rodent uterotrophic and reproductive toxicology studies. In contrast, the lowest active dose level of NP (0.073 mg/kg/day) in the Noble rat mammary gland study was about 600 times lower than its minimum detection level in rat uterotrophic and multigeneration studies. The apparent enhanced sensitivity of the Noble rat mammary gland to the estrogenic activity of NP was considered worthy of further study. Ovariectomized Noble rat uterotrophic assays with NP (minimum detection level approximately 40 mg/kg/day, 3 or 11 days, oral gavage) revealed similar assay sensitivity to that observed for earlier immature and ovariectomized Alderley Park (AP) rat uterotrophic assays of this chemical. The response of the ovariectomized Noble rat uterotrophic assay to DES and estradiol was also as expected from earlier immature AP rat assays. It is concluded that the general sensitivity to estrogens of the Noble rat and the AP rat is similar. A repeat of the Noble rat mammary gland study with DES (11 x 0.076 mg/kg/day) and NP (11 x either 0.073 or 53.2 mg/kg/day), as originally reported by Colerangle and Roy (1996), revealed a strong positive response to DES and no response to NP. It is concluded that the minimum detection level of NP as a weakly estrogenic material in the rat should be based on the results of rat uterotrophic and multigeneration studies and therefore be set at approximately 40 mg/kg/day. It is also concluded that induced S-phase in the rodent mammary gland is best monitored using BRDU, as opposed to PCNA staining, and that use of

  14. Key signalling nodes in mammary gland development and cancer. Mitogen-activated protein kinase signalling in experimental models of breast cancer progression and in mammary gland development.

    Science.gov (United States)

    Whyte, Jacqueline; Bergin, Orla; Bianchi, Alessandro; McNally, Sara; Martin, Finian

    2009-01-01

    Seven classes of mitogen-activated protein kinase (MAPK) intracellular signalling cascades exist, four of which are implicated in breast disease and function in mammary epithelial cells. These are the extracellular regulated kinase (ERK)1/2 pathway, the ERK5 pathway, the p38 pathway and the c-Jun N-terminal kinase (JNK) pathway. In some forms of human breast cancer and in many experimental models of breast cancer progression, signalling through the ERK1/2 pathway, in particular, has been implicated as being important. We review the influence of ERK1/2 activity on the organised three-dimensional association of mammary epithelial cells, and in models of breast cancer cell invasion. We assess the importance of epidermal growth factor receptor family signalling through ERK1/2 in models of breast cancer progression and the influence of ERK1/2 on its substrate, the oestrogen receptor, in this context. In parallel, we consider the importance of these MAPK-centred signalling cascades during the cycle of mammary gland development. Although less extensively studied, we highlight the instances of signalling through the p38, JNK and ERK5 pathways involved in breast cancer progression and mammary gland development.

  15. Incidental radiation to uninvolved internal mammary lymph nodes in breast cancer.

    Science.gov (United States)

    Arora, Divya; Frakes, Jessica; Scott, Jacob; Opp, Daniel; Johnson, Carol; Song, Juhee; Harris, Eleanor

    2015-06-01

    Routine treatment of clinically uninvolved internal mammary nodes in breast cancer patients requiring post-mastectomy radiation therapy is controversial. The purpose of this study was to measure the incidental radiation dose to the internal mammary lymph nodes not included in the planning target volume (PTV) in women with breast cancer receiving post-mastectomy radiation therapy. This retrospective protocol utilized CT-based 3D conformal treatment plans. Fifty consecutive patients were included in the analysis: 25 left breast and 25 right breast patients. 3D conformal treatment plans chest wall tangent fields and matched supraclavicular were used. All plans were prescribed to a total dose of 50 Gy in 25 fractions to the chest wall and 46 Gy in 23 fractions to the supraclavicular field. The internal mammary node chain was intentionally not included in the target volume. For purposes of this study, internal mammary vessels were contoured following the Radiation Therapy Oncologist Group atlas with a 7-mm PTV expansion, utilizing original CT simulation images. The internal mammary nodes were contoured in between the first 3 and first 5 intercostal spaces for comparison. Percent volume of internal mammary node PTV receiving 95 % of the prescribed dose (47.5 Gy) with 7-mm expansion and first 5 intercostal spaces for all patients was 25.2 % (range 0.04-97.6 %, standard deviation (SD) 23.5). The mean internal mammary node dose for all patients was 24.98 Gy (range 3.54-55.93 Gy, SD 16). Results of this study suggest the incidental dose to the internal mammary nodes does not achieve clinically significant therapeutic levels in post-mastectomy breast cancer patients treated with standard 3D conformal radiation therapy chest wall irradiation. If risk factors for microscopic involvement are present, internal mammary nodes must be specifically included in target volumes in order to be adequately treated.

  16. Mammary fat of breast cancer: gene expression profiling and functional characterization.

    Science.gov (United States)

    Wang, Fengliang; Gao, Sheng; Chen, Fei; Fu, Ziyi; Yin, Hong; Lu, Xun; Yu, Jing; Lu, Cheng

    2014-01-01

    Mammary fat is the main composition of breast, and is the most probable candidate to affect tumor behavior because the fat produces hormones, growth factors and adipokines, a heterogeneous group of signaling molecules. Gene expression profiling and functional characterization of mammary fat in Chinese women has not been reported. Thus, we collected the mammary fat tissues adjacent to breast tumors from 60 subjects, among which 30 subjects had breast cancer and 30 had benign lesions. We isolated and cultured the stromal vascular cell fraction from mammary fat. The expression of genes related to adipose function (including adipogenesis and secretion) was detected at both the tissue and the cellular level. We also studied mammary fat browning. The results indicated that fat tissue close to malignant and benign lesions exhibited distinctive gene expression profiles and functional characteristics. Although the mammary fat of breast tumors atrophied, it secreted tumor growth stimulatory factors. Browning of mammary fat was observed and browning activity of fat close to malignant breast tumors was greater than that close to benign lesions. Understanding the diversity between these two fat depots may possibly help us improve our understanding of breast cancer pathogenesis and find the key to unlock new anticancer therapies.

  17. Mammary fat of breast cancer: gene expression profiling and functional characterization.

    Directory of Open Access Journals (Sweden)

    Fengliang Wang

    Full Text Available Mammary fat is the main composition of breast, and is the most probable candidate to affect tumor behavior because the fat produces hormones, growth factors and adipokines, a heterogeneous group of signaling molecules. Gene expression profiling and functional characterization of mammary fat in Chinese women has not been reported. Thus, we collected the mammary fat tissues adjacent to breast tumors from 60 subjects, among which 30 subjects had breast cancer and 30 had benign lesions. We isolated and cultured the stromal vascular cell fraction from mammary fat. The expression of genes related to adipose function (including adipogenesis and secretion was detected at both the tissue and the cellular level. We also studied mammary fat browning. The results indicated that fat tissue close to malignant and benign lesions exhibited distinctive gene expression profiles and functional characteristics. Although the mammary fat of breast tumors atrophied, it secreted tumor growth stimulatory factors. Browning of mammary fat was observed and browning activity of fat close to malignant breast tumors was greater than that close to benign lesions. Understanding the diversity between these two fat depots may possibly help us improve our understanding of breast cancer pathogenesis and find the key to unlock new anticancer therapies.

  18. Mixtures of environmentally relevant endocrine disrupting chemicals affect mammary gland development in female and male rats

    DEFF Research Database (Denmark)

    Mandrup, Karen Riiber; Johansson, Hanna Katarina Lilith; Boberg, Julie

    2015-01-01

    Estrogenic chemicals are able to alter mammary gland development in female rodents, but little is known on the effects of anti-androgens and mixtures of endocrine disrupting chemicals (EDCs) with dissimilar modes of action. Pregnant rat dams were exposed during gestation and lactation to mixtures...... and the mRNA level of matrix metalloproteinase-3, which may be a potential biomarker for increased outgrowth. Mixtures of EDCs gave rise to ductal hyperplasia in adult males. Adult female mammary glands of the TotalMix group showed morphological changes possibly reflecting increased prolactin levels...

  19. Relationship between immune state and tumor growth rate in rats bearing progressive and non-progressive mammary tumors.

    Science.gov (United States)

    Remedi, M M; Hliba, E; Demarchi, M; Depiante-Depaoli, M

    1998-08-01

    Impaired immune responses occur frequently in cancer patients or in tumor-bearing animals, but the mechanisms of the tumor-induced immune defects remain poorly understood. The aim of the present study was to determine the relevance of the immune system in the control of tumor growth. We have developed a model of progressive and non-progressive mammary tumor, chemically induced in female Wistar rats. In this model we evaluated the development of an immune response after immunization of rats bearing progressive and non-progressive tumors with a non-related antigen, such as sheep red blood cells. We also studied the activation state of peritoneal macrophages from animals bearing tumors by evaluating the production of free radicals. Our findings indicated that the cell-mediated immunity in rats bearing progressive tumors fails to respond to heterologous antigen in vivo, as demonstrated by a negative delayed-type hypersensitivity reaction, and is accompanied by minor nitric oxide production by peritoneal exudate cells as well as a lower capacity for macrophage activation. The study of non-progressive tumor-bearing rats indicated that the cell-mediated immune response was intact and an activated state of macrophages was found in vivo. The results described in this paper should be taken into account when therapies based on cancer vaccines are chosen for the treatment of cancer.

  20. Mammary Development and Breast Cancer: A Wnt Perspective

    OpenAIRE

    Qing Cissy Yu; Verheyen, Esther M.; Yi Arial Zeng

    2016-01-01

    The Wnt pathway has emerged as a key signaling cascade participating in mammary organogenesis and breast oncogenesis. In this review, we will summarize the current knowledge of how the pathway regulates stem cells and normal development of the mammary gland, and discuss how its various components contribute to breast carcinoma pathology.

  1. Identification and characterization of cancer stem cells in canine mammary tumors.

    Science.gov (United States)

    Rybicka, Agata; Król, Magdalena

    2016-12-19

    Cancer stem cells (CSC) represent a small subpopulation of cells in malignant tumors that possess the unique ability to self-renew, differentiate and resist chemo- and radiotherapy. These cells have been postulated to be the basis for some of the difficulties in treating cancer, and therefore, numerous approaches have been developed to specifically target and eliminate CSC in diverse types of cancer, including breast cancer. Spontaneously occurring mammary tumors in canines share clinical and molecular similarities with the human counterpart, making the dog a potentially powerful model for the study of human breast cancer and clinical trials. Studies focused on canine mammary CSC might therefore enhance our understanding of the biology and possible treatment of the disease in both dogs and humans. In this review, we discuss various approaches currently in use to isolate and characterize canine mammary CSC.

  2. Review: Animal models of N-Methyl-N-nitrosourea-induced mammary cancer and retinal degeneration with special emphasis on therapeutic trials.

    Science.gov (United States)

    Tsubura, Airo; Lai, Yen-Chang; Miki, Hisanori; Sasaki, Tomo; Uehara, Norihisa; Yuri, Takashi; Yoshizawa, Katsuhiko

    2011-01-01

    N-Methyl-N-nitrosourea (MNU) is a direct-acting alkylating agent that interacts with DNA. Accumulation of mutations may enhance cancer risk in target organs or cause cell death in susceptible tissues or cells when excessive DNA damage is not repaired. MNU targets various organs in a variety of animal species. MNU-induced carcinogenesis can be used as organ-specific animal models for human cancer, and MNU has been most extensively utilized for the induction of mammary cancer in rats. MNU-induced rat mammary tumors possess many similarities to those of human breast cancer, and the model is utilized for screening cancer modulators. MNU-induced cell disruption is also seen in several organs and tissues, especially when MNU is applied before maturity. However, photoreceptor cells in adults are highly sensitive to MNU, which causes cell death due to apoptosis. MNU-induced photoreceptor apoptosis mimics human retinitis pigmentosa and can be used for studies of therapeutic intervention. In this review, the targets of MNU in various animal species are described, and special emphasis is given to therapeutic trials against MNU-induced mammary cancer and retinal degeneration in animal models.

  3. A Comparative Approach of Tumor-Associated Inflammation in Mammary Cancer between Humans and Dogs

    Directory of Open Access Journals (Sweden)

    Maria Isabel Carvalho

    2016-01-01

    Full Text Available Infiltrating cells of the immune system are widely accepted to be generic constituents of tumor microenvironment. It has been well established that the development of mammary cancer, both in humans and in dogs, is associated with alterations in numbers and functions of immune cells at the sites of tumor progression. These tumor infiltrating immune cells seem to exhibit exclusive phenotypic and functional characteristics and mammary cancer cells can take advantage of signaling molecules released by them. Cancer related inflammation has an important role in mammary carcinogenesis, contributing to the acquisition of core hallmark capabilities that allow cancer cells to survive, proliferate, and disseminate. Indeed, recent studies in human breast cancer and in canine mammary tumors have identified a growing list of signaling molecules released by inflammatory cells that serve as effectors of their tumor-promoting actions. These include the COX-2, the tumor EGF, the angiogenic VEGF, other proangiogenic factors, and a large variety of chemokines and cytokines that amplify the inflammatory state. This review describes the intertwined signaling pathways shared by T-lymphocytic/macrophage infiltrates and important tissue biomarkers in both human and dog mammary carcinogenesis.

  4. A Comparative Approach of Tumor-Associated Inflammation in Mammary Cancer between Humans and Dogs.

    Science.gov (United States)

    Carvalho, Maria Isabel; Silva-Carvalho, Ricardo; Pires, Isabel; Prada, Justina; Bianchini, Rodolfo; Jensen-Jarolim, Erika; Queiroga, Felisbina L

    2016-01-01

    Infiltrating cells of the immune system are widely accepted to be generic constituents of tumor microenvironment. It has been well established that the development of mammary cancer, both in humans and in dogs, is associated with alterations in numbers and functions of immune cells at the sites of tumor progression. These tumor infiltrating immune cells seem to exhibit exclusive phenotypic and functional characteristics and mammary cancer cells can take advantage of signaling molecules released by them. Cancer related inflammation has an important role in mammary carcinogenesis, contributing to the acquisition of core hallmark capabilities that allow cancer cells to survive, proliferate, and disseminate. Indeed, recent studies in human breast cancer and in canine mammary tumors have identified a growing list of signaling molecules released by inflammatory cells that serve as effectors of their tumor-promoting actions. These include the COX-2, the tumor EGF, the angiogenic VEGF, other proangiogenic factors, and a large variety of chemokines and cytokines that amplify the inflammatory state. This review describes the intertwined signaling pathways shared by T-lymphocytic/macrophage infiltrates and important tissue biomarkers in both human and dog mammary carcinogenesis.

  5. Photodynamic therapy for the treatment of induced mammary tumor in rats.

    Science.gov (United States)

    Ferreira, Isabelle; Ferreira, Juliana; Vollet-Filho, José Dirceu; Moriyama, Lilian T; Bagnato, Vanderlei S; Salvadori, Daisy Maria Favero; Rocha, Noeme S

    2013-02-01

    The objective of this work was to evaluate photodynamic therapy (PDT) by using a hematoporphyrin derivative as a photosensitizer and light-emitting diodes (LEDs) as light source in induced mammary tumors of Sprague-Dawley (SD) rats. Twenty SD rats with mammary tumors induced by DMBA were used. Animals were divided into four groups: control (G1), PDT only (G2), surgical removal of tumor (G3), and submitted to PDT immediately after surgical removal of tumor (G4). Tumors were measured over 6 weeks. Lesions and surgical were LEDs lighted up (200 J/cm(2) dose). The light distribution in vivo study used two additional animals without mammary tumors. In the control group, the average growth of tumor diameter was approximately 0.40 cm/week. While for PDT group, a growth of less than 0.15 cm/week was observed, suggesting significant delay in tumor growth. Therefore, only partial irradiation of the tumors occurred with a reduction in development, but without elimination. Animals in G4 had no tumor recurrence during the 12 weeks, after chemical induction, when compared with G3 animals that showed 60 % recurrence rate after 12 weeks of chemical induction. PDT used in the experimental model of mammary tumor as a single therapy was effective in reducing tumor development, so the surgery associated with PDT is a safe and efficient destruction of residual tumor, preventing recurrence of the tumor.

  6. Erythrocyte Protoporphyrin Fluorescence as a Biomarker to Monitor the Anticancer Effect of Semecarpus Anacardium in DMBA Induced Mammary Carcinoma Rat Model.

    Science.gov (United States)

    Khan, Haseena Banu Hedayathullah; Vani, S; Palanivelu, Shanthi; Panchanadham, Sachdanandam

    2015-07-01

    Endogenous fluorescence has been proposed as a means of aiding the diagnosis of various malignancies. It has been suggested that erythrocytes may be the carriers of fluorophors that accumulate in cancer tissue and may be useful in the diagnosis and treatment of malignancies. Hence, the present study was designed to explore the spectrofluorimetric analysis of blood components as a marker for the analysis of mammary carcinoma treatment and also to bring about the protective effect of the drug Semecarpus anacardium on oxidative stress mediated damage of erythrocytes. Fluorescence spectra of the blood components were studied and also the level of lipid per oxides and antioxidant enzymes status in erythrocytes were determined in DMBA induced mammary carcinoma rats treated with Semecarpus anacardium Linn nut milk extract. Fluorescence emission spectroscopy of blood components are altered under cancer conditions and the drug effectively ameliorated these alterations in mammary carcinoma induced rats. The drug also effectively reduced the oxidative stress induced erythrocyte damage thereby restoring the erythrocytes antioxidant status. These results suggest that erythrocytes may be the carriers of fluorophors that accumulate in cancer tissue and hence acts as new biomarkers for the diagnosis and treatment.

  7. New methods in mammary gland development and cancer: proteomics, epigenetics, symmetric division and metastasis

    OpenAIRE

    Bentires-Alj, Mohamed; Glukhova, Marina; Hynes, Nancy; Vivanco, Maria dM.

    2012-01-01

    The European Network for Breast Development and Cancer (ENBDC) meeting on 'Methods in Mammary Gland Development and Cancer' has become an annual international rendezvous for scientists with interests in the normal and neoplastic breast. The fourth meeting in this series, held in April in Weggis, Switzerland, focused on proteomics, epigenetics, symmetric division, and metastasis.

  8. A new ligand for the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), GW7845, inhibits rat mammary carcinogenesis.

    Science.gov (United States)

    Suh, N; Wang, Y; Williams, C R; Risingsong, R; Gilmer, T; Willson, T M; Sporn, M B

    1999-11-15

    We have tested a new ligand for peroxisome proliferator-activated receptor-gamma, GW7845, as an inhibitor of experimental mammary carcinogenesis, using the classic rat model with nitrosomethylurea as carcinogen. Rats were first treated with a single dose of nitrosomethylurea (50 mg/kg body weight, i.p.). Starting 1 week later, they were fed GW7845, at either 60 or 30 mg/kg of diet, for 2 months. This agent significantly reduced tumor incidence, tumor number, and tumor weight at both doses. This is the first report of the use of a ligand for peroxisome proliferator-activated receptor-gamma to prevent experimental breast cancer.

  9. Antiproliferative and Apoptotic Effects of Shemamruthaa, a Herbal Preparation, in 7,12-Dimethylbenz(a)Anthracene-Induced Breast Cancer Rats.

    Science.gov (United States)

    Purushothaman, Ayyakkannu; Nandhakumar, Elumalai; Shanthi, Palanivelu; Sachidanandam, Thiruvaiyaru Panchanatham

    2015-10-01

    A herbal preparation, Shemamruthaa (SM), was formulated to investigate the molecular mechanism by which it exhibits anticancer effects in mammary carcinoma bearing rats. Female Sprague-Dawley rats were used for the study, and mammary carcinoma was induced by administration of 7,12-dimethylbenz(a)anthracene, intragastrically. After 3 months of induction period, the rats were treated with SM (400 mg/kg body weight) for 14 days. Our study shows that SM-treated mammary carcinoma rats showed regression in tumor volume with concomitant increase in p(53), Bax, caspase-3, and caspase-9 mRNA and protein levels compared with mammary carcinoma-induced rats. Proliferating cell nuclear antigen and anti-apoptotic Bcl-2 were markedly increased in mammary carcinoma-induced rats, whereas the SM treatment significantly decreased the expression of these proteins. The expression pattern of apoptotic signaling molecules analyzed in the present study signifies the therapeutic efficacy of SM against breast cancer.

  10. Prediction of Breast Cancer Risk by Aberrant Methylation in Mammary Duct Lavage

    Science.gov (United States)

    2006-07-01

    DNA was extracted from two aneuploid tumor cells lines ( cervical cancer cell line HeLa [13] and breast cancer cell line HCC1806 [14]), two diploid...Breast Cancer Res Treat 2000;61:139–43. [4] Kersting M, Friedl C, Kraus A, Behn M, Pankow W, Schuermann M. Differential frequencies of p16 (INK4a) promoter...DAMD17-01-1-0421 TITLE: Prediction of Breast Cancer Risk by Aberrant Methylation in Mammary Duct Lavage PRINCIPAL INVESTIGATOR

  11. Pregnancy-dependent initiation in tumorigenesis of Wistar rat mammary glands by sup 60 Co-irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Inano, Hiroshi; Suzuki, Keiko; Ishii-Ohba, Hiroko; Ikeda, Kiyomi (National Inst. of Radiological Sciences, Chiba (Japan)); Wakabayashi, Katsumi (Gunma Univ., Maebashi (Japan). Hormone Assay Center)

    1991-06-01

    Pregnant Wistar rats received whole body irradiation with 260 cGy {gamma}-rays at days 7, 14 and 20 of pregnancy and then were treated with diethylstilbestrol (DES) for 1 year. The highest incidence (92.9%) for tumorigenesis of mammary glands was observed in the rats irradiated in late pregnancy. Histological examination showed that tumors were classified as fibroadenoma and adenocarcinoma. To determine the reasons for specific induction of mammary tumors by irradiation in late pregnancy, hormone concentrations in serum and estrogen receptors in mammary glands during pregnancy were measured. Concentrations of estradiol, progesterone, 11-deoxycorticosterone and placental lactogen at day 20 were higher than at days 7 and/or 14, but no difference was observed in the concentrations of prolactin and thyroid-stimulating hormone during pregnancy. The estrogen receptor in mammary glands at day 20 was indicated to have the highest affinity and the highest binding capacity during pregnancy. Normal mammary glands at day 20 were suggested to have more abundant epithelial cells in the mammary lobes than those at days 7 and 14. The data suggest that the critical requirements for the initiation of tumorigenesis by {gamma}-rays are dependent upon the differentiated state of mammary glands exposed to various hormones, and that the concentration and persistence of the synthetic estrogen (DES) are necessary for the promotion of tumorigenesis of the irradiated mammary glands. (Author).

  12. Effect of PSC 833, an inhibitor of P-glycoprotein on N-methyl-N-nitrosourea induced mammary carcinogenesis in rats.

    Science.gov (United States)

    Kankesan, Janarthanan; Vanama, Ramesh; Yusuf, Aroon; Thiessen, Jake J; Ling, Victor; Rao, Prema M; Rajalakshmi, Srinivasan; Sarma, Dittakavi S R

    2004-03-01

    Studies in our laboratory on the role of P-glycoprotein (Pgp, coded by mdr1 gene) have led to the hypothesis that over-expression of Pgp is closely associated with the development of cancer. It was conceived therefore that inhibitors of Pgp should inhibit the development of cancer. We have reported that PSC833 (PSC), a potent inhibitor of Pgp, inhibits the development of liver cancer in rats. Similarly, based on the intrinsic over-expression of Pgp in experimental mammary carcinogenesis, we studied the effect of PSC on N-methyl-N-nitrosourea induced mammary cancer in female Sprague-Dawley rats. The study indicates that PSC at daily dietary doses of 15 (PSC15) and 30 mg/kg (PSC30) body wt resulted in dose-dependent inhibition of the incidence as well as the growth of mammary tumors. Compared with controls, PSC15 and PSC30 inhibited: (i) mean tumor multiplicity by 32 and 67%, (ii) median tumor burden by 46 and 93% and (iii) incidence of ulcerated tumors by 40 and 82%, respectively. Most remarkably, PSC delayed median tumor incidence by 8 weeks, and exerted a 100% inhibitory effect on the incidence of large tumors, 4 cm(3) and greater. In all the cases, although the inhibitory effect of PSC was evident at both doses, only PSC30 exhibited statistical significance. A possible compounding effect that was also observed in PSC30-treated rats was a decrease in body weight gain not attributed to diminished food consumption. All in all, consistent with recent reports, which have demonstrated inhibition of cancer development by compromising Pgp function, this study introduces a novel role for Pgp in breast cancer and potentially an unexplored therapeutic approach in treating the disease.

  13. MTA family of transcriptional metaregulators in mammary gland morphogenesis and breast cancer.

    Science.gov (United States)

    Singh, Rajesh R; Kumar, Rakesh

    2007-09-01

    Since breast cancer and its associated metastasis are a global health problem and a major cause of mortality among women, research efforts to understand the development, morphogenesis, and functioning of the mammary gland are a high priority. Myriad signaling pathways, transcription factors, and associated transcriptional coregulators have been identified in both normal functioning and neoplastic transformation of the mammary gland. The discovery of the metastasis tumor antigen 1 (MTA1) gene, its overexpression in cancer and metastasis and its subsequent identification as an integral part of the chromatin remodeling complex heralded extensive research on its physiological role. Subsequent identification of additional gene family members, namely MTA1s, MTA2, and MTA3, and their functions in the cell has resulted in the establishment of the significance of the MTA family. The role of these proteins in modulating hormonal responses in normal mammary glands and in breast cancer has resulted in their identification as important molecular markers and potential therapeutic targets.

  14. Modulation of mammary gland development in prepubertal male rats exposed to genistein and methoxychlor.

    Science.gov (United States)

    You, Li; Sar, Madhabananda; Bartolucci, Erika J; McIntyre, Barry S; Sriperumbudur, Rajagopal

    2002-04-01

    The estrogenic isoflavone genistein is a common dietary component that has been shown to affect reproductive development in experimental animals at high doses. The objective of the present study was to examine interactions of genistein and the hormonally active pesticide methoxychlor on mammary gland development in juvenile rats. Timed-pregnant Sprague-Dawley rats were fed a soy- and alfalfa-free diet containing different combinations of genistein (300 and 800 ppm) and methoxychlor (800 ppm). Rats were fed these diets starting on gestation day (GD)1 and continuing through pregnancy and lactation until postnatal day (PND) 22, when the pups were killed. Inguinal mammary glands from both female and male pups were processed as whole-mount preparations for morphometric analysis. The total glandular area and the numbers of branch points, lateral buds, and terminal end buds in the male rats were found to be significantly greater in the groups exposed to methoxychlor than those exposed to genistein only. These effects were not observed in the female rats. In the male rats, methoxychlor had the most prominent effect on elongating the glandular ducts, while genistein enhanced the ductile branching. The 2 compounds in combination promoted the development of alveolar-lobular structure, an effect not observed with either compound alone. Immunostaining for proliferating cell nuclear antigen revealed a high percentage of immunopositive cells in the mammary epithelia of the males exposed to methoxychlor and genistein (800 ppm) compared to the controls. While no significant changes in serum levels of mammotrophic hormones were detected, increased immunostaining for insulin-like growth factor-1 receptor, estrogen receptor alpha, and progesterone receptor in the genistein + methoxychlor group suggested that local factors involved in regulating mammary growth may have played a role in propagating the endocrine effects of these two compounds. These results indicated that the mammary

  15. Benign and malignant mammary tumors induced by DMBA in female Wistar rats

    OpenAIRE

    Dias, M.; Cabrita, S; Sousa, E.; França, B; Patrício, J; Oliveira, CF

    1999-01-01

    This study pretends to characterize 7, 12-dimetylbenz[a]anthracene-induced benign and malignant tumors. One hundred and twenty female Wistar rats were randomly allocated to two groups: Control Group and Induction Group; IG animals were given a single dose of DMBA and killed 24 weeks after. Other tumors besides breast tumors were diagnosed, mainly tumors of the salivary glands and ovarian benign epithelial tumors. Incidence of breast disorders was about 60%. Macroscopic mammary tumors varied i...

  16. Effect of dietary protein quality and feeding level on milk secretion and mammary protein synthesis in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Sampson, D.A.; Jansen, G.R.

    1985-04-01

    Protein synthesis was studied in mammary tissue of rats fed diets deficient in protein quality and/or restricted in food intake throughout gestation and lactation. Diets containing 25% wheat gluten (WG), wheat gluten plus lysine and threonine (WGLT), or casein (C) were pair-fed from conception until day 15 of lactation at 100% or 85% of WG ad libitum consumption (PF100 and PF85, respectively). A seventh group was fed C ad libitum. Rates of protein synthesis were measured in vivo at day 15 of lactation from incorporation of (3-/sup 3/H)phenylalanine. At both PF100 and PF85, fractional and absolute rates of mammary gland protein synthesis were two- to three-fold higher in rats fed C than in those fed WG. Pup weights showed similar treatment effects. Both mammary protein synthesis rates and pup weights were significantly higher in rats fed C at PF85 than rats fed WG ad libitum. Food restriction from PF100 to PF85 depressed pup weights and mammary protein synthesis rates in rats fed WGLT, but had no effect in rats fed WG. These results demonstrate that when food intake is restricted, improvement of protein quality of the maternal diet increases milk output in the rat in association with increased rates of mammary protein synthesis.

  17. Anti-hyperplasia effects of Rosa rugosa polyphenols in rats with hyperplasia of mammary gland.

    Science.gov (United States)

    Chen, Tao; Li, Jingjing; Chen, Jinglou; Song, Hongping; Yang, Chuhao

    2015-03-01

    Rosa rugosa (Thunb.) is used in Chinese traditional medicine with the functions of promoting blood circulation, relieving the depressed liver and attenuating breast disorders. This study was to investigate the anti-hyperplasia effects of the polyphenols-rich fraction from R. rugosa (FRR) in rat. Rat model of hyperplasia of mammary gland (HMG) was induced by intramuscularly injected with estrogen (0.5mg/kg/d) for 25 days, and followed with progestogen (5mg/kg/d) for another 5 days. Meanwhile, FRR was orally given for 30 days. Then, the levels of estradiol and oxidative stress were assessed. The mammary expressions of AKT and JNK were evaluated by Western blot analysis. The expressions of NFκB-p65, COX-2 and VEGF were measured by immunohistochemical analysis. The whole results indicated that FRR could exert anti-hyperplasia effects in rat via modulating the mammary expression of JNK and AKT, as well as alleviating the NFκB related oxidative stress and inflammatory responses.

  18. On the possible role of mammary-derived growth hormone in human breast cancer.

    Science.gov (United States)

    Thijssen, Jos H H

    2009-12-01

    The incidence of breast cancer has risen worldwide, especially in countries where it used to be low, very probably as a result of economic prosperity and changes in life-style. In women, the available data have resulted in the concept of progression from normal breast development to cancer through precursor lesions sensitive to hormones and growth factors that can be produced locally in the mammary gland, acting as paracrine or autocrine stimulating agents. The local endocrine environment in the breast can be different from the situation in the circulation. In the dog, growth hormone (GH) can be produced locally in the mammary glands and its production can be stimulated by progestins. This GH probably plays a paracrine role in the progesterone-induced proliferation and differentiation of mammary epithelium. There is increasing evidence that the local mammary progestin/GH-axis is operational not only in dogs but also in human breast cancer. No data are yet available on the production of mammary-derived GH in women.

  19. The mammary stem cell hierarchy: a looking glass into heterogeneous breast cancer landscapes.

    Science.gov (United States)

    Sreekumar, Amulya; Roarty, Kevin; Rosen, Jeffrey M

    2015-12-01

    The mammary gland is a dynamic organ that undergoes extensive morphogenesis during the different stages of embryonic development, puberty, estrus, pregnancy, lactation and involution. Systemic and local cues underlie this constant tissue remodeling and act by eliciting an intricate pattern of responses in the mammary epithelial and stromal cells. Decades of studies utilizing methods such as transplantation and lineage-tracing have identified a complex hierarchy of mammary stem cells, progenitors and differentiated epithelial cells that fuel mammary epithelial development. Importantly, these studies have extended our understanding of the molecular crosstalk between cell types and the signaling pathways maintaining normal homeostasis that often are deregulated during tumorigenesis. While several questions remain, this research has many implications for breast cancer. Fundamental among these are the identification of the cells of origin for the multiple subtypes of breast cancer and the understanding of tumor heterogeneity. A deeper understanding of these critical questions will unveil novel breast cancer drug targets and treatment paradigms. In this review, we provide a current overview of normal mammary development and tumorigenesis from a stem cell perspective.

  20. Citrus auraptene suppresses cyclin D1 and significantly delays N-methyl nitrosourea induced mammary carcinogenesis in female Sprague-Dawley rats

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    Grand Robert

    2009-07-01

    Full Text Available Abstract Background Breast cancer is a major problem in the United States leading to tens of thousands of deaths each year. Although citrus auraptene suppresses cancer in numerous rodent models, its role in breast cancer prevention previously has not been reported. Thus, our goal was to determine the anticarcinogenic effects of auraptene against breast cancer. Methods The effects of auraptene on cell proliferation of MCF-7 and MDA-MB-231 human breast carcinoma cells in culture was assessed by measuring metabolism of a substrate to a formazan dye. Dietary effects of auraptene on tumor incidence, multiplicity and latency were studied in the N-methyl nitrosourea (MNU induced mammary carcinogenesis model in female Sprague Dawley rats. The concentration of auraptene in rat tissues was analyzed by reverse phase HPLC. Cyclin D1 expression in MCF-7 cells and rat tumors was measured by western blot. Results Auraptene (500 ppm significantly delayed median time to tumor by 39 days compared to the MNU only group (p Conclusion Overall, these observations suggest that the predominant effect of auraptene was to delay the development of tumors possibly through the suppression of cyclin D1 expression. These results point to the potential chemopreventive effects of auraptene in mammary carcinogenesis.

  1. Prenatal exposure to BPA alters the epigenome of the rat mammary gland and increases the propensity to neoplastic development.

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    Eugen Dhimolea

    Full Text Available Exposure to environmental estrogens (xenoestrogens may play a causal role in the increased breast cancer incidence which has been observed in Europe and the US over the last 50 years. The xenoestrogen bisphenol A (BPA leaches from plastic food/beverage containers and dental materials. Fetal exposure to BPA induces preneoplastic and neoplastic lesions in the adult rat mammary gland. Previous results suggest that BPA acts through the estrogen receptors which are detected exclusively in the mesenchyme during the exposure period by directly altering gene expression, leading to alterations of the reciprocal interactions between mesenchyme and epithelium. This initiates a long sequence of altered morphogenetic events leading to neoplastic transformation. Additionally, BPA induces epigenetic changes in some tissues. To explore this mechanism in the mammary gland, Wistar-Furth rats were exposed subcutaneously via osmotic pumps to vehicle or 250 µg BPA/kg BW/day, a dose that induced ductal carcinomas in situ. Females exposed from gestational day 9 to postnatal day (PND 1 were sacrificed at PND4, PND21 and at first estrus after PND50. Genomic DNA (gDNA was isolated from the mammary tissue and immuno-precipitated using anti-5-methylcytosine antibodies. Detection and quantification of gDNA methylation status using the Nimblegen ChIP array revealed 7412 differentially methylated gDNA segments (out of 58207 segments, with the majority of changes occurring at PND21. Transcriptomal analysis revealed that the majority of gene expression differences between BPA- and vehicle-treated animals were observed later (PND50. BPA exposure resulted in higher levels of pro-activation histone H3K4 trimethylation at the transcriptional initiation site of the alpha-lactalbumin gene at PND4, concomitantly enhancing mRNA expression of this gene. These results show that fetal BPA exposure triggers changes in the postnatal and adult mammary gland epigenome and alters gene

  2. Met induces diverse mammary carcinomas in mice and is associated with human basal breast cancer

    OpenAIRE

    Graveel, Carrie R.; DeGroot, Jack D.; Su, Yanli; Koeman, Julie; Dykema, Karl; Leung, Samuel; Snider, Jacqueline; Davies, Sherri R.; Swiatek, Pamela J.; Cottingham, Sandra; Watson, Mark A.; Matthew J Ellis; Sigler, Robert E.; Furge, Kyle A.; Vande Woude, George F

    2009-01-01

    Understanding the signaling pathways that drive aggressive breast cancers is critical to the development of effective therapeutics. The oncogene MET is associated with decreased survival in breast cancer, yet the role that MET plays in the various breast cancer subtypes is unclear. We describe a knockin mouse with mutationally activated Met (Metmut) that develops a high incidence of diverse mammary tumors with basal characteristics, including metaplasia, absence of progesterone receptor and E...

  3. Integrated extracellular matrix signaling in mammary gland development and breast cancer progression.

    Science.gov (United States)

    Zhu, Jieqing; Xiong, Gaofeng; Trinkle, Christine; Xu, Ren

    2014-09-01

    Extracellular matrix (ECM), a major component of the cellular microenvironment, plays critical roles in normal tissue morphogenesis and disease progression. Binding of ECM to membrane receptor proteins, such as integrin, discoidin domain receptors, and dystroglycan, elicits biochemical and biomechanical signals that control cellular architecture and gene expression. These ECM signals cooperate with growth factors and hormones to regulate cell migration, differentiation, and transformation. ECM signaling is tightly regulated during normal mammary gland development. Deposition and alignment of fibrillar collagens direct migration and invasion of mammary epithelial cells during branching morphogenesis. Basement membrane proteins are required for polarized acinar morphogenesis and milk protein expression. Deregulation of ECM proteins in the long run is sufficient to promote breast cancer development and progression. Recent studies demonstrate that the integrated biophysical and biochemical signals from ECM and soluble factors are crucial for normal mammary gland development as well as breast cancer progression.

  4. Genomic profiling of murine mammary tumors identifies potential personalized drug targets for p53-deficient mammary cancers

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    Adam D. Pfefferle

    2016-07-01

    Full Text Available Targeted therapies against basal-like breast tumors, which are typically ‘triple-negative breast cancers (TNBCs’, remain an important unmet clinical need. Somatic TP53 mutations are the most common genetic event in basal-like breast tumors and TNBC. To identify additional drivers and possible drug targets of this subtype, a comparative study between human and murine tumors was performed by utilizing a murine Trp53-null mammary transplant tumor model. We show that two subsets of murine Trp53-null mammary transplant tumors resemble aspects of the human basal-like subtype. DNA-microarray, whole-genome and exome-based sequencing approaches were used to interrogate the secondary genetic aberrations of these tumors, which were then compared to human basal-like tumors to identify conserved somatic genetic features. DNA copy-number variation produced the largest number of conserved candidate personalized drug targets. These candidates were filtered using a DNA-RNA Pearson correlation cut-off and a requirement that the gene was deemed essential in at least 5% of human breast cancer cell lines from an RNA-mediated interference screen database. Five potential personalized drug target genes, which were spontaneously amplified loci in both murine and human basal-like tumors, were identified: Cul4a, Lamp1, Met, Pnpla6 and Tubgcp3. As a proof of concept, inhibition of Met using crizotinib caused Met-amplified murine tumors to initially undergo complete regression. This study identifies Met as a promising drug target in a subset of murine Trp53-null tumors, thus identifying a potential shared driver with a subset of human basal-like breast cancers. Our results also highlight the importance of comparative genomic studies for discovering personalized drug targets and for providing a preclinical model for further investigations of key tumor signaling pathways.

  5. Volatile organic metabolites identify patients with breast cancer, cyclomastopathy, and mammary gland fibroma.

    Science.gov (United States)

    Wang, Changsong; Sun, Bo; Guo, Lei; Wang, Xiaoyang; Ke, Chaofu; Liu, Shanshan; Zhao, Wei; Luo, Suqi; Guo, Zhigang; Zhang, Yang; Xu, Guowang; Li, Enyou

    2014-06-20

    The association between cancer and volatile organic metabolites in exhaled breaths has attracted increasing attention from researchers. The present study reports on a systematic study of gas profiles of metabolites in human exhaled breath by pattern recognition methods. Exhaled breath was collected from 85 patients with histologically confirmed breast disease (including 39 individuals with infiltrating ductal carcinoma, 25 individuals with cyclomastopathy and from 21 individuals with mammary gland fibroma) and 45 healthy volunteers. Principal component analysis and partial least squares discriminant analysis were used to process the final data. The volatile organic metabolites exhibited significant differences between breast cancer and normal controls, breast cancer and cyclomastopathy, and breast cancer and mammary gland fibroma; 21, 6, and 8 characteristic metabolites played decisive roles in sample classification, respectively (P fibroma patients, and patients with cyclomastopathy (P < 0.05). The identified three volatile organic metabolites associated with breast cancer may serve as novel diagnostic biomarkers.

  6. Mammary gland development and response to prenatal atrazine exposure in the Sprague Dawley and Long-Evans rats.

    Science.gov (United States)

    Mammary gland (MG) tumor development in Sprague Dawley (SD) rats is increased by longterm dietary exposure to the chlorotriazine herbicide atrazine (ATR). ATR is proposed to cause these changes in the adult SD rat by altering hormonally-regulated estrous cyclicity. In Long-Evans...

  7. Immunohistochemical analysis of oxidative stress and DNA repair proteins in normal mammary and breast cancer tissues

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    Nardulli Ann M

    2010-01-01

    Full Text Available Abstract Background During the course of normal cellular metabolism, oxygen is consumed and reactive oxygen species (ROS are produced. If not effectively dissipated, ROS can accumulate and damage resident proteins, lipids, and DNA. Enzymes involved in redox regulation and DNA repair dissipate ROS and repair the resulting damage in order to preserve a functional cellular environment. Because increased ROS accumulation and/or unrepaired DNA damage can lead to initiation and progression of cancer and we had identified a number of oxidative stress and DNA repair proteins that influence estrogen responsiveness of MCF-7 breast cancer cells, it seemed possible that these proteins might be differentially expressed in normal mammary tissue, benign hyperplasia (BH, ductal carcinoma in situ (DCIS and invasive breast cancer (IBC. Methods Immunohistochemistry was used to examine the expression of a number of oxidative stress proteins, DNA repair proteins, and damage markers in 60 human mammary tissues which were classified as BH, DCIS or IBC. The relative mean intensity was determined for each tissue section and ANOVA was used to detect statistical differences in the relative expression of BH, DCIS and IBC compared to normal mammary tissue. Results We found that a number of these proteins were overexpressed and that the cellular localization was altered in human breast cancer tissue. Conclusions Our studies suggest that oxidative stress and DNA repair proteins not only protect normal cells from the damaging effects of ROS, but may also promote survival of mammary tumor cells.

  8. Raman spectra of normal and cancerous mouse mammary gland tissue using near infrared excitation energy

    Science.gov (United States)

    Naik, Vaman; Serhatkulu, G. K.; Dai, H.; Shukla, N.; Weber, R.; Thakur, J. S.; Freeman, D. C.; Pandya, A. K.; Auner, G. W.; Naik, R.; Miller, R. F.; Cao, A.; Klein, M. D.; Rabah, R.

    2006-03-01

    Raman spectra of normal mammary gland tissues, malignant mammary gland tumors, and lymph nodes have been recorded using fresh tissue from mice. Tumors were induced in mice by subcutaneously injecting 4T1 BALB/c mammary tumor (a highly malignant) cell line. The Raman spectra were collected using the same tissues that were examined by histopathology for determining the cancerous/normal state of the tissue. Differences in various peak intensities, peak shifts and peak ratios were analyzed to determine the Raman spectral features that differentiate mammary gland tumors from non-tumorous tissue. Tissues that were confirmed by pathology as cancerous (tumors) show several distinctive features in the Raman spectra compared to the spectra of the normal tissues. For example, the cancerous tissues show Raman peaks at 621, 642, 1004, 1032, 1175 and 1208 cm-1 that are assignable to amino acids containing aromatic side-chains such as phenylalanine, tryptophan and tyrosine. Further, the cancerous tissues show a greatly reduced level of phospholipids compared to the normal tissues. The Raman spectral regions that are sensitive to pathologic alteration in the tissue will be discussed.

  9. Induction of mammary tumors in rat by intraperitoneal injection of NMU: histopathology and estral cycle influence.

    Science.gov (United States)

    Rivera, E S; Andrade, N; Martin, G; Melito, G; Cricco, G; Mohamad, N; Davio, C; Caro, R; Bergoc, R M

    1994-11-11

    In order to obtain an experimental model we induced mammary tumors in female Sprague-Dawley rats. The carcinogen N-nitroso-N-methylurea (NMU) was injected intraperitoneally (i.p.) at doses of 50 mg/kg body weight when animals were 50, 80 and 110 days old. Tumor sizes were measured with a caliper and their growth parameters and histopathological properties were tested. For 100 rats, 88.4% of developed lesions were ductal carcinomas, histologically classified as 52.8% cribiform variety, 30.6% solid carcinoma. Metastases in liver, spleen and lung were present. Other primary tumors were detected with low incidence. The influence of the rat estrous cycle during the first exposure to intraperitoneal NMU injection was studied. The latency period in estrus, proestrus and diestrus was 82 +/- 15, 77 +/- 18 and 79 +/- 18 days, respectively. Tumor incidence was significantly higher in estrus (95.2%) than proestrus (71.4%) or diestrus (77.4), (P rats.

  10. Effect of dietary supplementation on the prognostic value of urinary and serum 8-isoprostaglandin F2α in chemically-induced mammary carcinogenesis in the rat

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    Białek Sławomir

    2011-03-01

    Full Text Available Abstract Backround The aim of the present study was to assess the effects of zinc or copper and polyphenolic compounds on the 8-isoprostaglandin F2α concentration in the serum and urine of rats with mammary cancer (adenocarcinoma induced with 7,12-dimethylbenz[a]antracene. The research focused on the kinetics of alterations in urinary 8-isoPGF2α at the early stage of carcinogenesis as well as the influence of dietary factors on the process. The impact of selected compounds on the intensity of DMBA - induced carcinogenesis was also assessed. Result and conclusions Administration of DMBA, a compound that inducers mammary tumors in experimental animals, increased the serum and urinary 8-isoPGF2α levels in study rats. In the rat model, diet supplementation with zinc, combined with selected polyphenolic compounds (resveratrol or genistein yielded a statistically significant decrease in the rat serum and urinary biomarker concentration with a simultaneously significant stimulation of carcinogenesis. The results indicate that there is an inverse correlation between the intensity of DMBA-induced carcinogenicity and the level of 8-isoPGF2α in urine and serum of rats.

  11. Axillary and internal mammary sentinel lymph node biopsy in male breast cancer patients: case series and review

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    Cao X

    2015-06-01

    Full Text Available Xiaoshan Cao,1,2 Chunjian Wang,1 Yanbing Liu,1 Pengfei Qiu,1 Binbin Cong,1,2 Yongsheng Wang1 1Breast Cancer Center, Shandong Cancer Hospital and Institute, Jinan, Shandong, People’s Republic of China; 2School of Medicine and Life Sciences, Jinan University-Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China Abstract: Male breast cancer (MBC is considered as a rare disease that accounts for less than 1% of all breast cancers, and its treatment has been based on the evidence available from female breast cancer. Axillary sentinel lymph node biopsy (SLNB is now regarded as the standard of care for both female and male patients without clinical and imaging evidence of axillary lymph node metastases, while internal mammary SLNB has rarely been performed. Internal mammary chain metastasis is an independent prognostic predictor. Internal mammary SLNB should be performed to complete nodal staging and guide adjuvant therapy in MBC patients with preoperative lymphoscintigraphic internal mammary chain drainage. We report both axillary and internal mammary SLNB in two cases with MBC. Internal mammary sentinel lymph node did contain metastasis in one case. Keywords: male breast cancer, internal mammary lymph node, sentinel lymph node biopsy, case report

  12. Increased levels of interleukins 8 and 10 as findings of canine inflammatory mammary cancer.

    Science.gov (United States)

    de Andrés, Paloma Jimena; Illera, Juan Carlos; Cáceres, Sara; Díez, Lucía; Pérez-Alenza, Maria Dolores; Peña, Laura

    2013-04-15

    Inflammatory mammary cancer (IMC) is a distinct form of mammary cancer that affects dogs and women [in humans, IMC is known as inflammatory breast cancer (IBC)], and is characterized by a sudden onset and an aggressive clinical course. Spontaneous canine IMC shares epidemiologic, histopathological and clinical characteristics with the disease in humans and has been proposed as the best spontaneous animal model for studying IBC, although several aspects remain unstudied. Interleukins (ILs) play an important role in cancer as potential modulators of angiogenesis, leukocyte infiltration and tumor growth. The aims of the present study were to assess serum and tumor levels of several ILs (IL-1α, IL-1β, IL-6, IL-8 and IL-10) by enzyme-immunoassay in dogs bearing benign and malignant mammary tumors, including dogs with IMC, for a better understanding of this disease. Forty-eight dogs were prospectively included. Animals consisted of 7 healthy Beagles used as donors for normal mammary glands (NMG) and serum controls (SCs), 10 dogs with hyperplasias and benign mammary tumors (HBMT), 24 with non-inflammatory malignant mammary tumors (non-IMC MMT) and 7 dogs with clinical and pathological IMC. IL-8 (serum) and IL-10 (serum and tissue homogenate) levels were higher in the dogs with IMC compared with the non-IMC MMT group. ILs were increased with tumor malignancy as follows: in tumor homogenates IL-6 levels were higher in malignant tumors (IMC and non-IMC MMT) versus HBMT and versus NMG and tumor IL-8 was increased in malignant tumors versus NMG; in serum, IL-1α and IL-8 levels were higher in the malignant groups respect to HBMT and SCs; interestingly, IL-10 was elevated only in the serum of IMC animals. To the best of our knowledge, this is the first report that analyzes ILs in IMC and IL-10 in canine mammary tumors. Our results indicate a role for IL-6, IL-8 and IL-10 in canine mammary malignancy and specific differences in ILs content in IMC versus non-IMC MMT that could

  13. Influence of Age on the Relative Biological Effectiveness of Carbon Ion Radiation for Induction of Rat Mammary Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Imaoka, Tatsuhiko, E-mail: t_imaoka@nirs.go.jp [Radiobiology for Children' s Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba (Japan); Nishimura, Mayumi; Daino, Kazuhiro [Radiobiology for Children' s Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba (Japan); Kokubo, Toshiaki [Department of Technical Support and Development, Research Development and Support Center, National Institute of Radiological Sciences, Chiba (Japan); Doi, Kazutaka [Regulatory Sciences Research Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba (Japan); Iizuka, Daisuke [Radiobiology for Children' s Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba (Japan); Department of Molecular Radiobiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima (Japan); Nishimura, Yukiko [Radiobiology for Children' s Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba (Japan); Okutani, Tomomi [Radiobiology for Children' s Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba (Japan); Department of Biology, Graduate School of Science, Chiba University, Chiba (Japan); Takabatake, Masaru [Radiobiology for Children' s Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba (Japan); Department of Radiological Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo (Japan); Kakinuma, Shizuko; Shimada, Yoshiya [Radiobiology for Children' s Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba (Japan)

    2013-03-15

    Purpose: The risk of developing secondary cancer after radiotherapy, especially after treatment of childhood cancers, remains a matter of concern. The high biological effects of carbon-ion radiation have enabled powerful radiotherapy, yet the approach is commonly restricted to the treatment of adults. Susceptibility of the fetus to particle radiation–induced cancer is also unclear. The present study is aimed to investigate the effect of carbon-ion irradiation in childhood on breast carcinogenesis. Methods and Materials: We irradiated female Sprague-Dawley rats of various ages (embryonic days 3, 13, and 17 and 1, 3, 7, and 15 weeks after birth) with {sup 137}Cs γ rays or a 290-MeV/u monoenergetic carbonion beam (linear energy transfer, 13 keV/μm). All animals were screened weekly for mammary carcinoma by palpation until they were 90 weeks old. Results: Irradiation of fetal and mature (15-week-old) rats with either radiation source at a dose of 0.2 or 1 Gy did not substantially increase the hazard ratio compared with the nonirradiated group. Dose responses (0.2-2.0 Gy) to γ rays were similar among the groups of rats irradiated 1, 3, and 7 weeks after birth. The effect of carbon ions increased along with the age at the time of irradiation, indicating relative biological effectiveness values of 0.2 (−0.3, 0.7), 1.3 (1.0, 1.6), and 2.8 (1.8, 3.9) (mean and 95% confidence interval) for animals that were 1, 3, and 7 weeks of age, respectively. Conclusions: Our findings imply that carbonion therapy may be associated with a risk of secondary breast cancer in humans, the extent of which may depend on the age of the patient at the time of irradiation.

  14. The role of mammary ductoscopy in breast cancer: a review of the literature.

    Science.gov (United States)

    Kapenhas-Valdes, Edna; Feldman, Sheldon M; Boolbol, Susan K

    2008-12-01

    Breast cancer is the most frequently diagnosed malignancy among American women. It is the second most common cause of cancer death. Genetic analysis using comparative genetic hybridization (CGH) has shown evidence that the majority of breast cancers, approximately 85%, begin in the ductal epithelium with normal cells progressing to atypia and finally to carcinoma. Mammary ductoscopy, also referred to as the intraductal approach, is a new tool that allows direct visualization of the breast ductal system. It enables one to sample the ductal epithelium and may allow identification of early changes cytologically as well as potentially play an important role in aiding surgical excision. This may aid in detection of breast masses long before they are palpable or visible via mammography. Mammary ductoscopy may have a role in the evaluation of women with nipple discharge, high-risk women, or limiting the amount of tissue removed in breast conservation surgery for cancer.

  15. Effect of Thyroid Function on MNU-Induced Mammary Carcinogenesis.

    Science.gov (United States)

    Vermey, Mackenzie L; Marks, Gregory T; Baldridge, Monika G

    2015-06-01

    Mammary cancer is a disease that affects many women. Extensive research has been conducted to elucidate which variables are involved in the development of this cancer. Studies have highlighted thyroid function as a modulator of tumor growth and development. Thyroxine and 3,3',5-triiodothyronine are responsible for regulating the development, differentiation, homeostasis, and metabolism of cells in the body including mammary tissue. Thyroid hormones also have estrogen-like effects on mammary cancer cell growth by regulating the estrogen receptor. The present study was designed to determine whether medically induced hyperthyroidism increases the multiplicity, prevalence, and mammary tumor burden in rats; and to elucidate whether surgically induced hypothyroidism conversely attenuates the rate of mammary cancer cell growth. Female Sprague-Dawley rats were randomly divided into three groups (euthyroid-control, hyperthyroid, and hypothyroid). Hyperthyroidism was induced via oral administration of levothyroxine; whereas, hypothyroidism was induced by thyroidectomy. Mammary carcinogenesis was induced with a single intraperitoneal injection of N-methyl-N-nitrosurea (MNU). Rats were sacrificed at 38 weeks, and the mammary tumors were excised, fixed for histology and analyzed. Analysis included evaluation of malignancy and immunohistochemistry for ER. MNU-induced mammary carcinogenesis among the groups resulted in a significant difference in tumor burden. The hyperthyroid group had a statistically higher tumor burden than did the euthyroid group, and the hypothyroid group had no tumors of mammary tissue origin at 38 weeks. All excised mammary tumors were ER alpha negative. These data support the hypothesis that thyroid function is one of potentially many factors that contribute to modulation of MNU-induced mammary tumor growth.

  16. Antiproliferative effect of berberine on canine mammary gland cancer cell culture.

    Science.gov (United States)

    Sefidabi, Reyhaneh; Mortazavi, Pejman; Hosseini, Saeed

    2017-01-01

    Canine mammary gland tumors are the most frequent cause of cancer in female dogs. Numerous studies using cancer cell lines and clinical trials have indicated that various natural products and antioxidants reduce or possibly prevent the development of cancer. Berberine (BBR), the most important alkaloid in the Berberidaceae, which exerts a wide range of pharmacological and biochemical effects, has drawn much attention due to its particularly high antitumor activity in vitro and in animal studies. The aim of the present study was to investigate the antiproliferative effect of BBR against a canine mammary gland carcinoma cell line (CF41.Mg) in vitro. CF41.Mg cells were cultured in RPMI-1640 medium containing 10% heat inactived fetal bovine serum (FBS) and 100 mg/ml peniciline-streptomycin. Subsequently the cells were treated with different concentrations of BBR chloride (10, 25, 50, 100 and 200 µM) at a density of 12,000 cells/well in 96-well plates. Following treatment, the MTT assay was used to detect cell viability after 24-, 48- and 72-h incubations at 37°C with 5% CO2. The results indicated that BBR inhibited proliferation of canine mammary gland carcinoma cells, as treatment with 100 µM BBR for 24 h resulted in a significant decrease in cell viability (Pcancer cell death, it is proposed that BBR may serve as a candidate agent against canine mammary tumor cells via its antiproliferative activity.

  17. Study of internal mammary sentinel lymph node biopsy in breast cancer patients after neoadjuvant chemotherapy

    Directory of Open Access Journals (Sweden)

    Cao XS

    2015-10-01

    Full Text Available Xiao-Shan Cao,1,2 Bin-Bin Cong,1,2 Xiao Sun,1 Peng-Fei Qiu,1 Yong-Sheng Wang1 1Breast Cancer Center, Shandong Cancer Hospital and Institute, Jinan, Shandong, People’s Republic of China; 2School of Medicine and Life Sciences, Jinan University-Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of ChinaInternal mammary lymph node (IMLN metastasis has a similar prognostic importance as axillary lymph nodal involvement in breast cancer patients.1 Patients with both axillary- and internal mammary-positive nodes have a very poor prognosis.2 Reliable data for internal mammary nodal metastases are reported to be present in 18%–33% (mean 23.4% of patients who have not been treated with neoadjuvant chemotherapy (NAC mostly concomitant with axillary metastases, and metastases exclusively situated in the internal mammary chain occur in 2%–11% of patients,3 but limited data are available in the context of NAC.

  18. Establishment and Characterization of a New Cell Line of Canine Inflammatory Mammary Cancer: IPC-366

    OpenAIRE

    Sara Caceres; Laura Peña; de Andres, Paloma J.; Maria J Illera; Mirtha S Lopez; Woodward, Wendy A; Reuben, James M.; Illera, Juan C.

    2015-01-01

    Canine inflammatory mammary cancer (IMC) shares epidemiologic, histopathological and clinical characteristics with the disease in humans and has been proposed as a natural model for human inflammatory breast cancer (IBC). The aim of this study was to characterize a new cell line from IMC (IPC-366) for the comparative study of both IMC and IBC. Tumors cells from a female dog with clinical IMC were collected. The cells were grown under adherent conditions. The growth, cytological, ultrastructur...

  19. Field cancerization in mammary carcinogenesis - Implications for prevention and treatment of breast cancer.

    Science.gov (United States)

    Rivenbark, Ashley G; Coleman, William B

    2012-12-01

    The natural history of breast cancer unfolds with the development of ductal carcinoma in situ (DCIS) in normal breast tissue, and evolution of this pre-invasive neoplasm into invasive cancer. The mechanisms that drive these processes are poorly understood, but evidence from the literature suggests that mammary carcinogenesis may occur through the process of field cancerization. Clinical observations are consistent with the idea that (i) DCIS may arise in a field of altered breast epithelium, (ii) narrow surgical margins do not remove the entire altered field (contributing to recurrence and/or disease progression), and (iii) whole-breast radiation therapy is effective in elimination of the residual field of altered cells adjacent to the resected DCIS. Molecular studies suggest that the field of altered breast epithelial cells may carry cancer-promoting genetic mutations (or other molecular alterations) or cancer promoting epimutations (oncogenic alterations in the epigenome). In fact, most breast cancers develop through a succession of molecular events involving both genetic mutations and epimutations. Hence, in hereditary forms of breast cancer, the altered field reflects the entire breast tissue which is composed of cells with a predisposing molecular lesion (such as a BRCA1 mutation). In the example of a BRCA1-mutant patient, it is evident that local resection of a DCIS lesion or localized but invasive cancer will not result in elimination of the altered field. In sporadic breast cancer patients, the mechanistic basis for the altered field may not be so easily recognized. Nonetheless, identification of the nature of field cancerization in a given patient may guide clinical intervention. Thus, patients with DCIS that develops in response to an epigenetic lesion (such as a hypermethylation defect affecting the expression of tumor suppressor genes) might be treated with epigenetic therapy to normalize the altered field and reduce the risk of secondary occurrence of

  20. Dysfunctional telomeres promote genomic instability and metastasis in the absence of telomerase activity in oncogene induced mammary cancer.

    Science.gov (United States)

    Bojovic, Bojana; Crowe, David L

    2013-02-01

    Telomerase is a ribonucleoprotein that maintains the ends of chromosomes (telomeres). In normal cells lacking telomerase activity, telomeres shorten with each cell division because of the inability to completely synthesize the lagging strand. Critically shortened telomeres elicit DNA damage responses and limit cellular division and lifespan, providing an important tumor suppressor function. Most human cancer cells express telomerase which contributes significantly to the tumor phenotype. In human breast cancer, telomerase expression is predictive of clinical outcomes such as lymph node metastasis and survival. In mouse models of mammary cancer, telomerase expression is also upregulated. Telomerase overexpression resulted in spontaneous mammary tumor development in aged female mice. Increased mammary cancer also was observed when telomerase deficient mice were crossed with p53 null mutant animals. However, the effects of telomerase and telomere length on oncogene driven mammary cancer have not been completely characterized. To address these issues we characterized neu proto-oncogene driven mammary tumor formation in G1 Terc-/- (telomerase deficient with long telomeres), G3 Terc-/- (telomerase deficient with short telomeres), and Terc+/+ mice. Telomerase deficiency reduced the number of mammary tumors and increased tumor latency regardless of telomere length. Decreased tumor formation correlated with increased apoptosis in Terc deficient tumors. Short telomeres dramatically increased lung metastasis which correlated with increased genomic instability, and specific alterations in DNA copy number and gene expression. We concluded that short telomeres promote metastasis in the absence of telomerase activity in neu oncogene driven mammary tumors.

  1. Mammary-Stem-Cell-Based Somatic Mouse Models Reveal Breast Cancer Drivers Causing Cell Fate Dysregulation

    Directory of Open Access Journals (Sweden)

    Zheng Zhang

    2016-09-01

    Full Text Available Cancer genomics has provided an unprecedented opportunity for understanding genetic causes of human cancer. However, distinguishing which mutations are functionally relevant to cancer pathogenesis remains a major challenge. We describe here a mammary stem cell (MaSC organoid-based approach for rapid generation of somatic genetically engineered mouse models (GEMMs. By using RNAi and CRISPR-mediated genome engineering in MaSC-GEMMs, we have discovered that inactivation of Ptpn22 or Mll3, two genes mutated in human breast cancer, greatly accelerated PI3K-driven mammary tumorigenesis. Using these tumor models, we have also identified genetic alterations promoting tumor metastasis and causing resistance to PI3K-targeted therapy. Both Ptpn22 and Mll3 inactivation resulted in disruption of mammary gland differentiation and an increase in stem cell activity. Mechanistically, Mll3 deletion enhanced stem cell activity through activation of the HIF pathway. Thus, our study has established a robust in vivo platform for functional cancer genomics and has discovered functional breast cancer mutations.

  2. MicroRNA-regulated gene networks during mammary cell differentiation are associated with breast cancer.

    Science.gov (United States)

    Aydoğdu, Eylem; Katchy, Anne; Tsouko, Efrosini; Lin, Chin-Yo; Haldosén, Lars-Arne; Helguero, Luisa; Williams, Cecilia

    2012-08-01

    MicroRNAs (miRNAs) play pivotal roles in stem cell biology, differentiation and oncogenesis and are of high interest as potential breast cancer therapeutics. However, their expression and function during normal mammary differentiation and in breast cancer remain to be elucidated. In order to identify which miRNAs are involved in mammary differentiation, we thoroughly investigated miRNA expression during functional differentiation of undifferentiated, stem cell-like, murine mammary cells using two different large-scale approaches followed by qPCR. Significant changes in expression of 21 miRNAs were observed in repeated rounds of mammary cell differentiation. The majority, including the miR-200 family and known tumor suppressor miRNAs, was upregulated during differentiation. Only four miRNAs, including oncomiR miR-17, were downregulated. Pathway analysis indicated complex interactions between regulated miRNA clusters and major pathways involved in differentiation, proliferation and stem cell maintenance. Comparisons with human breast cancer tumors showed the gene profile from the undifferentiated, stem-like stage clustered with that of poor-prognosis breast cancer. A common nominator in these groups was the E2F pathway, which was overrepresented among genes targeted by the differentiation-induced miRNAs. A subset of miRNAs could further discriminate between human non-cancer and breast cancer cell lines, and miR-200a/miR-200b, miR-146b and miR-148a were specifically downregulated in triple-negative breast cancer cells. We show that miR-200a/miR-200b can inhibit epithelial-mesenchymal transition (EMT)-characteristic morphological changes in undifferentiated, non-tumorigenic mammary cells. Our studies propose EphA2 as a novel and important target gene for miR-200a. In conclusion, we present evidentiary data on how miRNAs are involved in mammary cell differentiation and indicate their related roles in breast cancer.

  3. Sesamin synergistically potentiates the anticancer effects of γ-tocotrienol in mammary cancer cell lines.

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    Akl, Mohamed R; Ayoub, Nehad M; Abuasal, Bilal S; Kaddoumi, Amal; Sylvester, Paul W

    2013-01-01

    γ-Tocotrienol and sesamin are phytochemicals that display potent anticancer activity. Since sesamin inhibits the metabolic degradation of tocotrienols, studies were conducted to determine if combined treatment with sesamin potentiates the antiproliferative effects of γ-tocotrienol on neoplastic mouse (+SA) and human (MCF-7 and MDA-MB-231) mammary cancer cells. Results showed that treatment with γ-tocotrienol or sesamin alone induced a significant dose-responsive growth inhibition, whereas combination treatment with these agents synergistically inhibited the growth of +SA, MCF-7 and MDA-MB-231 mammary cancer cells, while similar treatment doses were found to have little or no effect on normal (mouse CL-S1 and human MCF-10A) mammary epithelial cell growth or viability. However, sesamin synergistic enhancement of γ-tocotrienol-induced anticancer effects was not found to be mediated from a reduction in γ-tocotrienol metabolism. Rather, combined treatment with subeffective doses of γ-tocotrienol and sesamin was found to induce G1 cell cycle arrest, and a corresponding decrease in cyclin D1, CDK2, CDK4, CDK6, phospho-Rb, and E2F1 levels, and increase in p27 and p16 levels. Additional studies showed that the antiproliferative effect of combination treatment did not initiate apoptosis or result in a decrease in mammary cancer cell viability. Taken together, these findings indicate that the synergistic antiproliferative action of combined γ-tocotrienol and sesamin treatment in mouse and human mammary cancer cells is cytostatic, not cytotoxic, and results from G1 cell cycle arrest.

  4. Antiproliferative and apoptotic effect of Pleurotus ostreatus on human mammary carcinoma cell line (michigan cancer foundation-7

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    Krishnamoorthy Deepalakshmi

    2016-01-01

    Conclusion: The study demonstrates a potent anticancer property of P. ostreatus against human mammary carcinoma cells which might be of value in nutraceutical industry. Further investigations are essential to establish it as a treatment against breast cancer.

  5. Internal Mammary Sentinel Lymph Nodes in Breast Cancer - Effects on Disease Prognosis and Therapeutic Protocols - A Case Report

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    Sinisa Stojanoski

    2015-03-01

    CONCLUSION: Detection of internal mammary lymph node metastases improves N (nodal grading of breast cancer by selecting a high risk subgroup of patients that require adjuvant hormone therapy, chemotherapy and/or radiotherapy.

  6. Human breast cancer cells are redirected to mammary epithelial cells upon interaction with the regenerating mammary gland microenvironment in-vivo.

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    Bussard, Karen M; Smith, Gilbert H

    2012-01-01

    Breast cancer is the second leading cause of cancer deaths in the United States. At present, the etiology of breast cancer is unknown; however the possibility of a distinct cell of origin, i.e. a cancer stem cell, is a heavily investigated area of research. Influencing signals from the tissue niche are known to affect stem cells. Literature has shown that cancer cells lose their tumorigenic potential and display 'normal' behavior when placed into 'normal' ontogenic environments. Therefore, it may be the case that the tissue microenvironment is able to generate signals to redirect cancer cell fate. Previously, we showed that pluripotent human embryonal carcinoma cells could be redirected by the regenerating mammary gland microenvironment to contribute epithelial progeny for 'normal' gland development in-vivo. Here, we show that that human metastatic, non-metastatic, and metastasis-suppressed breast cancer cells proliferate and contribute to normal mammary gland development in-vivo without tumor formation. Immunochemistry for human-specific mitochondria, keratin 8 and 14, as well as human-specific milk proteins (alpha-lactalbumin, impregnated transplant hosts) confirmed the presence of human cell progeny. Features consistent with normal mammary gland development as seen in intact hosts (duct, lumen formation, development of secretory acini) were recapitulated in both primary and secondary outgrowths from chimeric implants. These results suggest the dominance of the tissue microenvironment over cancer cell fate. This work demonstrates that cultured human breast cancer cells (metastatic and non-metastatic) respond developmentally to signals generated by the mouse mammary gland microenvironment during gland regeneration in-vivo.

  7. Human breast cancer cells are redirected to mammary epithelial cells upon interaction with the regenerating mammary gland microenvironment in-vivo.

    Directory of Open Access Journals (Sweden)

    Karen M Bussard

    Full Text Available Breast cancer is the second leading cause of cancer deaths in the United States. At present, the etiology of breast cancer is unknown; however the possibility of a distinct cell of origin, i.e. a cancer stem cell, is a heavily investigated area of research. Influencing signals from the tissue niche are known to affect stem cells. Literature has shown that cancer cells lose their tumorigenic potential and display 'normal' behavior when placed into 'normal' ontogenic environments. Therefore, it may be the case that the tissue microenvironment is able to generate signals to redirect cancer cell fate. Previously, we showed that pluripotent human embryonal carcinoma cells could be redirected by the regenerating mammary gland microenvironment to contribute epithelial progeny for 'normal' gland development in-vivo. Here, we show that that human metastatic, non-metastatic, and metastasis-suppressed breast cancer cells proliferate and contribute to normal mammary gland development in-vivo without tumor formation. Immunochemistry for human-specific mitochondria, keratin 8 and 14, as well as human-specific milk proteins (alpha-lactalbumin, impregnated transplant hosts confirmed the presence of human cell progeny. Features consistent with normal mammary gland development as seen in intact hosts (duct, lumen formation, development of secretory acini were recapitulated in both primary and secondary outgrowths from chimeric implants. These results suggest the dominance of the tissue microenvironment over cancer cell fate. This work demonstrates that cultured human breast cancer cells (metastatic and non-metastatic respond developmentally to signals generated by the mouse mammary gland microenvironment during gland regeneration in-vivo.

  8. microRNAs and EMT in mammary cells and breast cancer.

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    Wright, Josephine A; Richer, Jennifer K; Goodall, Gregory J

    2010-06-01

    MicroRNAs are master regulators of gene expression in many biological and pathological processes, including mammary gland development and breast cancer. The differentiation program termed the epithelial to mesenchymal transition (EMT) involves changes in a number of microRNAs. Some of these microRNAs have been shown to control cellular plasticity through the suppression of EMT-inducers or to influence cellular phenotype through the suppression of genes involved in defining the epithelial and mesenchymal cell states. This has led to the suggestion that microRNAs maybe a novel therapeutic target for the treatment of breast cancer. In this review, we will discuss microRNAs that are involved in EMT in mammary cells and breast cancer.

  9. A Role for T-Lymphocytes in Human Breast Cancer and in Canine Mammary Tumors

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    Maria Isabel Carvalho

    2014-01-01

    Full Text Available Chronic inflammation in the tumor microenvironment has a prominent role in carcinogenesis and benefits the proliferation and survival of malignant cells, promoting angiogenesis and metastasis. Mammary tumors are frequently infiltrated by a heterogeneous population of immune cells where T-lymphocytes have a great importance. Interestingly, similar inflammatory cell infiltrates, cytokine and chemokine expression in humans and canine mammary tumors were recently described. However, in both species, despite all the scientific evidences that appoint for a significant role of T-lymphocytes, a definitive conclusion concerning the effectiveness of T-cell dependent immune mechanisms has not been achieved yet. In the present review, we describe similarities between human breast cancer and canine mammary tumors regarding tumor T-lymphocyte infiltration, such as relationship of TILs and mammary tumors malignancy, association of ratio CD4+/ CD8+ T-cells with low survival rates, promotion of tumor progression by Th2 cells actions, and association of great amounts of Treg cells with poor prognostic factors. This apparent parallelism together with the fact that dogs develop spontaneous tumors in the context of a natural immune system highlight the dog as a possible useful biological model for studies in human breast cancer immunology.

  10. Raloxifene inhibits tumor growth and lymph node metastasis in a xenograft model of metastatic mammary cancer

    Directory of Open Access Journals (Sweden)

    Li Zhong-Lian

    2010-10-01

    Full Text Available Abstract Background The effects of raloxifene, a novel selective estrogen receptor modulator, were studied in a mouse metastatic mammary cancer model expressing cytoplasmic ERα. Methods Mammary tumors, induced by inoculation of syngeneic BALB/c mice with BJMC3879luc2 cells, were subsequently treated with raloxifene at 0, 18 and 27 mg/kg/day using mini-osmotic pumps. Results In vitro study demonstrated that the ERα in BJMC3879luc2 cells was smaller (between 50 and 64 kDa than the normal-sized ERα (66 kDa and showed cytoplasmic localization. A statistically significant but weak estradiol response was observed in this cell line. When BJMC3879luc2 tumors were implanted into mice, the ERα mRNA levels were significantly higher in females than in males. In vitro studies showed that raloxifene induced mitochondria-mediated apoptosis and cell-cycle arrest in the G1-phase and a decrease in the cell population in the S-phase. In animal experiments, tumor volumes were significantly suppressed in the raloxifene-treated groups. The multiplicity of lymph node metastasis was significantly decreased in the 27 mg/kg group. Levels of apoptosis were significantly increased in the raloxifene-treated groups, whereas the levels of DNA synthesis were significantly decreased in these groups. No differences in microvessel density in tumors were observed between the control and raloxifene-treated groups. The numbers of dilated lymphatic vessels containing intraluminal tumor cells were significantly reduced in mammary tumors in the raloxifene-treated groups. The levels of ERα mRNA in mammary tumors tended to be decreased in the raloxifene-treated groups. Conclusion These results suggest that the antimetastatic activity of raloxifene in mammary cancer expressing cytoplasmic ERα may be a crucial finding with clinical applications and that raloxifene may be useful as an adjuvant therapy and for the chemoprevention of breast cancer development.

  11. Different role of COX-2 and angiogenesis in canine inflammatory and non-inflammatory mammary cancer.

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    Clemente, Mónica; Sánchez-Archidona, Ana Rodríguez; Sardón, David; Díez, Lucía; Martín-Ruiz, Asunción; Caceres, Sara; Sassi, Francesco; Dolores Pérez-Alenza, M; Illera, Juan C; Dunner, Susana; Peña, Laura

    2013-08-01

    Human inflammatory breast cancer (IBC) and canine inflammatory mammary cancer (IMC) are the most aggressive and fatal types of mammary cancer, and both have a very poor prognosis and low survival rate. Human IBC is characterised by exacerbated angiogenesis, lymphangiogenesis, and lymphangiotropism. Lymphangiotropism is also characteristic of IMC, but microvascular density (MVD) and lymphangiogenesis have not been previously studied in canine IMC. In this study immunohistochemical expression of several angiogenesis-related factors (cyclooxygenase [COX]-2, vascular endothelial growth factors A and D [VEGF-A, VEGF-D], and vascular endothelial growth factor receptor 3 [VEGFR-3]), MVD, lymphatic proliferation index (LPI), and Ki-67 tumour proliferation index (PI) were studied in 21 canine IMC samples, 20 canine high-grade malignant non-IMC mammary tumours (MMTs), and four normal mammary gland samples (NMGs). All mammary neoplasms were histologically categorised as grade III. COX-2 values were also analysed by RT-PCR in seven IMCs, six MMTs and four NMGs. The expressions of COX-2, VEGF-A, and VEGF-D were significantly higher in IMC, MVD and LPI tumours, but not PI. In MMTs, COX-2 immunoexpression was significantly associated with VEGF-A, while in IMCs COX-2 was associated with VEGF-D (lymphangiogenic factor), its receptor VEGFR-3, and LPI. These results suggested that lymphangiogenic pathway stimulation isa specific role of COX-2 in IMC angiogenesis, which justifies the use of COX-2-based targeted palliative therapies in dogs. The exacerbated angiogenesis and lymphangiogenesis and the increased expression of angiogenesis-related factors further support canine IMC as a natural model for the study of human IBC.

  12. Alcohol exposure in utero leads to enhanced prepubertal mammary development and alterations in mammary IGF and estradiol systems.

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    Polanco, Tiffany A; Crismale-Gann, Catina; Cohick, Wendie S

    2011-08-01

    Exposure to alcohol during fetal development increases susceptibility to mammary cancer in adult rats. This study determined if early changes in mammary morphology and the insulin-like growth factor (IGF)/estradiol axis are involved in the mechanisms that underlie this increased susceptibility. Pregnant Sprague-Dawley rats were fed a liquid diet containing 6.7% ethanol (alcohol), an isocaloric liquid diet (pair-fed), or rat chow ad libitum from days 11 to 21 of gestation. At birth, female pups were cross-fostered to ad libitum-fed control dams. Offspring were euthanized at postnatal days (PND) 20, 40, or 80. Animals were injected with BrdU before euthanasia, then mammary glands, serum, and livers were collected. Mammary glands from animals exposed to alcohol in utero displayed increased epithelial cell proliferation and aromatase expression at PND 20 and 40. Mammary IGF-I mRNA was higher in alcohol-exposed animals relative to controls at PND 20, while mammary IGFBP-5 mRNA was lower in this group at PND 40. Hepatic IGF-I mRNA expression was increased at all time points in alcohol-exposed animals, however, circulating IGF-I levels were not altered. These data indicate that alcohol exposure in utero may advance mammary development via the IGF and estradiol systems, which could contribute to increased susceptibility to mammary cancer later in life.

  13. ErbB/EGF signaling and EMT in mammary development and breast cancer.

    Science.gov (United States)

    Hardy, Katharine M; Booth, Brian W; Hendrix, Mary J C; Salomon, David S; Strizzi, Luigi

    2010-06-01

    Activation of the ErbB family of receptor tyrosine kinases via cognate Epidermal Growth Factor (EGF)-like peptide ligands constitutes a major group of related signaling pathways that control proliferation, survival, angiogenesis and metastasis of breast cancer. In this respect, clinical trials with various ErbB receptor blocking antibodies and specific tyrosine kinase inhibitors have proven to be partially efficacious in the treatment of this heterogeneous disease. Induction of an embryonic program of epithelial-to-mesenchymal transition (EMT) in breast cancer, whereupon epithelial tumor cells convert to a more mesenchymal-like phenotype, facilitates the migration, intravasation, and extravasation of tumor cells during metastasis. Breast cancers which exhibit properties of EMT are highly aggressive and resistant to therapy. Activation of ErbB signaling can regulate EMT-associated invasion and migration in normal and malignant mammary epithelial cells, as well as modulating discrete stages of mammary gland development. The purpose of this review is to summarize current information regarding the role of ErbB signaling in aspects of EMT that influence epithelial cell plasticity during mammary gland development and tumorigenesis. How this information may contribute to the improvement of therapeutic approaches in breast cancer will also be addressed.

  14. Elimination of progressive mammary cancer by repeated administrations of chimeric antigen receptor-modified T cells.

    Science.gov (United States)

    Globerson-Levin, Anat; Waks, Tova; Eshhar, Zelig

    2014-05-01

    Continuous oncogenic processes that generate cancer require an on-going treatment approach to eliminate the transformed cells, and prevent their further development. Here, we studied the ability of T cells expressing a chimeric antibody-based receptor (CAR) to offer a therapeutic benefit for breast cancer induced by erbB-2. We tested CAR-modified T cells (T-bodies) specific to erbB-2 for their antitumor potential in a mouse model overexpressing a human erbB-2 transgene that develops mammary tumors. Comparing the antitumor reactivity of CAR-modified T cells under various therapeutic settings, either prophylactic, prior to tumor development, or therapeutically. We found that repeated administration of CAR-modified T cells is required to eliminate spontaneously developing mammary cancer. Systemic, as well as intratumoral administered CAR-modified T cells accumulated at tumor sites and eventually eliminated the malignant cells. Interestingly, within a few weeks after a single CAR T cells' administration, and rejection of primary lesion, tumors usually relapsed both in treated mammary gland and at remote sites; however, repeated injections of CAR-modified T cells were able to control the secondary tumors. Since spontaneous tumors can arise repeatedly, especially in the case of syndromes characterized by specific susceptibility to cancer, multiple administrations of CAR-modified T cells can serve to control relapsing disease.

  15. STAT5A Regulates the Survival of Mammary Epithelial Cells and the Development of Mammary Cancer

    Science.gov (United States)

    2002-07-01

    Western Blot Recycling Kit according to the manufacturer’s protocol (a AQ: J Pierce Chemical Co. (Rockford, IL). Diagnostic, San Antonio , TX). Blots...Peters G, Lu X and Barnes DM. (1999). Bonilla M, Ramirez M, Lopez- Cueto J and Gariglio P. J. Pathol., 187, 200-206. (1988). J. Nati. Cancer Inst., 80

  16. [Progenotoxic shift in mammary adipose tissue (adipogenotoxicosis): association with clinical and biological characteristics of breast cancer].

    Science.gov (United States)

    Bershtein, L M; Kovalevskiĭ, A Iu; Poroshina, T E; Revskoĭ, S Iu; Kotov, A V; Kovalenko, I G; Tsyrlina, E V; Semiglazov, V F; Turkevich, E A; Pozharisskiĭ, K M

    2008-01-01

    The study is concerned with identification of a relationship between levels of production and accumulation of compounds capable of hormonal and progenotoxic effects in mammary fat, on the one hand, and characteristics of tumor tissue in breast cancer, on the other. Mammary fat was sampled at a distance of 1.5-2 cm from tumor edge (79 pts.). Case histories were used to provide data on clinical stage, size, grade and regional lymph node involvement. Levels were assayed of leptin, adiponectin, tumor necrosis factor (TNF-alpha), interleukin-6 (IL-6), nitric oxide (NO), thiobarbiturate-reactive products (TBRP) and DNA oxidative damage marker (8-OH-dG) from 4hr-incubates of fat tissue culture. Mammary fat aromatase was assayed by radiometrical means while macrophage-assisted fat infiltration (CD68) and estrogen-4-hydroxylase (CYP1B1) expression were evaluated immunohistochemically. Radio-competitive and immunohistochemical methods were used to assay estrogen (ER) and progesterone (PR) receptor levels in tumor and tumor-related expression of cytokeratins 5/6 ("basal") and 7/8 ("luminal" epithelium), respectively. As far as hormonal properties of mammary fat were concerned, there were direct correlations between aromatase concentration, on the one hand, and tumor stage and size, on the other, and adiponectin secretion and CK7 expression in tumor. Besides, an inverse correlation was found between mammary fat-mediated release of leptin and adiponectin, on the one hand, and stage and regional lymph node involvement, on the other. The following main relationships were identified by comparison of the clinico-biological characteristics of tumor and markers of proinflammatory/progenotoxic properties of mammary adipose tissue: tendency toward direct correlation with IL-6 and 8-OH-dG in fat (tumor progress stage); direct correlation with TNF-alpha secretion rate (malignancy grade); lymph node involvement--tendency toward direct correlation with NO generation; CK5 expression in

  17. Developmental signaling pathways regulating mammary stem cells and contributing to the etiology of triple-negative breast cancer.

    Science.gov (United States)

    Rangel, Maria Cristina; Bertolette, Daniel; Castro, Nadia P; Klauzinska, Malgorzata; Cuttitta, Frank; Salomon, David S

    2016-04-01

    Cancer has been considered as temporal and spatial aberrations of normal development in tissues. Similarities between mammary embryonic development and cell transformation suggest that the underlying processes required for mammary gland development are also those perturbed during various stages of mammary tumorigenesis and breast cancer (BC) development. The master regulators of embryonic development Cripto-1, Notch/CSL, and Wnt/β-catenin play key roles in modulating mammary gland morphogenesis and cell fate specification in the embryo through fetal mammary stem cells (fMaSC) and in the adult organism particularly within the adult mammary stem cells (aMaSC), which determine mammary progenitor cell lineages that generate the basal/myoepithelial and luminal compartments of the adult mammary gland. Together with recognized transcription factors and embryonic stem cell markers, these embryonic regulatory molecules can be inappropriately augmented during tumorigenesis to support the tumor-initiating cell (TIC)/cancer stem cell (CSC) compartment, and the effects of their deregulation may contribute for the etiology of BC, in particular the most aggressive subtype of BC, triple-negative breast cancer (TNBC). This in depth review will present evidence of the involvement of Cripto-1, Notch/CSL, and Wnt/β-catenin in the normal mammary gland morphogenesis and tumorigenesis, from fMaSC/aMaSC regulation to TIC generation and maintenance in TNBC. Specific therapies for treating TNBC by targeting these embryonic pathways in TICs will be further discussed, providing new opportunities to destroy not only the bulk tumor, but also TICs that initiate and promote the metastatic spread and recurrence of this aggressive subtype of BC.

  18. PKCδ Inhibition Impairs Mammary Cancer Proliferative Capacity But Selects Cancer Stem Cells, Involving Autophagy.

    Science.gov (United States)

    Berardi, Damián E; Flumian, Carolina; Rodriguez, Cristina E; Bessone, María I Díaz; Cirigliano, Stefano M; Joffé, Elisa D Bal de Kier; Fiszman, Gabriel L; Urtreger, Alejandro J; Todaro, Laura B

    2016-03-01

    Protein kinase C (PKC) is a family of serine/threonine kinases that regulate diverse cellular functions including cell death, proliferation, and survival. Recent studies have reported that PKCδ, are involved in apoptosis or autophagy induction. In the present study we focused on how PKCδ regulates proliferation and cancer stem cell (CSC) properties of the hormone-independent mammary cancer cell line LM38-LP, using pharmacological and genetic approaches. We found that pharmacological inhibition of PKCδ, by Rottlerin treatment, impairs in vitro LM38-LP proliferation through cell cycle arrest, inducing the formation of cytoplasmic-vacuoles. Using immunofluorescence we confirmed that Rottlerin treatment induced the apparition of LC3 dots in cell cytoplasm, and increased autophagy flux. On the other side, the same treatment increased CSC growth rate and self-renewal. Furthermore, Rottlerin pre-treatment induced in CSC the development of a "grape-like" morphology when they are growing in 3D cultures (Matrigel), usually associated with a malignant phenotype, as well as an increase in the number of experimental lung metastasis when these cells were inoculated in vivo. The PKCδ knockdown, by RNA interference, induced autophagy and increased CSC number, indicating that these effects are indeed exerted through a PKCδ dependent pathway. Finally, the increase in the number of mammospheres could be reversed by a 3MA treatment, suggesting that autophagy mechanism is necessary for the increased of CSC self-renewal induced by PKCδ inhibition. Here we demonstrated that PKCδ activity exerts a dual role through the autophagy mechanism, decreasing proliferative capacity of mammary tumor cells but also regulating tumor stem cell self-renewal. © 2015 Wiley Periodicals, Inc.

  19. Macrophages: Regulators of the Inflammatory Microenvironment during Mammary Gland Development and Breast Cancer.

    Science.gov (United States)

    Brady, Nicholas J; Chuntova, Pavlina; Schwertfeger, Kathryn L

    2016-01-01

    Macrophages are critical mediators of inflammation and important regulators of developmental processes. As a key phagocytic cell type, macrophages evolved as part of the innate immune system to engulf and process cell debris and pathogens. Macrophages produce factors that act directly on their microenvironment and also bridge innate immune responses to the adaptive immune system. Resident macrophages are important for acting as sensors for tissue damage and maintaining tissue homeostasis. It is now well-established that macrophages are an integral component of the breast tumor microenvironment, where they contribute to tumor growth and progression, likely through many of the mechanisms that are utilized during normal wound healing responses. Because macrophages contribute to normal mammary gland development and breast cancer growth and progression, this review will discuss both resident mammary gland macrophages and tumor-associated macrophages with an emphasis on describing how macrophages interact with their surrounding environment during normal development and in the context of cancer.

  20. Antiproliferative effect of berberine on canine mammary gland cancer cell culture

    Science.gov (United States)

    Sefidabi, Reyhaneh; Mortazavi, Pejman; Hosseini, Saeed

    2017-01-01

    Canine mammary gland tumors are the most frequent cause of cancer in female dogs. Numerous studies using cancer cell lines and clinical trials have indicated that various natural products and antioxidants reduce or possibly prevent the development of cancer. Berberine (BBR), the most important alkaloid in the Berberidaceae, which exerts a wide range of pharmacological and biochemical effects, has drawn much attention due to its particularly high antitumor activity in vitro and in animal studies. The aim of the present study was to investigate the antiproliferative effect of BBR against a canine mammary gland carcinoma cell line (CF41.Mg) in vitro. CF41.Mg cells were cultured in RPMI-1640 medium containing 10% heat inactived fetal bovine serum (FBS) and 100 mg/ml peniciline-streptomycin. Subsequently the cells were treated with different concentrations of BBR chloride (10, 25, 50, 100 and 200 µM) at a density of 12,000 cells/well in 96-well plates. Following treatment, the MTT assay was used to detect cell viability after 24-, 48- and 72-h incubations at 37°C with 5% CO2. The results indicated that BBR inhibited proliferation of canine mammary gland carcinoma cells, as treatment with 100 µM BBR for 24 h resulted in a significant decrease in cell viability (P<0.005). As the present study demonstrated that BBR (10–200 µM) induced cancer cell death, it is proposed that BBR may serve as a candidate agent against canine mammary tumor cells via its antiproliferative activity.

  1. The myoepithelial cell: its role in normal mammary glands and breast cancer.

    Science.gov (United States)

    Sopel, M

    2010-02-01

    Mammary gland epithelium is composed of an inner layer of secretory cells (luminal) and an outer layer of myoepithelial cells (MEC) bordering the basal lamina which separates the epithelial layer from the extracellular matrix. Mature MECs morphologically resemble smooth muscle cells; however, they exhibit features typical for epithelial cells, such as the presence of specific cytokeratin filaments. During lactation, secretory cells synthesize milk components, which are collected in alveoli and duct lumen, and transported to the nipple as a result of MEC contraction. Although the induction of MEC contraction results from oxytocin action, also other, still unknown auto/paracrine mechanisms participate in the regulation of this process. As well as milk ejection, MECs are involved in mammary gland morphogenesis in all developmental stages, modulating proliferation and differentiation of luminal cells. They take part in the formation of extracellular matrix, synthesizing its components and secreting proteinases and their inhibitors. In addition, MECs are regarded as natural cancer suppressors, stabilizing the normal structure of the mammary gland, they secrete suppressor proteins (e.g. maspin) limiting cancer growth, invasiveness, and neoangiogenesis. The majority of malignant breast cancers are derived from luminal cells, whereas neoplasms of MEC origin are the most seldom and usually benign form of breast tumours. MECs are markedly resistant to malignant transformation and they are able to suppress the transformation of neighboring luminal cells. Therefore, a deeper insight into the role of MECs in the physiology and pathology of mammary glands would allow a better understanding of cancerogenesis mechanisms and possible application of specific MEC markers in the diagnosis and therapy of breast cancer.

  2. VRP immunotherapy targeting neu: treatment efficacy and evidence for immunoediting in a stringent rat mammary tumor model.

    Science.gov (United States)

    Laust, Amanda K; Sur, Brandon W; Wang, Kehui; Hubby, Bolyn; Smith, Jonathan F; Nelson, Edward L

    2007-12-01

    The ability to overcome intrinsic tolerance to a strict "self" tumor-associated antigen (TAA) and successfully treat pre-existing tumor is the most stringent test for anti-tumor immunotherapeutic strategies. Although this capacity has been demonstrated in various models using complicated strategies that may not be readily translated into the clinical arena, straightforward antigen-specific immunotherapeutic strategies in the most stringent models of common epithelial cancers have largely failed to meet this standard. We employed an immunotherapeutic strategy using an alphavirus-based, virus-like replicon particle (VRP), which has in vivo tropism for dendritic cells, to elicit immune responses to the non-mutated TAA rat neu in an aggressive rat mammary tumor model. Using this VRP-based immunotherapeutic strategy targeting a single TAA, we generated effective anti-tumor immunity in the setting of pre-existing tumor resulting in the cure of 36% of rats over multiple experiments, P = 0.002. We also observed down-regulation of rat neu expression in tumors that showed initial responses followed by tumor escape with resumption of rapid tumor growth. These responses were accompanied by significant anti-tumor proliferative responses and CD8+ cellular tumor infiltrates, all of which were restricted to animals receiving the anti-neu immunotherapy. Together these data, obtained in a stringent "self" TAA model, indicate that the VRP-based antigen-specific immunotherapy elicits sufficiently potent immune responses to exert immunologic pressure, selection, and editing of the growing tumors, thus supporting the activity of this straightforward immunotherapy and suggesting that it is a promising platform upon which to build even more potent strategies.

  3. Mammary gland involution as an immunotherapeutic target for postpartum breast cancer.

    Science.gov (United States)

    Fornetti, Jaime; Martinson, Holly A; Betts, Courtney B; Lyons, Traci R; Jindal, Sonali; Guo, Qiuchen; Coussens, Lisa M; Borges, Virginia F; Schedin, Pepper

    2014-07-01

    Postpartum mammary gland involution has been identified as tumor-promotional and is proposed to contribute to the increased rates of metastasis and poor survival observed in postpartum breast cancer patients. In rodent models, the involuting mammary gland microenvironment is sufficient to induce enhanced tumor cell growth, local invasion, and metastasis. Postpartum involution shares many attributes with wound healing, including upregulation of genes involved in immune responsiveness and infiltration of tissue by immune cells. In rodent models, treatment with non-steroidal anti-inflammatory drugs (NSAIDs) ameliorates the tumor-promotional effects of involution, consistent with the immune milieu of the involuting gland contributing to tumor promotion. Currently, immunotherapy is being investigated as a means of breast cancer treatment with the purpose of identifying ways to enhance anti-tumor immune responses. Here we review evidence for postpartum mammary gland involution being a uniquely defined 'hot-spot' of pro-tumorigenic immune cell infiltration, and propose that immunotherapy should be explored for prevention and treatment of breast cancers that arise in this environment.

  4. Characterization of the autonomic innervation of mammary gland in lactating rats studied by retrograde transynaptic virus labeling and immunohistochemistry.

    Science.gov (United States)

    Köves, Katalin; Györgyi, Z; Szabó, F K; Boldogkői, Zs

    2012-06-01

    The aim of experiments was to characterize the neurons of the autonomic chain that innervates the nipple and the mammary gland of lactating rats using retrograde transynaptic virus labeling and neurotransmitter and neuropeptide immunohistochemistry. Two days after injection of green fluorescence protein labeled virus in two nipples and underlying mammary glands, labeling was observed in the ipsilateral paravertebral sympathetic trunk and the lateral horn. Three days after inoculation the labeling appeared in the brain stem and the hypothalamic paraventricular nucleus. Above the spinal cord the labeling was bilateral. A subpopulation of virus labeled cells in the paraventricular nuclei synthesized oxytocin. Labeled neurons in the lateral horn showed cholinergic immunoreactivity. These cholinergic neurons innervated the paravertebral ganglia where the virus labeled neurons were partially noradrenergic. The noradrenergic fibers in the mammary gland innervate the smooth muscle wall of vessels, but not the mammary gland in rats. The neurons in the lateral horn receive afferents from the brain stem, and paraventricular nucleus and these afferents are noradrenergic and oxytocinergic. New findings in our work: Some oxytocinergic fibers may descend to the neurons of the lateral horn which innervate noradrenergic neurons in the paravertebral sympathetic trunk, and in turn these noradrenergic neurons reach the vessels of the mammary gland.

  5. 4-Vinylcyclohexene diepoxide (VCD) inhibits mammary epithelial differentiation and induces fibroadenoma formation in female Sprague Dawley rats.

    Science.gov (United States)

    Wright, Laura E; Frye, Jennifer B; Lukefahr, Ashley L; Marion, Samuel L; Hoyer, Patricia B; Besselsen, David G; Funk, Janet L

    2011-07-01

    4-Vinylcyclohexene diepoxide (VCD), an occupational chemical that targets ovarian follicles and accelerates ovarian failure in rodents, was used to test the effect of early-onset reproductive senescence on mammary fibroadenoma formation. One-month female Sprague Dawley rats were dosed with VCD (80 mg/kg or 160 mg/kg) and monitored for 22 months for persistent estrus and tumor development. Only high-dose VCD treatment accelerated the onset of persistent estrus relative to controls. However, both doses of VCD accelerated mammary tumor onset by 5 months, increasing incidence to 84% (vs. 38% in controls). Tumor development was independent of time in persistent estrus, 17 β-estradiol, androstenedione and prolactin. Delay in VCD administration until after completion of mammary epithelial differentiation (3 months) did not alter tumor formation despite acceleration of ovarian senescence. VCD administration to 1-month rats acutely decreased mammary alveolar bud number and expression of β-casein, suggesting that VCD's tumorigenic effect requires exposure during mammary epithelial differentiation.

  6. Strain Differences in Dimethylbenz[a]anthracene-Induced Mammary Tumor Incidence in Long Evans and Sprague Dawley Rat Offspring Following Prenatal Atrazine Exposure

    Science.gov (United States)

    It has been shown that prenatal exposure to the chlorotriazine herbicide atrazine (ATR) during mammary bud outgrowth (late gestation) delays postnatal mammary epithelial progression in Long Evans (LE) rats. Our laboratory has recently found that prenatal exposure to ATR also effe...

  7. Exogenous normal mammary epithelial mitochondria suppress glycolytic metabolism and glucose uptake of human breast cancer cells.

    Science.gov (United States)

    Jiang, Xian-Peng; Elliott, Robert L; Head, Jonathan F

    2015-10-01

    We hypothesized that normal mitochondria inhibited cancer cell proliferation and increased drug sensitivity by the mechanism of suppression of cancer aerobic glycolysis. To demonstrate the mechanism, we used real-time PCR and glycolysis cell-based assay to measure gene expression of glycolytic enzymes and glucose transporters, and extracellular lactate production of human breast cancer cells. We found that isolated fluorescent probe-stained mitochondria of MCF-12A (human mammary epithelia) could enter into human breast cancer cell lines MCF-7, T47D, and MDA-MB-231, confirmed by fluorescent and confocal microscopy. Mitochondria from the untransformed human mammary epithelia increased drug sensitivity of MCF-7 cells to paclitaxel. Real-time PCR showed that exogenous normal mitochondria of MCF-12A suppressed gene expression of glycolytic enzymes, lactate dehydrogenase A, and glucose transporter 1 and 3 of MCF-7 and MDA-MB-231 cells. Glycolysis cell-based assay revealed that normal mitochondria significantly suppressed lactate production in culture media of MCF-7, T47D, and MDA-MB-231 cells. In conclusion, normal mitochondria suppress cancer proliferation and increase drug sensitivity by the mechanism of inhibition of cancer cell glycolysis and glucose uptake.

  8. A new immunization and treatment strategy for mouse mammary tumor virus (MMTV) associated cancers

    Science.gov (United States)

    Braitbard, Ori; Roniger, Maayan; Bar-Sinai, Allan; Rajchman, Dana; Gross, Tamar; Abramovitch, Hillel; Ferla, Marco La; Franceschi, Sara; Lessi, Francesca; Naccarato, Antonio Giuseppe; Mazzanti, Chiara M.; Bevilacqua, Generoso; Hochman, Jacob

    2016-01-01

    Mouse Mammary Tumor Virus (MMTV) causes mammary carcinoma or lymphoma in mice. An increasing body of evidence in recent years supports its involvement also in human sporadic breast cancer. It is thus of importance to develop new strategies to impair the development, growth and metastasis of MMTV-associated cancers. The signal peptide of the envelope precursor protein of this virus: MMTV-p14 (p14) is an excellent target for such strategies, due to unique characteristics distinct from its regular endoplasmic reticulum targeting function. These include cell surface expression in: murine cancer cells that harbor the virus, human breast cancer (MCF-7) cells that ectopically express p14, as well as cultured human cells derived from an invasive ductal breast carcinoma positive for MMTV sequences. These findings support its use in signal peptide-based immune targeting. Indeed, priming and boosting mice with p14 elicits a specific anti-signal peptide immune response sufficient for protective vaccination against MMTV-associated tumors. Furthermore, passive immunization using a combination of anti-p14 monoclonal antibodies or the transfer of T-cells from immunized mice (Adoptive Cell Transfer) is also therapeutically effective. With reports demonstrating involvement of MMTV in human breast cancer, we propose the immune-mediated targeting of p14 as a strategy for prevention, treatment and diagnosis of MMTV-associated cancers. PMID:26934560

  9. The potential role of COX-2 in cancer stem cell-mediated canine mammary tumor initiation: an immunohistochemical study

    OpenAIRE

    Huang, Jian; Zhang, Di; Xie, Fuqiang; LIN, Degui

    2015-01-01

    Increasing evidence suggests that cancer stem cells (CSCs) are responsible for tumor initiation and maintenance. Additionally, it is becoming apparent that cyclooxygenase (COX) signaling is associated with canine mammary tumor development. The goals of the present study were to investigate COX-2 expression patterns and their effect on CSC-mediated tumor initiation in primary canine mammary tissues and tumorsphere models using immunohistochemistry. Patterns of COX-2, CD44, octamer-binding tran...

  10. Canine Mammary Cancer Stem Cells are Radio- and Chemo- Resistant and Exhibit an Epithelial-Mesenchymal Transition Phenotype

    OpenAIRE

    Argyle, David J.; Else, Rod W.; Alejandro Cervantes-Arias; Pang, Lisa Y

    2011-01-01

    Canine mammary carcinoma is the most common cancer among female dogs and is often fatal due to the development of distant metastases. In humans, solid tumors are made up of heterogeneous cell populations, which perform different roles in the tumor economy. A small subset of tumor cells can hold or acquire stem cell characteristics, enabling them to drive tumor growth, recurrence and metastasis. In veterinary medicine, the molecular drivers of canine mammary carcinoma are as yet undefined. Her...

  11. Transcription factors link mouse WAP-T mammary tumors with human breast cancer.

    Science.gov (United States)

    Otto, Benjamin; Streichert, Thomas; Wegwitz, Florian; Gevensleben, Heidrun; Klätschke, Kristin; Wagener, Christoph; Deppert, Wolfgang; Tolstonog, Genrich V

    2013-03-15

    Mouse models are important tools to decipher the molecular mechanisms of mammary carcinogenesis and to mimic the respective human disease. Despite sharing common phenotypic and genetic features, the proper translation of murine models to human breast cancer remains a challenging task. In a previous study we showed that in the SV40 transgenic WAP-T mice an active Met-pathway and epithelial-mesenchymal characteristics distinguish low- and high-grade mammary carcinoma. To assign these murine tumors to corresponding human tumors we here incorporated the analysis of expression of transcription factor (TF) coding genes and show that thereby a more accurate interspecies translation can be achieved. We describe a novel cross-species translation procedure and demonstrate that expression of unsupervised selected TFs, such as ELF5, HOXA5 and TFCP2L1, can clearly distinguish between the human molecular breast cancer subtypes--or as, for example, expression of TFAP2B between yet unclassified subgroups. By integrating different levels of information like histology, gene set enrichment, expression of differentiation markers and TFs we conclude that tumors in WAP-T mice exhibit similarities to both, human basal-like and non-basal-like subtypes. We furthermore suggest that the low- and high-grade WAP-T tumor phenotypes might arise from distinct cells of tumor origin. Our results underscore the importance of TFs as common cross-species denominators in the regulatory networks underlying mammary carcinogenesis.

  12. Vitamin D receptor regulates autophagy in the normal mammary gland and in luminal breast cancer cells.

    Science.gov (United States)

    Tavera-Mendoza, Luz E; Westerling, Thomas; Libby, Eric; Marusyk, Andriy; Cato, Laura; Cassani, Raymundo; Cameron, Lisa A; Ficarro, Scott B; Marto, Jarrod A; Klawitter, Jelena; Brown, Myles

    2017-03-14

    Women in North America have a one in eight lifetime risk of developing breast cancer (BC), and a significant proportion of these individuals will develop recurrent BC and will eventually succumb to the disease. Metastatic, therapy-resistant BC cells are refractory to cell death induced by multiple stresses. Here, we document that the vitamin D receptor (VDR) acts as a master transcriptional regulator of autophagy. Activation of the VDR by vitamin D induces autophagy and an autophagic transcriptional signature in BC cells that correlates with increased survival in patients; strikingly, this signature is present in the normal mammary gland and is progressively lost in patients with metastatic BC. A number of epidemiological studies have shown that sufficient vitamin D serum levels might be protective against BC. We observed that dietary vitamin D supplementation in mice increases basal levels of autophagy in the normal mammary gland, highlighting the potential of vitamin D as a cancer-preventive agent. These findings point to a role of vitamin D and the VDR in modulating autophagy and cell death in both the normal mammary gland and BC cells.

  13. Establishment and characterization of a new feline mammary cancer cell line, FkMTp.

    Science.gov (United States)

    Borges, Ana; Adega, Filomena; Chaves, Raquel

    2016-08-01

    Studies on tumours in domestic animals are believed to greatly contribute to a better understanding of similar diseases in humans. Comparative studies have shown that feline mammary carcinomas share important features with human breast cancers, including a similar biological behaviour and histological appearance. In the present study we have established and characterized at different cellular levels one feline mammary cancer cell line, FkMTp, derived from a cat mammary carcinoma. The FkMTp cell line revealed to be a promising resource and tool to study tumour microevolution and all the mechanisms and processes involved in carcinogenesis from the tumour (primary culture) to the immortalized cell line. Several assays were conducted to assess the growth behaviour, differentiated morphology, anchorage independent growth in soft agar, wound-healing invasion and migration of the cell line across time (from the primary culture until the 160th passage). FkMTp revealed increased levels of anchorage independence, migration and invasion according to the course of time as well as different numbers of ploidy. These results demonstrate and validate the in vitro tumorigenicity of the FkMTp cell line. During the cell line establishment, it was cryopreserved approximately every six passages, including the tumour primary culture, allowing now the possibility to access almost any specific momento of the tumour progression.

  14. Fingerprinting Breast Cancer vs. Normal Mammary Cells by Mass Spectrometric Analysis of Volatiles

    Science.gov (United States)

    He, Jingjing; Sinues, Pablo Martinez-Lozano; Hollmén, Maija; Li, Xue; Detmar, Michael; Zenobi, Renato

    2014-06-01

    There is increasing interest in the development of noninvasive diagnostic methods for early cancer detection, to improve the survival rate and quality of life of cancer patients. Identification of volatile metabolic compounds may provide an approach for noninvasive early diagnosis of malignant diseases. Here we analyzed the volatile metabolic signature of human breast cancer cell lines versus normal human mammary cells. Volatile compounds in the headspace of conditioned culture medium were directly fingerprinted by secondary electrospray ionization-mass spectrometry. The mass spectra were subsequently treated statistically to identify discriminating features between normal vs. cancerous cell types. We were able to classify different samples by using feature selection followed by principal component analysis (PCA). Additionally, high-resolution mass spectrometry allowed us to propose their chemical structures for some of the most discriminating molecules. We conclude that cancerous cells can release a characteristic odor whose constituents may be used as disease markers.

  15. A mammary stem cell population identified and characterized in late embryogenesis reveals similarities to human breast cancer.

    Science.gov (United States)

    Spike, Benjamin T; Engle, Dannielle D; Lin, Jennifer C; Cheung, Samantha K; La, Justin; Wahl, Geoffrey M

    2012-02-03

    Gene expression signatures relating mammary stem cell populations to breast cancers have focused on adult tissue. Here, we identify, isolate, and characterize the fetal mammary stem cell (fMaSC) state since the invasive and proliferative processes of mammogenesis resemble phases of cancer progression. fMaSC frequency peaks late in embryogenesis, enabling more extensive stem cell purification than achieved with adult tissue. fMaSCs are self-renewing, multipotent, and coexpress multiple mammary lineage markers. Gene expression, transplantation, and in vitro analyses reveal putative autocrine and paracrine regulatory mechanisms, including ErbB and FGF signaling pathways impinging on fMaSC growth. Expression profiles from fMaSCs and associated stroma exhibit significant similarities to basal-like and Her2+ intrinsic breast cancer subtypes. Our results reveal links between development and cancer and provide resources to identify new candidates for diagnosis, prognosis, and therapy.

  16. Rat mammary carcinogenesis induced by in situ expression of constitutive Raf kinase activity is prevented by tethering Raf to the plasma membrane.

    Science.gov (United States)

    McFarlin, Daniel R; Gould, Michael N

    2003-06-01

    Mammary carcinogenesis induced through expression of activated Raf was investigated using a model in which retroviral vectors were infused into the central ducts of rat mammary glands. This model allows efficient expression of experimental proteins in a small fraction of endogenous mammary epithelial cells in situ. We previously reported that Raf is the dominant oncogenic signaling pathway from activated Ras in rat mammary glands. We show here that mammary gland carcinogenesis is rapidly induced by the expression of c-Raf-1 kinase that is activated by N-terminal truncation (Delta-Raf). Interestingly, targeting Raf to the plasma membrane via C-terminal fusion with Ras membrane localization signals (Raf-Caax) induces Raf kinase activity that transforms 3T3 cells more frequently than Delta-Raf, yet in situ expression of Raf-Caax does not induce mammary carcinomas. To investigate these contrasting results and begin elucidating the mechanisms of Raf-induced mammary carcinogenesis, we combined both activating mutations (N-terminal truncation and C-terminal membrane localization motifs) in one Raf construct (Delta-Raf-Caax). While Delta-Raf-Caax transforms 3T3 cells more efficiently than Delta-Raf or Raf-Caax, in situ expression of Delta-Raf-Caax does not induce carcinomas in vivo, demonstrating that lipid modification on the C-terminus of Delta-Raf negates its oncogenic potential in rat mammary gland.

  17. Postmastectomy radiation in supraclavicular and internal mammary regions of patients with breast cancer of stage II/III

    Institute of Scientific and Technical Information of China (English)

    MEI Xin; GUO Xiao-mao; ZHANG Zhen; CHEN Jia-yi

    2009-01-01

    @@ Adjuvant radiotherapy plays a vital role in the treatment of breast cancer, but irradiated area was not standardized. The ipsilateral chest wall and supraclavicular regions with or without internal mammary lymph nodes were reported in patients receiving postmastectomy radiotherapy.1,2 In our study, 133 consecutive patients with breast cancer of stage II/III who had received postmastectomy radiotherapy of supraclavicular and internal mammary regions at Cancer Hospital of Fudan University were analyzed for their survival and locoregional control as well as their relative prognostic predicator.

  18. Canine Mammary Cancer Stem Cells are Radio- and Chemo- Resistant and Exhibit an Epithelial-Mesenchymal Transition Phenotype.

    Science.gov (United States)

    Pang, Lisa Y; Cervantes-Arias, Alejandro; Else, Rod W; Argyle, David J

    2011-03-30

    Canine mammary carcinoma is the most common cancer among female dogs and is often fatal due to the development of distant metastases. In humans, solid tumors are made up of heterogeneous cell populations, which perform different roles in the tumor economy. A small subset of tumor cells can hold or acquire stem cell characteristics, enabling them to drive tumor growth, recurrence and metastasis. In veterinary medicine, the molecular drivers of canine mammary carcinoma are as yet undefined. Here we report that putative cancer stem cells (CSCs) can be isolated form a canine mammary carcinoma cell line, REM134. We show that these cells have an increased ability to form tumorspheres, a characteristic of stem cells, and that they express embryonic stem cell markers associated with pluripotency. Moreover, canine CSCs are relatively resistant to the cytotoxic effects of common chemotherapeutic drugs and ionizing radiation, indicating that failure of clinical therapy to eradicate canine mammary cancer may be due to the survival of CSCs. The epithelial to mesenchymal transition (EMT) has been associated with cancer invasion, metastasis, and the acquisition of stem cell characteristics. Our results show that canine CSCs predominantly express mesenchymal markers and are more invasive than parental cells, indicating that these cells have a mesenchymal phenotype. Furthermore, we show that canine mammary cancer cells can be induced to undergo EMT by TGFβ and that these cells have an increased ability to form tumorspheres. Our findings indicate that EMT induction can enrich for cells with CSC properties, and provide further insight into canine CSC biology.

  19. Canine Mammary Cancer Stem Cells are Radio- and Chemo-Resistant and Exhibit an Epithelial-Mesenchymal Transition Phenotype

    Energy Technology Data Exchange (ETDEWEB)

    Pang, Lisa Y., E-mail: lisa.pang@ed.ac.uk; Cervantes-Arias, Alejandro; Else, Rod W.; Argyle, David J. [Royal (Dick) School of Veterinary Studies and Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, EH25 9RG (United Kingdom)

    2011-03-30

    Canine mammary carcinoma is the most common cancer among female dogs and is often fatal due to the development of distant metastases. In humans, solid tumors are made up of heterogeneous cell populations, which perform different roles in the tumor economy. A small subset of tumor cells can hold or acquire stem cell characteristics, enabling them to drive tumor growth, recurrence and metastasis. In veterinary medicine, the molecular drivers of canine mammary carcinoma are as yet undefined. Here we report that putative cancer stem cells (CSCs) can be isolated form a canine mammary carcinoma cell line, REM134. We show that these cells have an increased ability to form tumorspheres, a characteristic of stem cells, and that they express embryonic stem cell markers associated with pluripotency. Moreover, canine CSCs are relatively resistant to the cytotoxic effects of common chemotherapeutic drugs and ionizing radiation, indicating that failure of clinical therapy to eradicate canine mammary cancer may be due to the survival of CSCs. The epithelial to mesenchymal transition (EMT) has been associated with cancer invasion, metastasis, and the acquisition of stem cell characteristics. Our results show that canine CSCs predominantly express mesenchymal markers and are more invasive than parental cells, indicating that these cells have a mesenchymal phenotype. Furthermore, we show that canine mammary cancer cells can be induced to undergo EMT by TGFβ and that these cells have an increased ability to form tumorspheres. Our findings indicate that EMT induction can enrich for cells with CSC properties, and provide further insight into canine CSC biology.

  20. Soy isoflavone exposure through all life stages accelerates 17β-estradiol-induced mammary tumor onset and growth, yet reduces tumor burden, in ACI rats.

    Science.gov (United States)

    Möller, Frank Josef; Pemp, Daniela; Soukup, Sebastian T; Wende, Kathleen; Zhang, Xiajie; Zierau, Oliver; Muders, Michael H; Bosland, Maarten C; Kulling, Sabine E; Lehmann, Leane; Vollmer, Günter

    2016-08-01

    There is an ongoing debate whether the intake of soy-derived isoflavones (sISO) mediates beneficial or adverse effects with regard to breast cancer risk. Therefore, we investigated whether nutritional exposure to a sISO-enriched diet from conception until adulthood impacts on 17β-estradiol (E2)-induced carcinogenesis in the rat mammary gland (MG). August-Copenhagen-Irish (ACI) rats were exposed to dietary sISO from conception until postnatal day 285. Silastic tubes containing E2 were used to induce MG tumorigenesis. Body weight, food intake, and tumor growth were recorded weekly. At necropsy, the number, position, size, and weight of each tumor were determined. Plasma samples underwent sISO analysis, and the morphology of MG was analyzed. Tumor incidence and multiplicity were reduced by 20 and 56 %, respectively, in the sISO-exposed rats compared to the control rats. Time-to-tumor onset was shortened from 25 to 20 weeks, and larger tumors developed in the sISO-exposed rats. The histological phenotype of the MG tumors was independent of the sISO diet received, and it included both comedo and cribriform phenotypes. Morphological analyses of the whole-mounted MGs also showed no diet-dependent differences. Lifelong exposure to sISO reduced the overall incidence of MG carcinomas in ACI rats, although the time-to-tumor was significantly shortened.

  1. Altered expression of glycosaminoglycans in metastatic 13762NF rat mammary adenocarcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Steck, P.A.; Cheong, P.H.; Nakajima, M.; Yung, W.K.A.; Moser, R.P.; Nicolson, G.L.

    1987-02-24

    A difference in the expression and metabolism of (/sup 35/S)sulfated glycosaminoglycans between rat mammary tumor cells derived from a primary tumor and those from its metastatic lesions has been observed. Cells from the primary tumor possessed about equal quantities of chondroitin sulfate and heparan sulfate on their cell surfaces but released fourfold more chondroitin sulfate than heparan sulfate into their medium. In contrast, cells from distal metastatic lesions expressed approximately 5 times more heparan sulfate than chondroitin sulfate in both medium and cell surface fractions. This was observed to be the result of differential synthesis of the glycosaminoglycans and not of major structural alterations of the individual glycosaminoglycans. The degree of sulfation and size of heparan sulfate were similar for all cells examined. However, chondroitin sulfate, observed to be only chondroitin 4-sulfate, from the metastases-derived cells had a smaller average molecular weight on gel filtration chromatography and showed a decreased quantity of sulfated disaccharides upon degradation with chondroitin ABC lyase compared to the primary tumor derived cells. Major qualitative or quantitative alterations were not observed for hyaluronic acid among the various 13762NF cells. The metabolism of newly synthesized sulfated glycosaminoglycans was also different between cells from primary tumor and metastases. A pulse-chase kinetics study demonstrated that both heparan sulfate and chondroitin sulfate were degraded by the metastases-derived cells, whereas the primary tumor derived cells degraded only heparan sulfate and degraded it at a slower rate. These results suggested that altered glycosaminoglycan expression and metabolism may be associated with the metastatic process in 13762NF rat mammary tumor cells.

  2. Genetic mapping in mice identifies DMBT1 as a candidate modifier of mammary tumors and breast cancer risk

    DEFF Research Database (Denmark)

    Blackburn, Anneke C; Hill, Linda Z; Roberts, Amy L;

    2007-01-01

    Low-penetrance breast cancer susceptibility alleles seem to play a significant role in breast cancer risk but are difficult to identify in human cohorts. A genetic screen of 176 N2 backcross progeny of two Trp53(+/-) strains, BALB/c and C57BL/6, which differ in their susceptibility to mammary...

  3. Tracing anti-cancer and cancer-promoting actions of all-trans retinoic acid in breast cancer to a RARα epigenetic mechanism of mammary epithelial cell fate.

    Science.gov (United States)

    Rossetti, Stefano; Ren, MingQiang; Visconti, Nicolo; Corlazzoli, Francesca; Gagliostro, Vincenzo; Somenzi, Giulia; Yao, Jin; Sun, Yijun; Sacchi, Nicoletta

    2016-12-27

    A hallmark of cancer cells is the ability to evade the growth inhibitory/pro-apoptotic action of physiological all-trans retinoic acid (RA) signal, the bioactive derivative of Vitamin A. However, as we and others reported, RA can also promote cancer cell growth and invasion. Here we show that anticancer and cancer-promoting RA actions in breast cancer have roots in a mechanism of mammary epithelial cell morphogenesis that involves both transcriptional (epigenetic) and non-transcriptional RARα (RARA) functions. We found that the mammary epithelial cell-context specific degree of functionality of the RARA transcriptional (epigenetic) component of this mechanism, by tuning the effects of the non-transcriptional RARA component, determines different cell fate decisions during mammary morphogenesis. Indeed, factors that hamper the RARA epigenetic function make physiological RA drive aberrant morphogenesis via non-transcriptional RARA, thus leading to cell transformation. Remarkably, also the cell context-specific degree of functionality of the RARA epigenetic component retained by breast cancer cells is critical to determine cell fate decisions in response to physiological as well as supraphysiological RA variation. Overall this study supports the proof of principle that the epigenetic functional plasticity of the mammary epithelial cell RARA mechanism, which is essential for normal morphogenetic processes, is necessary to deter breast cancer onset/progression consequent to the insidious action of physiological RA.

  4. The T-box transcription factors TBX2 and TBX3 in mammary gland development and breast cancer.

    Science.gov (United States)

    Douglas, Nataki C; Papaioannou, Virginia E

    2013-06-01

    TBX2 and TBX3, closely related members of the T-box family of transcription factor genes, are expressed in mammary tissue in both humans and mice. Ulnar mammary syndrome (UMS), an autosomal dominant disorder caused by mutations in TBX3, underscores the importance of TBX3 in human breast development, while abnormal mammary gland development in Tbx2 or Tbx3 mutant mice provides models for experimental investigation. In addition to their roles in mammary development, aberrant expression of TBX2 and TBX3 is associated with breast cancer. TBX2 is preferentially amplified in BRCA1/2-associated breast cancers and TBX3 overexpression has been associated with advanced stage disease and estrogen-receptor-positive breast tumors. The regulation of Tbx2 and Tbx3 and the downstream targets of these genes in development and disease are not as yet fully elucidated. However, it is clear that the two genes play unique, context-dependent roles both in mammary gland development and in mammary tumorigenesis.

  5. Trans-Resveratrol Alters Mammary Promoter Hypermethylation in Women at Increased Risk for Breast Cancer

    Science.gov (United States)

    Zhu, Weizhu; Qin, Wenyi; Zhang, Ke; Rottinghaus, George E.; Chen, Yin-Chieh; Kliethermes, Beth; Sauter, Edward R.

    2012-01-01

    Trans-resveratrol, present in high concentration in the skin of red grapes and red wine, has a dose-dependent antiproliferative effect in vitro, prevents the formation of mammary tumors, and has been touted as a chemopreventive agent. Based upon in vitro studies demonstrating that trans-resveratrol downregulates the expression of 1) DNA methyltransferases and 2) the cancer promoting prostaglandin (PG)E2, we determined if trans-resveratrol had a dose-related effect on DNA methylation and prostaglandin expression in humans. Thirty-nine adult women at increased breast cancer risk were randomized in double-blind fashion to placebo, 5 or 50 mg trans-resveratrol twice daily for 12 wk. Methylation assessment of 4 cancer-related genes (p16, RASSF-1α, APC, CCND2) was performed on mammary ductoscopy specimens. The predominant resveratrol species in serum was the glucuronide metabolite. Total trans-resveratrol and glucuronide metabolite serum levels increased after consuming both trans-resveratrol doses (P < .001 for both). RASSF-1α methylation decreased with increasing levels of serum trans-resveratrol (P = .047). The change in RASSF-1α methylation was directly related to the change in PGE2 (P = .045). This work provides novel insights into the effects of trans-resveratrol on the breast of women at increased breast cancer risk, including a decrease in methylation of the tumor suppressor gene RASSF-1α. Because of the limited sample size, our findings should be validated in a larger study. PMID:22332908

  6. Internal mammary chain irradiation in breast cancer: State of the art; Radiotherapie de la chaine mammaire interne dans les cancers du sein: etat des lieux

    Energy Technology Data Exchange (ETDEWEB)

    Auberdiac, P.; Cartier, L.; Hau Desbat, N.H.; De Laroche, G.; Magne, N. [Unite de curietherapie, departement de radiotherapie, institut de cancerologie de la Loire, 108 bis, avenue Albert-Raimond, BP 60008, 42271 Saint-Priest-en-Jarez cedex (France); Chargari, C. [Service d' oncologie radiotherapie, hopital d' instruction des armees du Val-de-Grace, 74, boulevard Port-Royal, 75230 Paris cedex 5 (France); Zioueche, A. [Service de radiotherapie, CHU Dupuytren, 2, avenue Martin-Luther-King, 87000 Limoges (France); Melis, A. [Departement d' oncologie medicale, institut de cancerologie de la Loire, 108 bis, avenue Albert-Raimond, 42271 Saint-Priest-en-Jarez cedex (France); Kirova, Y.M. [Service de radiotherapie oncologique, institut Curie, 26, rue d' Ulm, 75005 Paris (France)

    2011-04-15

    Radiation therapy has a major role in the management of infiltrative breast cancers. However, there is no consensus for the prophylactic treatment of the internal mammary chain (IMC), with strategies that show strong differences according to centers and physicians. Indications for internal mammary chain radiotherapy are debated, since this treatment significantly increases the dose delivered to the heart and leads to potential technical difficulties. Important prospective data recently suggested that internal mammary chain radiotherapy would not be necessary, even in cases of internal or central tumor locations, or in patients with positive axillary lymph nodes. Although these data warrant confirmation by two other prospective trials, there is evidence that the indications for internal mammary chain radiotherapy should be careful and that high quality techniques should be used for decreasing the dose delivered to the heart. This review of literature presents the state of art on the radiotherapy of internal mammary chain, with special focus on the indications, techniques, and potential toxicity. (authors)

  7. Protective Effect of Piper aduncum Capsule on DMBA-induced Breast Cancer in Rats.

    Science.gov (United States)

    Arroyo-Acevedo, J; Chávez-Asmat, R J; Anampa-Guzmán, A; Donaires, R; Ráez-Gonzáles, José

    2015-01-01

    The possible protective effect of Piper aduncum capsule on DMBA (dimethylbenz[α]anthracene)-induced breast cancer in rats was assessed by monitoring the tumor and lung metastases incidence and recording hematological and biochemical parameters and frequency of micronuclei. Mammary carcinogenesis was induced in 36 female Holtzman rats by providing a single subcutaneous injection of DMBA. Oral administration of P. aduncum capsule lowered adenocarcinoma and lymph node metastases incidence. Pulmonary metastasis was significantly lowered (P aduncum capsule significantly lowered the C reactive protein (CRP) level (P aduncum capsule, we conclude that it has a protective effect on DMBA-induced breast cancer in rats.

  8. The role of the microenvironment in mammary gland development and cancer.

    Science.gov (United States)

    Polyak, Kornelia; Kalluri, Raghu

    2010-11-01

    The mammary gland is composed of a diverse array of cell types that form intricate interaction networks essential for its normal development and physiologic function. Abnormalities in these interactions play an important role throughout different stages of tumorigenesis. Branching ducts and alveoli are lined by an inner layer of secretory luminal epithelial cells that produce milk during lactation and are surrounded by contractile myoepithelial cells and basement membrane. The surrounding stroma comprised of extracellular matrix and various cell types including fibroblasts, endothelial cells, and infiltrating leukocytes not only provides a scaffold for the organ, but also regulates mammary epithelial cell function via paracrine, physical, and hormonal interactions. With rare exceptions breast tumors initiate in the epithelial compartment and in their initial phases are confined to the ducts but this barrier brakes down with invasive progression because of a combination of signals emitted by tumor epithelial and various stromal cells. In this article, we overview the importance of cellular interactions and microenvironmental signals in mammary gland development and cancer.

  9. JS-K, a nitric oxide-releasing prodrug, induces breast cancer cell death while sparing normal mammary epithelial cells.

    Science.gov (United States)

    McMurtry, Vanity; Saavedra, Joseph E; Nieves-Alicea, René; Simeone, Ann-Marie; Keefer, Larry K; Tari, Ana M

    2011-04-01

    Targeted therapy with reduced side effects is a major goal in cancer research. We investigated the effects of JS-K, a nitric oxide (NO) prodrug designed to release high levels of NO when suitably activated, on human breast cancer cell lines, on non-transformed human MCF-10A mammary cells, and on normal human mammary epithelial cells (HMECs). Cell viability assay, flow cytometry, electron microscopy, and Western blot analysis were used to study the effects of JS-K on breast cancer and on mammary epithelial cells. After a 3-day incubation, the IC50s of JS-K against the breast cancer cells ranged from 0.8 to 3 µM. However, JS-K decreased the viability of the MCF-10A cells by only 20% at 10-µM concentration, and HMECs were unaffected by 10 µM JS-K. Flow cytometry indicated that JS-K increased the percentages of breast cancer cells under-going apoptosis. Interestingly, flow cytometry indicated that JS-K increased acidic vesicle organelle formation in breast cancer cells, suggesting that JS-K induced autophagy in breast cancer cells. Electron microscopy confirmed that JS-K-treated breast cancer cells underwent autophagic cell death. Western blot analysis showed that JS-K induced the expression of microtubule light chain 3-II, another autophagy marker, in breast cancer cells. However, JS-K did not induce apoptosis or autophagy in normal human mammary epithelial cells. These data indicate that JS-K selectively induces programmed cell death in breast cancer cells while sparing normal mammary epithelial cells under the same conditions. The selective anti-tumor activity of JS-K warrants its further investigation in breast tumors.

  10. Development of new therapy for canine mammary cancer with recombinant measles virus

    Directory of Open Access Journals (Sweden)

    Koichiro Shoji

    2016-01-01

    Full Text Available Oncolytic virotherapy is a promising treatment strategy for cancer. We previously generated a recombinant measles virus (rMV-SLAMblind that selectively uses a poliovirus receptor-related 4 (PVRL4/Nectin4 receptor, but not signaling lymphocyte activation molecule (SLAM. We demonstrated that the virus exerts therapeutic effects against human breast cancer cells. Here, we examined the applicability of rMV-SLAMblind to treating canine mammary cancers (CMCs. We found that the susceptibilities of host cells to rMV-SLAMblind were dependent on canine Nectin-4 expression. Nectin-4 was detected in four of nine CMC cell lines. The rMV-SLAMblind efficiently infected those four Nectin-4-positive cell lines and was cytotoxic for three of them (CF33, CHMm, and CTBm. In vivo experiment showed that the administration of rMV-SLAMblind greatly suppressed the progression of tumors in mice xenografted with a CMC cell line (CF33. Immunohistochemistry revealed that canine Nectin-4 was expressed in 45% of canine mammary tumors, and the tumor cells derived from one clinical specimen were efficiently infected with rMV-SLAMblind. These results suggest that rMV-SLAMblind infects CMC cells and displays antitumor activity in vitro, in xenografts, and ex vivo. Therefore, oncolytic virotherapy with rMV-SLAMblind can be a novel method for treating CMCs.

  11. Recuperative effect of Semecarpus anacardium linn. nut milk extract on carbohydrate metabolizing enzymes in experimental mammary carcinoma-bearing rats.

    Science.gov (United States)

    Sujatha, Venugopal; Sachdanandam, Panchanatham

    2002-03-01

    Semecarpus anacardium Linn. of the family Anacardiaceae has many applications in the Ayurvedic and Siddha systems of medicine. We have tested the antitumour activity of Semecarpus anacardium nut extract against experimental mammary carcinoma in animals. As there is a direct relationship between the proliferation of tumour cells and the activities of the glycolytic and gluconeogenic enzymes, we studied changes in the activities of enzymes involved in this metabolic pathway in the liver and kidney. The enzymes investigated were glycolytic enzymes, namely hexokinase, phosphoglucoisomerase, aldolase and the gluconeogenic enzymes, namely glucose-6-phosphatase and fructose-1,6-biphosphatase in experimental rats. A significant rise in glycolytic enzyme activities and a simultaneous fall in gluconeogenic enzyme activities were found in mammary carcinoma bearing rats. Drug administration returned these enzyme activities to their respective control activities. Copyright 2002 John Wiley & Sons, Ltd.

  12. Quantitative assessment of mammary gland development in female Long Evans rats following in utero exposure to atrazine.

    Science.gov (United States)

    Hovey, Russell C; Coder, Pragati Sawhney; Wolf, Jeffrey C; Sielken, Robert L; Tisdel, Merrill O; Breckenridge, Charles B

    2011-02-01

    In this study, we quantified the effects of in utero exposure to the herbicide atrazine on subsequent mammary gland development. Atrazine was administered to pregnant female Long Evans rats from gestation days 13-19 at doses of 0, 6.5, 50, or 100 mg/kg/day. A pair-fed control group was yoked to the high-dose atrazine-treated group. Litter size was standardized to 10 pups on postnatal day (PND) 4. Whole mounts of the left fourth mammary gland and histologic sections of the right fourth gland were obtained from a subgroup of offspring on PND1, 21, 33, on day of vaginal opening (VO), or around PND65 at diestrus. A blinded, quantitative analysis of key morphological features in mammary gland whole mounts (ductal elongation, ductal network area, epithelial area, terminal end bud [TEB] incidence, and epithelial density) as well as epithelial proliferation within different parenchymal structures was conducted. There was no effect of atrazine exposure on any of the measures of mammary gland development at the maternal dose of 6.5 mg/kg/day. On PND1, ductal elongation was increased by approximately 20% (p < 0.05) in the female offspring born to dams exposed to 50 and 100 mg/kg/day atrazine, coincident with decreased epithelial proliferation in the 100 mg/kg/day group at this age. These differences were not present on PND21, or thereafter. An increased incidence of TEB in the mammary glands from females that were born to both the pair-fed and 50 mg/kg/day-treated dams at the time of VO indicated that this response was a specific result of maternal caloric restriction. Collectively, these data indicate that maternal atrazine exposure has no long-term effects on mammary gland development in female offspring beyond a transitory response to high doses at PND1.

  13. Stage-specific embryonic antigen: determining expression in canine glioblastoma, melanoma, and mammary cancer cells

    Science.gov (United States)

    Ito, Daisuke

    2017-01-01

    The expression of stage-specific embryonic antigens (SSEAs) was determined in several types of canine cancer cells. Flow cytometry showed SSEA-1 expression in glioblastoma, melanoma, and mammary cancer cells, although none expressed SSEA-3 or SSEA-4. Expression of SSEA-1 was not detected in lymphoma, osteosarcoma, or hemangiosarcoma cell lines. Relatively stable SSEA-1 expression was observed between 24 and 72 h of culture. After 8 days in culture, sorted SSEA-1− and SSEA-1+ cells re-established SSEA-1 expression to levels comparable to those observed in unsorted cells. Our results document, for the first time, the expression of SSEA-1 in several canine cancer cell lines. PMID:27456773

  14. From milk to malignancy: the role of mammary stem cells in development, pregnancy and breast cancer.

    Science.gov (United States)

    Tiede, Benjamin; Kang, Yibin

    2011-02-01

    Adult stem cells of the mammary gland (MaSCs) are a highly dynamic population of cells that are responsible for the generation of the gland during puberty and its expansion during pregnancy. In recent years significant advances have been made in understanding how these cells are regulated during these developmentally important processes both in humans and in mice. Understanding how MaSCs are regulated is becoming a particularly important area of research, given that they may be particularly susceptible targets for transformation in breast cancer. Here, we summarize the identification of MaSCs, how they are regulated and the evidence for their serving as the origins of breast cancer. In particular, we focus on how changes in MaSC populations may explain both the increased risk of developing aggressive ER/PR(-) breast cancer shortly after pregnancy and the long-term decreased risk of developing ER/PR(+) tumors.

  15. From milk to malignancy: the role of mammary stem cells in development, pregnancy and breast cancer

    Institute of Scientific and Technical Information of China (English)

    Benjamin Tiede; Yibin Kang

    2011-01-01

    Adult stem cells of the mammary gland (MaSCs) are a highly dynamic population of cells that are responsible for the generation of the gland during puberty and its expansion during pregnancy, in recent years significant advances have been made in understanding how these cells are regulated during these developmentally important processes both in humans and in mice. Understanding how MaSCs are regulated is becoming a particularly important area of research, given that they may be particularly susceptible targets for transformation in breast cancer. Here, we summarize the identification of MaSCs, how they are regulated and the evidence for their serving as the origins of breast cancer, in particular, we focus on how changes in MaSC populations may explain both the increased risk of developing aggressive ERJPR(-) breast cancer shortly after pregnancy and the long-term decreased risk of developing ER/ PR(+) tumors.

  16. 4-Vinylcyclohexene Diepoxide (VCD) Inhibits Mammary Epithelial Differentiation and Induces Fibroadenoma Formation in Female Sprague Dawley Rats

    OpenAIRE

    Wright, Laura E; Frye, Jennifer B.; Lukefahr, Ashley L.; Samuel L. Marion; Hoyer, Patricia B.; Besselsen, David G.; Funk, Janet L.

    2011-01-01

    4-Vinylcyclohexene diepoxide (VCD), an occupational chemical that targets ovarian follicles and accelerates ovarian failure in rodents, was used to test the effect of early-onset reproductive senescence on mammary fibroadenoma formation. One-month female Sprague Dawley rats were dosed with VCD (80 mg/kg or 160 mg/kg) and monitored for 22 months for persistent estrus and tumor development. Only high-dose VCD treatment accelerated the onset of persistent estrus relative to controls. However, bo...

  17. Metastatic canine mammary carcinomas can be identified by a gene expression profile that partly overlaps with human breast cancer profiles

    Directory of Open Access Journals (Sweden)

    Hummel Michael

    2010-11-01

    Full Text Available Abstract Background Similar to human breast cancer mammary tumors of the female dog are commonly associated with a fatal outcome due to the development of distant metastases. However, the molecular defects leading to metastasis are largely unknown and the value of canine mammary carcinoma as a model for human breast cancer is unclear. In this study, we analyzed the gene expression signatures associated with mammary tumor metastasis and asked for parallels with the human equivalent. Methods Messenger RNA expression profiles of twenty-seven lymph node metastasis positive or negative canine mammary carcinomas were established by microarray analysis. Differentially expressed genes were functionally characterized and associated with molecular pathways. The findings were also correlated with published data on human breast cancer. Results Metastatic canine mammary carcinomas had 1,011 significantly differentially expressed genes when compared to non-metastatic carcinomas. Metastatic carcinomas had a significant up-regulation of genes associated with cell cycle regulation, matrix modulation, protein folding and proteasomal degradation whereas cell differentiation genes, growth factor pathway genes and regulators of actin organization were significantly down-regulated. Interestingly, 265 of the 1,011 differentially expressed canine genes are also related to human breast cancer and, vice versa, parts of a human prognostic gene signature were identified in the expression profiles of the metastatic canine tumors. Conclusions Metastatic canine mammary carcinomas can be discriminated from non-metastatic carcinomas by their gene expression profiles. More than one third of the differentially expressed genes are also described of relevance for human breast cancer. Many of the differentially expressed genes are linked to functions and pathways which appear to be relevant for the induction and maintenance of metastatic progression and may represent new therapeutic

  18. Description of the prevalence, histologic characteristics, concomitant abnormalities, and outcomes of mammary gland tumors in companion rats (Rattus norvegicus): 100 cases (1990-2015).

    Science.gov (United States)

    Vergneau-Grosset, Claire; Keel, M Kevin; Goldsmith, Dayna; Kass, Philip H; Paul-Murphy, Joanne; Hawkins, Michelle G

    2016-11-15

    OBJECTIVE To describe the prevalence, histologic characteristics, concomitant abnormalities, and outcomes for various types of mammary gland tumors in companion rats (Rattus norvegicus). DESIGN Retrospective case series. ANIMALS 100 client-owned rats. PROCEDURES Medical records of companion rats that had an SC mass and were examined at a veterinary teaching hospital between 1990 and 2015 were reviewed. Information regarding the signalment, age at mass detection, reproductive sterilization status, histologic diagnosis of the SC mass, location of the initial and all subsequent SC masses, treatments administered, and clinical outcomes was extracted from each record and summarized. RESULTS 105 SC masses were initially detected in 100 rats. The most prevalent SC mass identified was mammary gland fibroadenoma (56/105 [53%]), followed by mammary gland carcinoma (13/105 [12%]). Overall, 26 of 105 (25%) masses were malignant. Sexually intact males were more likely to have nonmammary SC tumors than sexually intact females. In rats receiving no adjunctive treatment after excision of a mammary gland fibroadenoma (n = 16), a second fibroadenoma was detected 1 to 8 months after initial excision, at a median of 4.5 months after surgery. A concomitant pituitary gland tumor was identified in most rats with mammary gland fibroadenoma (21/28 [75%]) and other types of mammary gland tumors (10/17 [59%]). Fourteen of 35 (40%) rats with mammary gland fibroadenoma had concomitant reproductive tract abnormalities. CONCLUSION AND CLINICAL RELEVANCE Results suggested that, like other species, companion rats with SC masses should undergo a thorough diagnostic workup that includes histologic examination of the excised mass.

  19. The plasticizer butyl benzyl phthalate induces genomic changes in rat mammary gland after neonatal/prepubertal exposure

    Directory of Open Access Journals (Sweden)

    Lamartiniere Coral A

    2007-12-01

    Full Text Available Abstract Background Phthalate esters like n-butyl benzyl phthalate (BBP are widely used plasticizers. BBP has shown endocrine-disrupting properties, thus having a potential effect on hormone-sensitive tissues. The aim of this study is to determine the effect of neonatal/prepubertal exposure (post-natal days 2–20 to BBP on maturation parameters and on the morphology, proliferative index and genomic signature of the rat mammary gland at different ages of development (21, 35, 50 and 100 days. Results Here we show that exposure to BBP increased the uterine weight/body weight ratio at 21 days and decreased the body weight at time of vaginal opening. BBP did not induce significant changes on the morphology of the mammary gland, but increased proliferative index in terminal end buds at 35 days and in lobules 1 at several ages. Moreover, BBP had an effect on the genomic profile of the mammary gland mainly at the end of the exposure (21 days, becoming less prominent thereafter. By this age a significant number of genes related to proliferation and differentiation, communication and signal transduction were up-regulated in the glands of the exposed animals. Conclusion These results suggest that BBP has an effect in the gene expression profile of the mammary gland.

  20. Genetic mapping in mice identifies DMBT1 as a candidate modifier of mammary tumors and breast cancer risk

    DEFF Research Database (Denmark)

    Blackburn, Anneke C; Hill, Linda Z; Roberts, Amy L

    2007-01-01

    Low-penetrance breast cancer susceptibility alleles seem to play a significant role in breast cancer risk but are difficult to identify in human cohorts. A genetic screen of 176 N2 backcross progeny of two Trp53(+/-) strains, BALB/c and C57BL/6, which differ in their susceptibility to mammary...... tumors, identified a modifier of mammary tumor susceptibility in an approximately 25-Mb interval on mouse chromosome 7 (designated SuprMam1). Relative to heterozygotes, homozygosity for BALB/c alleles of SuprMam1 significantly decreased mammary tumor latency from 70.7 to 61.1 weeks and increased risk...... twofold (P = 0.002). Dmbt1 (deleted in malignant brain tumors 1) was identified as a candidate modifier gene within the SuprMam1 interval because it was differentially expressed in mammary tissues from BALB/c-Trp53(+/-) and C57BL/6-Trp53(+/-) mice. Dmbt1 mRNA and protein was reduced in mammary glands...

  1. Luteolin suppresses development of medroxyprogesterone acetate-accelerated 7,12-dimethylbenz(a)anthracene-induced mammary tumors in Sprague-Dawley rats.

    Science.gov (United States)

    Cook, Matthew T; Mafuvadze, Benford; Besch-Williford, Cynthia; Ellersieck, Mark R; Goyette, Sandy; Hyder, Salman M

    2016-02-01

    Postmenopausal women undergoing hormone-replacement therapy containing both progestins and estrogens are at an increased risk of developing breast cancer compared with women taking estrogen alone. We recently demonstrated that medroxyprogesterone acetate, a progestin commonly used for hormone-replacement therapy, accelerates development of mammary carcinogenesis in 7,12-dimethylbenz(a)anthracene‑treated Sprague-Dawley rats. Synthetic antiprogestins used to block the deleterious effects of progestins, are themselves associated with toxic side-effects. In order to circumvent this, we used the aforementioned model to identify less toxic natural compounds that may prevent the development of progestin-accelerated tumors. Luteolin, a naturally-occurring flavonoid commonly found in fruits and vegetables, has previously been shown to possess anticancer properties. In our studies, both low (1 mg/kg) and high (25 mg/kg) doses of luteolin significantly suppressed progestin-dependent increases in tumor incidence, while increasing tumor latency and reducing the occurrence of large (>300 mm3) mammary tumors. However, an intermediate dose of luteolin (10 mg/kg), while suppressing the development of large tumors, did not affect either tumor incidence or latency. Immunohistochemical analysis of tumor tissues revealed that all concentrations of luteolin (1, 10, and 25 mg/kg) significantly reduced levels of VEGF within tumors. The suppressive effects of luteolin on tumor incidence and volume, together with its ability to reduce VEGF and blood vessels, persisted even after treatment was terminated. This suggests that luteolin possesses anti‑angiogenic properties which could mechanistically explain its capacity to control tumor progression. Thus luteolin may be a valuable, non-toxic, naturally-occurring anticancer compound which may potentially be used to combat progestin-accelerated mammary tumors.

  2. Antiproliferative Effects of Oxytocin and Desmopressin on Canine Mammary Cancer Cells

    Science.gov (United States)

    Benavente, Micaela Andrea; Bianchi, Carolina Paula; Imperiale, Fernanda; Aba, Marcelo Alfredo

    2016-01-01

    Neoplasms of the mammary gland represent the most frequent tumor type in the female dog, and according to the histologic criteria, approximately 50% of them are malignant. In the most aggressive cases of mammary cancer, surgery is not enough to warrant a favorable outcome, and adjuvant therapies are needed to improve the patient’s overall survival. The aim of the present study was to evaluate the effects of two peptides on proliferation of a canine mammary cancer cell line derived from a simple carcinoma. The cell line CMT-U27 was grown in 96-well plates, at two cell densities (4 × 103 and 8 × 103 cells/well). Cultures were treated with oxytocin (OT) or desmopressin at five concentrations (10, 50, 100, 500, and 1000 nM). After 72 h of incubation, cell proliferation was determined by the MTT assay. Results showed that with 4 × 103 cells/well, OT at 50, 500, and 1000 nM was growth inhibitory for the cells, being statistically significant at 1000 nM. On the contrary, no antiproliferative effect was observed with 10 or 100 nM. At 8 × 103 cells/well, OT showed a significant antiproliferative effect only with the highest concentration (1000 nM). Desmopressin at 4 × 103 cells/well decreased cell viability at concentrations of 50, 100, 500, and 1000 nM (statistically significant with the highest concentration), while no effect was observed with 10 nM. With 8 × 103 cells/well, this peptide reduced cell growth at 100, 500, and 1000 nM. In conclusion, we suggest that these peptides may be potential and promising compounds for the treatment of dogs with simple carcinomas of the mammary gland. In vivo studies are required to confirm this hypothesis. PMID:28083539

  3. Prevention of rat breast cancer by genistin and selenium.

    Science.gov (United States)

    Hamdy, Soha M; Latif, Abdel Karim M Abdel; Drees, Ehab A; Soliman, Sahar M

    2012-09-01

    Breast cancer is the second leading cause of cancer death among women and the third most common cancer. In this study, we investigated the chemoprevention efficacy of each of soy genistin, selenium or a combination of them against breast cancer. Seventy-five female rats were divided into five groups : control group (I); 7,12-dimethylbenz(a)anthracene (DMBA) group (II); DMBA treated with genistin group (III); DMBA treated with selenium group (IV); and DMBA treated with genistin combined with selenium group (V). The treatments were daily administered for 3 months. There were a significant decrease in body weight and serum total antioxidant, while a significant elevation in serum total sialic acid, carcinoembryonic antigen, prolactin, estradiol, nitric oxide, and malondialdhyde of DMBA injected rats compared with control group. Administration of genistin and selenium was associated with decreasing levels of tumorigenicity, endocrine derangement, and oxidative stress. Formation of breast carcinoma in DMBA-induced rats and abnormal changes were ameliorated in the rats treated with genistin/selenium or genistin alone. Supplementation of genistin alone or with selenium provided antioxidant defense with high-potential chemopreventive activity against DMBA-induced mammary tumors more than selenium alone.

  4. Elf5 inhibits the epithelial-mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2.

    Science.gov (United States)

    Chakrabarti, Rumela; Hwang, Julie; Andres Blanco, Mario; Wei, Yong; Lukačišin, Martin; Romano, Rose-Anne; Smalley, Kirsten; Liu, Song; Yang, Qifeng; Ibrahim, Toni; Mercatali, Laura; Amadori, Dino; Haffty, Bruce G; Sinha, Satrajit; Kang, Yibin

    2012-11-01

    The epithelial-mesenchymal transition (EMT) is a complex process that occurs during organogenesis and in cancer metastasis. Despite recent progress, the molecular pathways connecting the physiological and pathological functions of EMT need to be better defined. Here we show that the transcription factor Elf5, a key regulator of mammary gland alveologenesis, controls EMT in both mammary gland development and metastasis. We uncovered this role for Elf5 through analyses of Elf5 conditional knockout animals, various in vitro and in vivo models of EMT and metastasis, an MMTV-neu transgenic model of mammary tumour progression and clinical breast cancer samples. Furthermore, we demonstrate that Elf5 suppresses EMT by directly repressing the transcription of Snail2, a master regulator of mammary stem cells and a known inducer of EMT. These findings establish Elf5 not only as a key cell lineage regulator during normal mammary gland development, but also as a suppressor of EMT and metastasis in breast cancer.

  5. Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth

    DEFF Research Database (Denmark)

    Hojman, Pernille; Dethlefsen, Christine; Brandt, Claus

    2011-01-01

    Regular physical activity protects against the development of breast and colon cancer, since it reduces the risk of developing these by 25-30%. During exercise, humoral factors are released from the working muscles for endocrinal signaling to other organs. We hypothesized that these myokines...... mediate some of the inhibitory effects of exercise on mammary cancer cell proliferation. Serum and muscles were collected from mice after an exercise bout. Incubation with exercise-conditioned serum inhibited MCF-7 cell proliferation by 52% and increased caspase activity by 54%. A similar increase...... proliferation by 42%, increase caspase activity by 46%, and induce apoptosis. Blocking OSM signaling with anti-OSM antibodies reduced the induction of caspase activity by 51%. To verify that OSM was a myokine, we showed that it was significantly upregulated in serum and in three muscles, tibialis cranialis...

  6. Associated expressions of FGFR-2 and FGFR-3: from mouse mammary gland physiology to human breast cancer.

    Science.gov (United States)

    Cerliani, Juan P; Vanzulli, Silvia I; Piñero, Cecilia Pérez; Bottino, María C; Sahores, Ana; Nuñez, Myriam; Varchetta, Romina; Martins, Rubén; Zeitlin, Eduardo; Hewitt, Stephen M; Molinolo, Alfredo A; Lanari, Claudia; Lamb, Caroline A

    2012-06-01

    Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors which have been implicated in breast cancer. The aim of this study was to evaluate FGFR-1, -2, -3, and -4 protein expressions in normal murine mammary gland development, and in murine and human breast carcinomas. Using immunohistochemistry and Western blot, we report a hormonal regulation of FGFR during postnatal mammary gland development. Progestin treatment of adult virgin mammary glands resulted in changes in localization of FGFR-3 from the cytoplasm to the nucleus, while treatment with 17-β-estradiol induced changes in the expressions and/or localizations of FGFR-2 and -3. In murine mammary carcinomas showing different degrees of hormone dependence, we found progestin-induced increased expressions, mainly of FGFR-2 and -3. These receptors were constitutively activated in hormone-independent variants. We studied three luminal human breast cancer cell lines growing as xenografts, which particularly expressed FGFR-2 and -3, suggesting a correlation between hormonal status and FGFR expression. Most importantly, in breast cancer samples from 58 patients, we found a strong association (P FGFR-2 and -3 expressions and a weaker correlation of each receptor with estrogen receptor expression. FGFR-4 correlated with c-erbB2 over expression. We conclude that FGFR-2 and -3 may be mechanistically linked and can be potential targets for treatment of estrogen receptor-positive breast cancer patients.

  7. Transcriptomic profile of two canine mammary cancer cell lines with different proliferative and anti-apoptotic potential

    NARCIS (Netherlands)

    Krol, M.; Skierski, J.; Rao, N.A.; Hellmen, E.; Mol, J.A.; Motyl, T.

    2009-01-01

    J Physiol Pharmacol. 2009 May;60 Suppl 1:95-106. Transcriptomic profile of two canine mammary cancer cell lines with different proliferative and anti-apoptotic potential. Krol M, Pawlowski KM, Skierski J, Rao NA, Hellmen E, Mol JA, Motyl T. Department of Physiological Sciences, Faculty of Veterinary

  8. In-silico QTL mapping of postpubertal mammary ductal development in the mouse uncovers potential human breast cancer risk loci

    Science.gov (United States)

    Genetic background plays a dominant role in mammary gland development and breast cancer (BrCa). Despite this, the role of genetics is only partially understood. This study used strain-dependent variation in an inbred mouse mapping panel, to identify quantitative trait loci (QTL) underlying structura...

  9. Evaluation of the circulating glycoprotein CA549 in mammary cancer and other malignancies.

    Science.gov (United States)

    Clocchiatti, L; De Biasi, F; Cartei, G; Sibau, A; Vigevani, E; Signor, M; Giovannoni, M; Ceschia, V; Di Chiara, F; Grandis, S

    1991-10-31

    A prospective study was carried out on a recent marker for breast cancer, CA549, a mucine-like acid glycoprotein present in the fat membranes of human milk. Fifty healthy control subjects and 91 with benign conditions, 103 mammary cancer patients and 256 patients with other types of malignancy were studied. For comparison, CEA and CA15-3 were also investigated. The CA549 cutoff was 11 U/ml. In breast cancer the marker was below the cutoff in 9 cases (92.8%); in malignancies other than breast cancer it was above the cutoff in 5 to 50% of patients. In breast cancer it was raised in 83.3% of cases (CA15-3 showed 82.9% and CEA 50%). In breast cancer after radical surgery, CA549 was normal in patients who were in TNM stage I but above the cutoff in 57.1% of those at more advanced stages. The follow-up study is ongoing among these patients. In all the study conditions, CA549 favorably compared to CA15-3 values, with sensitivity and specificity greater than CEA.

  10. Whey Protein Hydrolysate but not Whole Whey Protein Protects Against 7,12-Dimethylbenz(a)anthracene-Induced Mammary Tumors in Rats.

    Science.gov (United States)

    Ronis, Martin J; Hakkak, Reza; Korourian, Soheila; Badger, Thomas M

    2015-01-01

    Effects of intact and processed bovine milk proteins on development of chemically induced mammary tumors in female rats were compared. AIN-93G diets were made with 20% casein (CAS), casein hydrolysate (CASH), intact whey protein (IWP), or whey protein hydrolysate (WPH). Pregnant Sprague-Dawley rats were fed the diets starting at Gestational Day 4. Offspring were fed the same diet. At 50 days, female offspring (44-49/group) were gavaged with sesame oil containing 80 mg/kg of the mammary carcinogen dimethylbenzanthracene (DMBA) and euthanized 62 days posttreatment. Rats fed WPH had an adenocarcinoma incidence of 17% compared to the rats fed CAS, CASH, and IWP diets (34%, 33%, and 36% respectively) (P whey protein is required for this diet to be effective in reducing DMBA-induced mammary tumors. The bioactive compounds produced during whey protein processing and mechanisms underlying the anticancer effects of WPH are yet to be identified.

  11. Tumor-protective and tumor-promoting actions of dietary whey proteins in an N-methyl-N-nitrosourea model of rat mammary carcinogenesis.

    Science.gov (United States)

    Eason, Renea R; Till, S Reneé; Frank, Julie A; Badger, Thomas M; Korourian, Sohelia; Simmen, Frank A; Simmen, Rosalia C M

    2006-01-01

    The mammary tumor-protective effects of dietary factors are considered to be mediated by multiple signaling pathways, consistent with the heterogeneous nature of the disease and the distinct genetic profiles of tumors arising from diverse mammary cell populations. In a 7,12-dimethylbenz(a)anthracene-induced model of carcinogenesis, we showed previously that female Sprague-Dawley rats exposed to AIN-93G diet containing whey protein hydrolysate (WPH) beginning at gestation Day 4 had reduced tumor incidence than those exposed to diet containing casein (CAS), due partly to increased mammary differentiation and reduced activity of phase I metabolic enzymes. Here, we evaluated the tumor-protective effects of these same dietary proteins to the direct-acting carcinogen N-methyl-N-nitrosourea (NMU). We found that lifetime exposure to WPH, relative to CAS, decreased mammary tumor incidence and prolonged the appearance of tumors in NMU-treated female rats, with no corresponding effects on tumor multiplicity. At 115 days post-NMU, histologically normal mammary glands from WPH-fed tumor-bearing rats had increased gene expression for the tumor suppressor BRCA1 and the differentiation marker kappa-casein than those of CAS-fed tumor-bearing rats. Tumor-bearing rats from the WPH group had more advanced tumors, with a greater incidence of invasive ductal carcinoma than ductal carcinoma in situ and higher serum C-peptide levels than corresponding rats fed CAS. WPH-fed tumor-bearing rats were also heavier after NMU administration than CAS tumor-bearing rats, although no correlation was noted between body weight and C-peptide levels for either diet group. Results demonstrate the context-dependent tumor-protective and tumor-promoting effects of WPH; provide support for distinct signaling pathways underlying dietary effects on development of mammary carcinoma; and raise provocative questions on the role of diet in altering the prognosis of existing breast tumors.

  12. Effect of Semecarpus anacardium nut extract on ECM and proteases in mammary carcinoma rats.

    Science.gov (United States)

    Mathivadhani, P; Shanthi, P; Sachdanandam, P

    2007-06-01

    The early stages of invasion are characterized by the extracellular proteolysis and the accumulation of specialized extracellular matrix (ECM) scaffold, that are responsible for the development of vascular bed, endothelial cell proliferation and invasion of tumour cells. The ground substance of provisional matrix consists of collagen, elastin, glycoaminoglycans and proteoglycans that facilitate the interaction of tumour cells with the host environment. In the present work, we have studied the influence of Semecarpus anacardium nut milk extract on localized differentials of ECM component and proteases involved in matrix metabolism of tumour tissue. Mammary carcinoma was induced in Sprague Dawley rats with 7,12, dimethyl benz(a)anthracene and treated with S. anacardium nut milk extract administered orally for 14 days. The altered amount of ECM components in tumour tissues was almost reverted back to normal level in the drug treated animals. The activities of reported proteases and glycohydrolases were also decreased on treatment with S. anacardium nut milk extract indicating decreased turnover of the matrix. Also, the factors associated with the matrix turnover and expression of MMP-1, MMP-2, MMP-3, TIMP-1 and TIMP-2 were restored back to near normal values. The stabilization of the ECM with the decreased activity of proteases might inhibit the epithelial-endothelial interaction and tumour cell migration thus, preventing the adjacent invasion and tumour growth and might be regarded as antineoplastic agent which demands further studies.

  13. Differential subcellular localization renders HAI-2 a matriptase inhibitor in breast cancer cells but not in mammary epithelial cells.

    Science.gov (United States)

    Chang, Hsiang-Hua D; Xu, Yuan; Lai, Hongyu; Yang, Xiaoyu; Tseng, Chun-Che; Lai, Ying-Jung J; Pan, Yu; Zhou, Emily; Johnson, Michael D; Wang, Jehng-Kang; Lin, Chen-Yong

    2015-01-01

    The type 2 transmembrane serine protease matriptase is under tight control primarily by the actions of the integral membrane Kunitz-type serine protease inhibitor HAI-1. Growing evidence indicates that HAI-2 might also be involved in matriptase inhibition in some contexts. Here we showed that matriptase inhibition by HAI-2 depends on the subcellular localizations of HAI-2, and is observed in breast cancer cells but not in mammary epithelial cells. HAI-2 is co-expressed with matriptase in 21 out of 26 human epithelial and carcinoma cells examined. HAI-2 is also a potent matriptase inhibitor in solution, but in spite of this, HAI-2 inhibition of matriptase is not observed in all contexts where HAI-2 is expressed, unlike what is seen for HAI-1. Induction of matriptase zymogen activation in mammary epithelial cells results in the formation of matriptase-HAI-1 complexes, but matriptase-HAI-2 complexes are not observed. In breast cancer cells, however, in addition to the appearance of matriptase-HAI-1 complex, three different matriptase-HAI-2 complexes, are formed following the induction of matriptase activation. Immunofluorescent staining reveals that activated matriptase is focused at the cell-cell junctions upon the induction of matriptase zymogen activation in both mammary epithelial cells and breast cancer cells. HAI-2, in contrast, remains localized in vesicle/granule-like structures during matriptase zymogen activation in human mammary epithelial cells. In breast cancer cells, however, a proportion of the HAI-2 reaches the cell surface where it can gain access to and inhibit active matriptase. Collectively, these data suggest that matriptase inhibition by HAI-2 requires the translocation of HAI-2 to the cell surface, a process which is observed in some breast cancer cells but not in mammary epithelial cells.

  14. Canine Mammary Cancer Stem Cells are Radio- and Chemo- Resistant and Exhibit an Epithelial-Mesenchymal Transition Phenotype

    Directory of Open Access Journals (Sweden)

    David J. Argyle

    2011-03-01

    Full Text Available Canine mammary carcinoma is the most common cancer among female dogs and is often fatal due to the development of distant metastases. In humans, solid tumors are made up of heterogeneous cell populations, which perform different roles in the tumor economy. A small subset of tumor cells can hold or acquire stem cell characteristics, enabling them to drive tumor growth, recurrence and metastasis. In veterinary medicine, the molecular drivers of canine mammary carcinoma are as yet undefined. Here we report that putative cancer stem cells (CSCs can be isolated form a canine mammary carcinoma cell line, REM134. We show that these cells have an increased ability to form tumorspheres, a characteristic of stem cells, and that they express embryonic stem cell markers associated with pluripotency. Moreover, canine CSCs are relatively resistant to the cytotoxic effects of common chemotherapeutic drugs and ionizing radiation, indicating that failure of clinical therapy to eradicate canine mammary cancer may be due to the survival of CSCs. The epithelial to mesenchymal transition (EMT has been associated with cancer invasion, metastasis, and the acquisition of stem cell characteristics. Our results show that canine CSCs predominantly express mesenchymal markers and are more invasive than parental cells, indicating that these cells have a mesenchymal phenotype. Furthermore, we show that canine mammary cancer cells can be induced to undergo EMT by TGFβ and that these cells have an increased ability to form tumorspheres. Our findings indicate that EMT induction can enrich for cells with CSC properties, and provide further insight into canine CSC biology.

  15. Unraveling the microenvironmental influences on the normal mammary gland and induction and progression of breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Weigelt, Britta; Bissell, Mina J.

    2008-06-26

    The normal mammary gland and invasive breast cancer are both complex 'organs' composed of multiple cell types as well as extracellular matrix (ECM) in three-dimensional (3D) space. Conventionally, both normal and malignant breast cells are studied in vitro as two-dimensional (2D) monolayers of epithelial cells, which results in the loss of structure and tissue function. Many laboratories are now investigating regulation of signaling function in normal mammary gland using 3D cultures. However, it is important also to assay malignant breast cells ex vivo in a physiologically relevant environment to more closely mimic tumor architecture, signal transduction regulation and tumor behavior in vivo. Here we present the potential of these 3D models for drug testing, target validation and guidance of patient selection for clinical trials. We argue also that in order to get full insight into the biology of the normal and malignant breast, and to create in vivo-like models for therapeutic approaches in humans, we need to continue to create more complex heterotypic models to approach the full context the cells encounter in the human body.

  16. Mammary stem cells and breast cancer--role of Notch signalling.

    Science.gov (United States)

    Farnie, Gillian; Clarke, Robert B

    2007-06-01

    Adult stem cells are found in numerous tissues of the body and play a role in tissue development, replacement and repair. Evidence shows that breast stem cells are multipotent and can self renew, which are key characteristics of stem cells, and a single cell enriched with cell surface markers has the ability to grow a fully functional mammary gland in vivo. Many groups have extrapolated the cancer stem cell hypothesis from the haematopoietic system to solid cancers, where using in vitro culture techniques and in vivo transplant models have established evidence of cancer stem cells in colon, pancreas, prostate, brain and breast cancers. In the report we describe the evidence for breast cancer stem cells; studies consistently show that stem cell like and breast cancer initiating populations can be enriched using cell surface makers CD44+/CD24- and have upregulated genes which include Notch. Notch signalling has been highlighted as a pathway involved in the development of the breast and is frequently dysregulated in invasive breast cancer. We have investigated the role of Notch in a pre-invasive breast lesion, ductal carcinoma in situ (DCIS), and have found that aberrant activation of Notch signalling is an early event in breast cancer. High expression of Notch 1 intracellular domain (NICD) in DCIS also predicted a reduced time to recurrence 5 years after surgery. Using a non-adherent sphere culture technique we have grown DCIS mammospheres from primary DCIS tissue, where self-renewal capacity, measured by the number of mammosphere initiating cells, were increased from normal breast tissue. A gamma-secretase inhibitor, DAPT, which inhibits all four Notch receptors and a Notch 4 neutralising antibody were shown to reduce DCIS mammosphere formation, indicating that Notch signalling and other stem cell self-renewal pathways may represent novel therapeutic targets to prevent recurrence of pre-invasive and invasive breast cancer.

  17. The biology of progesterone receptor in the normal mammary gland and in breast cancer.

    Science.gov (United States)

    Obr, Alison E; Edwards, Dean P

    2012-06-24

    This paper reviews work on progesterone and the progesterone receptor (PR) in the mouse mammary gland that has been used extensively as an experimental model. Studies have led to the concept that progesterone controls proliferation and morphogenesis of the luminal epithelium in a tightly orchestrated manner at distinct stages of development by paracrine signaling pathways, including receptor activator of nuclear factor κB ligand (RANKL) as a major paracrine factor. Progesterone also drives expansion of stem cells by paracrine signals to generate progenitors required for alveologenesis. During mid-to-late pregnancy, progesterone has another role to suppress secretory activation until parturition mediated in part by crosstalk between PR and prolactin/Stat5 signaling to inhibit induction of milk protein gene expression, and by inhibiting tight junction closure. In models of hormone-dependent mouse mammary tumors, the progesterone/PR signaling axis enhances pre-neoplastic progression by a switch from a paracrine to an autocrine mode of proliferation and dysregulation of the RANKL signaling pathway. Limited experiments with normal human breast show that progesterone/PR signaling also stimulates epithelial cell proliferation by a paracrine mechanism; however, the signaling pathways and whether RANKL is a major mediator remains unknown. Work with human breast cancer cell lines, patient tumor samples and clinical studies indicates that progesterone is a risk factor for breast cancer and that alteration in progesterone/PR signaling pathways contributes to early stage human breast cancer progression. However, loss of PR expression in primary tumors is associated with a less differentiated more invasive phenotype and worse prognosis, suggesting that PR may limit later stages of tumor progression.

  18. Mammary tumorigenesis by radiation and its prevention

    Energy Technology Data Exchange (ETDEWEB)

    Onoda, Makoto; Suzuki, Keiko; Inano, Hiroshi [National Inst. of Radiological Sciences, Chiba (Japan)

    1999-06-01

    Since the breast cancer in women emerged as an important risk associated with exposure to ionizing radiation, we have investigated to clarify the relationship between the induction of mammary tumors by irradiation and the developmental stage of the mammary glands that regulated by the action of endocrine hormones. Besides the radiation, epidemiological studies showed that the process of biosynthesis/metabolism of steroid hormones and hyperlipidemia may be associated with an increased risk of mammary carcinogenesis. In this context, we have undertaken investigations to evaluate the anti-carcinogenic activities of dehydroepiandrosterone (DHEA), a major secretory steroid of the adrenal glands, bezafibrate (BEZF), an anti-hyperlipidemic drug derived from clofibrate, and simvastatin (SIMV), a prodrug of a specific inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, against diethylstilbestrol (DES)-dependent promotion/progression of rat mammary tumors initiated by {gamma}-rays. Pregnant Wistar-MS rats received whole-body irradiation with 2.6 Gy of {gamma}-rays from a {sup 60}Co source at day-20 of pregnancy. The mother rats were fed a diet containing either 0.6% DHEA, 0.15% BEZF or 0.03% SIMV beginning immediately after weaning. They were then implanted subcutaneously with a pellet of DES (3 mg/pellet) in the interscapular area 30 days after termination of nursing and were observed for 1 year for detection of palpable mammary tumors starting from the time of pellet implantation. The administration of dietary DHEA, BEZF or SIMV together with DES implantation in rats irradiated in late pregnancy significantly decreased the total incidence of mammary tumors to 35%, 27% and 36%, respectively, for the 1 year period, while higher tumor incidence (96%, 90% and 88%) was observed in rats fed controldiet. However, neither the number of mammary tumors per tumor-bearing rat nor the latency period in the drug treated groups was different from that observed in the control group

  19. Differential Mammary Gland Development in FVB and C57Bl/6 Mice: Implications for Breast Cancer Research

    Directory of Open Access Journals (Sweden)

    Breanne M. Anderson

    2011-10-01

    Full Text Available A growing body of research suggests a linkage between pubertal mammary gland development and environmental factors such as diet as modifiers of long term breast cancer risk. Much of this research is dependent upon mouse models, which may vary between studies. However, effects may be strain dependent and further modified by diet, which has not been previously examined. Therefore, the objective of the present study was to determine whether mammary gland development differs between FVB and C57Bl/6 strains on diets containing either n-6 or n-3 polyunsaturated fats. Developmental measures related to onset of puberty and mammary gland development differed between strains. Mice fed the n-3 polyunsaturated fatty acids (PUFA diet were shown to have lower numbers of terminal end buds, a marker of mammary gland development. This study helps to further clarify differences in development and dietary response between FVB and C57Bl/6 mice in order to more appropriately relate mammary gland research to human populations.

  20. Amplification of tumor inducing putative cancer stem cells (CSCs) by vitamin A/retinol from mammary tumors

    Energy Technology Data Exchange (ETDEWEB)

    Sharma, Rohit B. [Department of Microbiology and Molecular Genetics, University of Pittsburgh, PA 15261 (United States); Wang, Qingde [Department of Surgery, University of Pittsburgh, PA 15261 (United States); Khillan, Jaspal S., E-mail: khillan@pitt.edu [Department of Microbiology and Molecular Genetics, University of Pittsburgh, PA 15261 (United States)

    2013-07-12

    Highlights: •Vitamin A supports self renewal of putative CSCs from mammary tumors. •These cells exhibit impaired retinol metabolism into retinoic acid. •CSCs from mammary tumors differentiate into mammary specific cell lineages. •The cells express mammary stem cell specific CD29 and CD49f markers. •Putative CSCs form highly metastatic tumors in NOD SCID mouse. -- Abstract: Solid tumors contain a rare population of cancer stem cells (CSCs) that are responsible for relapse and metastasis. The existence of CSC however, remains highly controversial issue. Here we present the evidence for putative CSCs from mammary tumors amplified by vitamin A/retinol signaling. The cells exhibit mammary stem cell specific CD29{sup hi}/CD49f{sup hi}/CD24{sup hi} markers, resistance to radiation and chemo therapeutic agents and form highly metastatic tumors in NOD/SCID mice. The cells exhibit indefinite self renewal as cell lines. Furthermore, the cells exhibit impaired retinol metabolism and do not express enzymes that metabolize retinol into retinoic acid. Vitamin A/retinol also amplified putative CSCs from breast cancer cell lines that form highly aggressive tumors in NOD SCID mice. The studies suggest that high purity putative CSCs can be isolated from solid tumors to establish patient specific cell lines for personalized therapeutics for pre-clinical translational applications. Characterization of CSCs will allow understanding of basic cellular and molecular pathways that are deregulated, mechanisms of tumor metastasis and evasion of therapies that has direct clinical relevance.

  1. Study on cow ghee versus soybean oil on 7,12-dimethylbenz(a)-anthracene induced mammary carcinogenesis & expression of cyclooxygenase-2 & peroxisome proliferators activated receptor-γ in rats.

    Science.gov (United States)

    Rani, Rita; Kansal, Vinod K

    2011-05-01

    Breast cancer is a leading cause of cancer death in women; dietary fat is the one of the factors that influences its incidence. In the present study we investigated the effect of feeding cow ghee versus soybean oil on 7,12-dimethylbenz(a)anthracene (DMBA) induced mammary cancer in rat and expression of cyclooxygenase-2 and peroxisome proliferators activated receptor-γ (PPAR-γ) in mammary gland. Two groups of 21 day old female rats (30 each) were fed for 44 wk diet containing cow ghee or soybean oil (10%). The animals were given DMBA (30 mg/kg body weight) through oral intubation after 5 wk feeding. Another two groups (8 each) fed similarly but not given DMBA served as control for the gene expression study. In DMBA treated groups, the animal fed soybean oil had higher tumour incidence (65.4%), tumour weight (6.18 g) and tumour volume (6285 mm3) compared to those fed cow ghee (26.6%, 1.67 g, 1925 mm3, respectively). Tumour latency period was 23 wk on soybean oil compared to 27 wk on cow ghee. Histological analysis of tumours showed that the progression of carcinogenesis was more rapid on soybean oil than on cow ghee. The expression of cyclooxygenase-2 was observed only in DMBA treated rats and it was significantly less on cow ghee than on soybean oil. The expression of PPAR-γ was significantly more on cow ghee than on soybean oil. Our results show that dietary cow ghee opposed to soybean oil attenuates mammary carcinogenesis induced by DMBA; and the effect is mediated by decreased expression of cyclooxygenase-2 and increased expression of PPAR-γ in the former group.

  2. Anti-Tumor Action, Clinical Biochemistry Profile and Phytochemical Constituents of a Pharmacologically Active Fraction of S. crispus in NMU-Induced Rat Mammary Tumour Model.

    Science.gov (United States)

    Yaacob, Nik Soriani; Yankuzo, Hassan Muhammad; Devaraj, Sutha; Wong, Jimmy Ka Ming; Lai, Choon-Sheen

    2015-01-01

    Cancer patients seek alternative remedies such as traditional medicinal plants for safe and effective treatment and help overcome the side effects of conventional therapy. Current knowledge indicates that extracts of Strobilanthes crispus of the Acanthaceae family exhibit potent anticancer properties in vitro and are non-toxic in vivo. S. crispus was also reported to be protective against chemical hepatocarcinogenesis. We previously showed that a bioactive fraction of S. crispus leaves also synergized with tamoxifen to cause apoptosis of human breast cancer cell lines without damaging non-malignant epithelial cells. The present study aimed to evaluate the antitumor effect of S. crispus dichloromethane fraction (F3) using N-methyl-N-Nitrosourea (NMU)-induced rat mammary tumor model. Tumor regression was observed in 75% of the rats following 8-week oral administration of F3 with no secondary tumour formation and no signs of anemia or infection. However, no improvement in the liver and renal function profiles was observed. Major constituents of F3 were identified as lutein, 131-hydroxy-132-oxo-pheophytin a, campesterol, stigmasterol, β-sitosterol, pheophytin a and 132-hydroxy-pheophytin a. These compounds however, may not significantly contribute to the antitumor effect of F3.

  3. Anti-Tumor Action, Clinical Biochemistry Profile and Phytochemical Constituents of a Pharmacologically Active Fraction of S. crispus in NMU-Induced Rat Mammary Tumour Model.

    Directory of Open Access Journals (Sweden)

    Nik Soriani Yaacob

    Full Text Available Cancer patients seek alternative remedies such as traditional medicinal plants for safe and effective treatment and help overcome the side effects of conventional therapy. Current knowledge indicates that extracts of Strobilanthes crispus of the Acanthaceae family exhibit potent anticancer properties in vitro and are non-toxic in vivo. S. crispus was also reported to be protective against chemical hepatocarcinogenesis. We previously showed that a bioactive fraction of S. crispus leaves also synergized with tamoxifen to cause apoptosis of human breast cancer cell lines without damaging non-malignant epithelial cells. The present study aimed to evaluate the antitumor effect of S. crispus dichloromethane fraction (F3 using N-methyl-N-Nitrosourea (NMU-induced rat mammary tumor model. Tumor regression was observed in 75% of the rats following 8-week oral administration of F3 with no secondary tumour formation and no signs of anemia or infection. However, no improvement in the liver and renal function profiles was observed. Major constituents of F3 were identified as lutein, 131-hydroxy-132-oxo-pheophytin a, campesterol, stigmasterol, β-sitosterol, pheophytin a and 132-hydroxy-pheophytin a. These compounds however, may not significantly contribute to the antitumor effect of F3.

  4. Contribution of xanthine oxidoreductase to mammary epithelial and breast cancer cell differentiation in part modulates inhibitor of differentiation-1.

    Science.gov (United States)

    Fini, Mehdi A; Monks, Jenifer; Farabaugh, Susan M; Wright, Richard M

    2011-09-01

    Loss of xanthine oxidoreductase (XOR) has been linked to aggressive breast cancer in vivo and to breast cancer cell aggressiveness in vitro. In the present study, we hypothesized that the contribution of XOR to the development of the normal mammary gland may underlie its capacity to modulate breast cancer. We contrasted in vitro and in vivo developmental systems by differentiation marker and microarray analyses. Human breast cancer microarray was used for clinical outcome studies. The role of XOR in differentiation and proliferation was examined in human breast cancer cells and in a mouse xenograft model. Our data show that XOR was required for functional differentiation of mammary epithelial cells both in vitro and in vivo. Poor XOR expression was observed in a mouse ErbB2 breast cancer model, and pharmacologic inhibition of XOR increased breast cancer tumor burden in mouse xenograft. mRNA microarray analysis of human breast cancer revealed that low XOR expression was significantly associated with time to tumor relapse. The opposing expression of XOR and inhibitor of differentiation-1 (Id1) during HC11 differentiation and mammary gland development suggested a potential functional relationship. While overexpression of Id1 inhibited HC11 differentiation and XOR expression, XOR itself modulated expression of Id1 in differentiating HC11 cells. Overexpression of XOR both inhibited Id1-induced proliferation and -stimulated differentiation of Heregulin-β1-treated human breast cancer cells. These results show that XOR is an important functional component of differentiation whose diminished expression contributes to breast cancer aggressiveness, and they support XOR as both a breast cancer biomarker and a target for pharmacologic activation in therapeutic management of aggressive breast cancer.

  5. Regulation of Wnt signaling activity for growth suppression induced by quercetin in 4T1 murine mammary cancer cells.

    Science.gov (United States)

    Kim, Haesung; Seo, Eun-Min; Sharma, Ashish R; Ganbold, Bilguun; Park, Jongbong; Sharma, Garima; Kang, Young-Hee; Song, Dong-Keun; Lee, Sang-Soo; Nam, Ju-Suk

    2013-10-01

    Quercetin is a promising chemopreventive agent against cancer that inhibits tumor progression by inducing cell cycle arrest and promoting apoptotic cell death. Recently, the Wnt/β-catenin signaling pathway has been implicated in mammary tumorigenesis, where its abnormal activation is associated with the development of breast cancer. Thus, the objective of this study was to examine the biological activities of quercetin against mammary cancer cells, and to determine whether quercetin could regulate the Wnt/β-catenin signaling pathway. Quercetin showed dose-dependent inhibition of cell growth and induced apoptosis in 4T1 cells. Treatment of 20 µM quercetin suppressed ~50% of basal TopFlash luciferase activity. Moreover, the inhibitory effect of quercetin on the Wnt/β-catenin signaling pathway was confirmed by the reduced stabilization of the β-catenin protein. Among various antagonists screened for the Wnt/β-catenin signaling pathway, the expression of DKK1, 2 and 3 was induced after treatment with 20 µM of quercetin. Stimulation with recombinant DKK1 protein, showed suppressive cell growth of mammary cancer cells instead of quercetin. When 4T1 cells were treated with recombinant Wnt3a or LiCl along with quercetin, both stimulators for the Wnt/β-catenin signaling pathway were able to restore the suppressed cell viability by quercetin. Thus, our data suggest that quercetin exerts its anticancer activity through the downregulation of Wnt/β-catenin signaling activity. These results indicate for the first time that quercetin decreases cell viability and induces apoptosis in murine mammary cancer cells, which is possibly mediated by DKK-dependent inhibition of the Wnt/β-catenin signaling pathway. In conclusion, our findings suggest that quercetin has great potential value as chemotherapeutic agent for cancer treatment, especially in breast cancer controlled by Wnt/β-catenin signaling activity.

  6. CD44+/CD24- Cancer Stem Cells Are Associated With Higher Grade of Canine Mammary Carcinomas.

    Science.gov (United States)

    Im, K S; Jang, Y G; Shin, J I; Kim, N H; Lim, H Y; Lee, S M; Kim, J H; Sur, J H

    2015-11-01

    The CD44+/CD24- phenotype identifies cancer stem cell (CSC) properties in canine mammary carcinoma (MC); however, the histopathological features associated with this phenotype remain to be elucidated. Here, we determined whether the CD44+/CD24- phenotype was associated with hormonal receptor (HR; estrogen receptor [ER] and/or progesterone receptor [PR]) status and/or triple (ER, PR, and human epithelial growth factor receptor 2)-negative (TN) subtype; conventional histological evaluation was also performed. We found that, as single markers, both CD44+ and CD24+ were associated with less aggressive histological types, low grade, and a non-TN subtype; both markers were associated with HR positivity. On the other hand, a CD44+/CD24- phenotype was associated with higher grade of carcinoma. Therefore, our results suggest that immunohistochemical phenotyping for CD44/CD24 is useful for the evaluation of tumor behavior as well as CSC-like properties in canine MCs.

  7. Establishment and characterization of a new cell line of canine inflammatory mammary cancer: IPC-366.

    Directory of Open Access Journals (Sweden)

    Sara Caceres

    Full Text Available Canine inflammatory mammary cancer (IMC shares epidemiologic, histopathological and clinical characteristics with the disease in humans and has been proposed as a natural model for human inflammatory breast cancer (IBC. The aim of this study was to characterize a new cell line from IMC (IPC-366 for the comparative study of both IMC and IBC. Tumors cells from a female dog with clinical IMC were collected. The cells were grown under adherent conditions. The growth, cytological, ultrastructural and immunohistochemical (IHC characteristics of IPC-366 were evaluated. Ten female Balb/SCID mice were inoculated with IPC-366 cells to assess their tumorigenicity and metastatic potential. Chromosome aberration test and Karyotype revealed the presence of structural aberration, numerical and neutral rearrangements, demonstrating a chromosomal instability. Microscopic examination of tumor revealed an epithelial morphology with marked anysocytosis. Cytological and histological examination of smears and ultrathin sections by electron microscopy revealed that IPC-366 is formed by highly malignant large round or polygonal cells characterized by marked atypia and prominent nucleoli and frequent multinucleated cells. Some cells had cytoplasmic empty spaces covered by cytoplasmic membrane resembling capillary endothelial cells, a phenomenon that has been related to s vasculogenic mimicry. IHC characterization of IPC-366 was basal-like: epithelial cells (AE1/AE3+, CK14+, vimentin+, actin-, p63-, ER-, PR-, HER-2, E-cadherin, overexpressed COX-2 and high Ki-67 proliferation index (87.15 %. At 2 weeks after inoculating the IPC-366 cells, a tumor mass was found in 100 % of mice. At 4 weeks metastases in lung and lymph nodes were found. Xenograph tumors maintained the original IHC characteristics of the female dog tumor. In summary, the cell line IPC-366 is a fast growing malignant triple negative cell line model of inflammatory mammary carcinoma that can be used for the

  8. Establishment and characterization of a new cell line of canine inflammatory mammary cancer: IPC-366.

    Science.gov (United States)

    Caceres, Sara; Peña, Laura; de Andres, Paloma J; Illera, Maria J; Lopez, Mirtha S; Woodward, Wendy A; Reuben, James M; Illera, Juan C

    2015-01-01

    Canine inflammatory mammary cancer (IMC) shares epidemiologic, histopathological and clinical characteristics with the disease in humans and has been proposed as a natural model for human inflammatory breast cancer (IBC). The aim of this study was to characterize a new cell line from IMC (IPC-366) for the comparative study of both IMC and IBC. Tumors cells from a female dog with clinical IMC were collected. The cells were grown under adherent conditions. The growth, cytological, ultrastructural and immunohistochemical (IHC) characteristics of IPC-366 were evaluated. Ten female Balb/SCID mice were inoculated with IPC-366 cells to assess their tumorigenicity and metastatic potential. Chromosome aberration test and Karyotype revealed the presence of structural aberration, numerical and neutral rearrangements, demonstrating a chromosomal instability. Microscopic examination of tumor revealed an epithelial morphology with marked anysocytosis. Cytological and histological examination of smears and ultrathin sections by electron microscopy revealed that IPC-366 is formed by highly malignant large round or polygonal cells characterized by marked atypia and prominent nucleoli and frequent multinucleated cells. Some cells had cytoplasmic empty spaces covered by cytoplasmic membrane resembling capillary endothelial cells, a phenomenon that has been related to s vasculogenic mimicry. IHC characterization of IPC-366 was basal-like: epithelial cells (AE1/AE3+, CK14+, vimentin+, actin-, p63-, ER-, PR-, HER-2, E-cadherin, overexpressed COX-2 and high Ki-67 proliferation index (87.15 %). At 2 weeks after inoculating the IPC-366 cells, a tumor mass was found in 100 % of mice. At 4 weeks metastases in lung and lymph nodes were found. Xenograph tumors maintained the original IHC characteristics of the female dog tumor. In summary, the cell line IPC-366 is a fast growing malignant triple negative cell line model of inflammatory mammary carcinoma that can be used for the comparative

  9. Active immunization to luteinizing hormone releasing hormone to inhibit the induction of mammary tumors in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Ravdin, P.M.; Jordan, V.C.

    1988-01-01

    Immunization of female rats with a bovine serum albumin-luteinizing hormone releasing hormone conjugate results in suppression of dimethylbenzanthracene mammary tumor incidence. Tumor incidence was 1.3, and 1.29 tumors per rat in bovine serum albumin alone (n = 10) and unimmunized (n = 18) control groups, but no tumors were found in the bovine serum albumin-luteinizing hormone releasing hormone conjugate immunized animals (n = 10). In a second experiment immunization with bovine serum albumin-luteinizing hormone releasing hormone conjugates reduced tumor incidence to 0.3 tumors per rat (n = 10) from the 1.2 tumors per animal seen in the control animals (n = 10) immunized with bovine serum albumin alone. Bovine serum albumin-luteinizing hormone immunization caused the production of anti-LHRH antibodies, an interruption of estrous cycles, lowered serum estradiol and progesterone levels, and atrophy of the ovaries and uteri. Immunization BSA-hormone conjugates is a novel anti-tumor strategy.

  10. Involvement of Different networks in mammary gland involution after the pregnancy/lactation cycle: Implications in breast cancer.

    Science.gov (United States)

    Zaragozá, Rosa; García-Trevijano, Elena R; Lluch, Ana; Ribas, Gloria; Viña, Juan R

    2015-04-01

    Early pregnancy is associated with a reduction in a woman's lifetime risk for breast cancer. However, different studies have demonstrated an increase in breast cancer risk in the years immediately following pregnancy. Early and long-term risk is even higher if the mother age is above 35 years at the time of first parity. The proinflammatory microenvironment within the mammary gland after pregnancy renders an "ideal niche" for oncogenic events. Signaling pathways involved in programmed cell death and tissue remodeling during involution are also activated in breast cancer. Herein, the major signaling pathways involved in mammary gland involution, signal transducer and activator of transcription (STAT3), nuclear factor-kappa B (NF-κB), transforming growth factor beta (TGFβ), and retinoid acid receptors (RARs)/retinoid X receptors (RXRs), are reviewed as part of the complex network of signaling pathways that crosstalk in a contextual-dependent manner. These factors, also involved in breast cancer development, are important regulatory nodes for signaling amplification after weaning. Indeed, during involution, p65/p300 target genes such as MMP9, Capn1, and Capn2 are upregulated. Elevated expression and activities of these proteases in breast cancer have been extensively documented. The role of these proteases during mammary gland involution is further discussed. MMPs, calpains, and cathepsins exert their effect by modification of the extracellular matrix and intracellular proteins. Calpains, activated in the mammary gland during involution, cleave several proteins located in cell membrane, lysosomes, mitochondria, and nuclei favoring cell death. Besides, during this period, Capn1 is most probably involved in the modulation of preadipocyte differentiation through chromatin remodeling. Calpains can be implicated in cell anchoring loss, providing a proper microenvironment for tumor growth. A better understanding of the role of any of these proteases in tumorigenesis may

  11. Functional Characteristics of Tumor-Associated Protein Spot14 and Interacting Proteins in Mouse Mammary Epithelial and Breast Cancer Cell Lines

    Science.gov (United States)

    2009-09-01

    Interacting Proteins in Mouse Mammary Epithelial and Breast Cancer Cell Lines PRINCIPAL INVESTIGATOR: Michael C. Rudolph, B.A...Spot14 and Interacting Proteins in Mouse Mammary Epithelial and 5b. GRANT NUMBER W81XWH-08-1-0596 Breast Cancer Cell Lines 5c. PROGRAM ELEMENT...S14 and to identify potential S14 interacting proteins that confer its function. Body The overarching goals of this proposal are to examine the

  12. Description of the prevalence, histologic characteristics, concomitant abnormalities, and outcomes of mammary gland tumors in companion rats (Rattus norvegicus): 100 cases (1990–2015)

    OpenAIRE

    Vergneau-Grosset, C; Keel, MK; Goldsmith, D.; Kass, PH; Paul-Murphy, J; Hawkins, MG

    2016-01-01

    © American Veterinary Medical Association. All rights reserved. OBJECTIVE To describe the prevalence, histologic characteristics, concomitant abnormalities, and outcomes for various types of mammary gland tumors in companion rats (Rattus norvegicus). DESIGN Retrospective case series. ANIMALS 100 client-owned rats. PROCEDURES Medical records of companion rats that had an SC mass and were examined at a veterinary teaching hospital between 1990 and 2015 were reviewed. Information regarding the s...

  13. Function of the vitamin D endocrine system in mammary gland and breast cancer.

    Science.gov (United States)

    Welsh, JoEllen

    2017-09-15

    The nuclear receptor for 1α,25-dihydroxycholecalciferol (1,25D), the active form of vitamin D, has anti-tumor actions in many tissues. The vitamin D receptor (VDR) is expressed in normal mammary gland and in many human breast cancers suggesting it may represent an important tumor suppressor gene in this tissue. When activated by 1,25D, VDR modulates multiple cellular pathways including those related to energy metabolism, terminal differentiation and inflammation. There is compelling pre-clinical evidence that alterations in vitamin D status affect breast cancer development and progression, while clinical and epidemiological data are suggestive but not entirely consistent. The demonstration that breast cells express CYP27B1 (which converts the precursor vitamin D metabolite 25D to the active metabolite 1,25D) and CYP24A1 (which degrades both 25D and 1,25D) provides insight into the difficulties inherent in using dietary vitamin D, sun exposure and/or serum biomarkers of vitamin D status to predict disease outcomes. Emerging evidence suggests that the normally tight balance between CYP27B1 and CYP24A1 becomes deregulated during cancer development, leading to abrogation of the tumor suppressive effects triggered by VDR. Research aimed at understanding the mechanisms that govern uptake, storage, metabolism and actions of vitamin D steroids in normal and neoplastic breast tissue remain an urgent priority. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Breast Cancer and Internal Mammary Sentinel Nodes: A Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Khaldoun Bekdache

    2014-05-01

    Full Text Available Background: The management of internal mammary (IM nodes in breast cancer lacks a well-defined consensus. Lymphoscintigraphy identifies up to one-third of breast cancer patients with extra-axillary drainage, which is mainly located in the IM chain. Our aim in this meta-analysis is to identify the lymphoscintigraphy technique variables that effect IM node identification.Methods: An internet database was utilized to review articles concerning sentinel nodes and breast cancer from 1993 through the end of 2011; 74 articles met our inclusion criteria. The total number of patients included was 22959. We grouped the citations by injection location and injection material. We then analyzed the rate of identification of IM nodes according to these groupings and their subsets.Results: The overall IM identification rate using the random effect model was 9%. The injection location had the most significant impact on IM identification rate; the deeper injections were associated with the highest rate of identification. Variation in IM identification was associated with the particle size of injection material; the smaller particle size group had a higher rate of identification. Increased dose of the tracer was also associated with increased identification rate.Conclusions: The use of smaller particle size tracers and a deeper injection location achieve the highest IM identification rate. The dose of the tracer also increased the identification rate. These observations can help in the selection of patients for IM sentinel node biopsy, which can affect their prognosis and treatment management.

  15. The 18-kDa translocator protein (TSPO disrupts mammary epithelial morphogenesis and promotes breast cancer cell migration.

    Directory of Open Access Journals (Sweden)

    Xiaoting Wu

    Full Text Available Mitochondria play important roles in cancer progression and have emerged as viable targets for cancer therapy. Increasing levels of the outer mitochondrial membrane protein, 18-kDa translocator protein (TSPO, are associated with advancing breast cancer stage. In particular, higher TSPO levels are found in estrogen receptor (ER-negative breast tumors, compared with ER-positive tumors. In this study, we sought to define the roles of TSPO in the acquisition of breast cancer malignancy. Using a three-dimensional Matrigel culture system, we determined the impact of elevated TSPO levels on mammary epithelial morphogenesis. Our studies demonstrate that stable overexpression of TSPO in mammary epithelial MCF10A acini drives proliferation and provides partial resistance to luminal apoptosis, resulting in enlarged acinar structures with partially filled lumen that resemble early stage breast lesions leading to breast cancer. In breast cancer cell lines, TSPO silencing or TSPO overexpression significantly altered the migratory activity. In addition, we found that combination treatment with the TSPO ligands (PK 11195 or Ro5-4864 and lonidamine, a clinical phase II drug targeting mitochondria, decreased viability of ER-negative breast cancer cell lines. Taken together, these data demonstrate that increases in TSPO levels at different stages of breast cancer progression results in the acquisition of distinct properties associated with malignancy. Furthermore, targeting TSPO, particularly in combination with other mitochondria-targeting agents, may prove useful for the treatment of ER-negative breast cancer.

  16. The 18-kDa translocator protein (TSPO) disrupts mammary epithelial morphogenesis and promotes breast cancer cell migration.

    Science.gov (United States)

    Wu, Xiaoting; Gallo, Kathleen A

    2013-01-01

    Mitochondria play important roles in cancer progression and have emerged as viable targets for cancer therapy. Increasing levels of the outer mitochondrial membrane protein, 18-kDa translocator protein (TSPO), are associated with advancing breast cancer stage. In particular, higher TSPO levels are found in estrogen receptor (ER)-negative breast tumors, compared with ER-positive tumors. In this study, we sought to define the roles of TSPO in the acquisition of breast cancer malignancy. Using a three-dimensional Matrigel culture system, we determined the impact of elevated TSPO levels on mammary epithelial morphogenesis. Our studies demonstrate that stable overexpression of TSPO in mammary epithelial MCF10A acini drives proliferation and provides partial resistance to luminal apoptosis, resulting in enlarged acinar structures with partially filled lumen that resemble early stage breast lesions leading to breast cancer. In breast cancer cell lines, TSPO silencing or TSPO overexpression significantly altered the migratory activity. In addition, we found that combination treatment with the TSPO ligands (PK 11195 or Ro5-4864) and lonidamine, a clinical phase II drug targeting mitochondria, decreased viability of ER-negative breast cancer cell lines. Taken together, these data demonstrate that increases in TSPO levels at different stages of breast cancer progression results in the acquisition of distinct properties associated with malignancy. Furthermore, targeting TSPO, particularly in combination with other mitochondria-targeting agents, may prove useful for the treatment of ER-negative breast cancer.

  17. Analysis of tumor heterogeneity and cancer gene networks using deep sequencing of MMTV-induced mouse mammary tumors.

    Directory of Open Access Journals (Sweden)

    Christiaan Klijn

    Full Text Available Cancer develops through a multistep process in which normal cells progress to malignant tumors via the evolution of their genomes as a result of the acquisition of mutations in cancer driver genes. The number, identity and mode of action of cancer driver genes, and how they contribute to tumor evolution is largely unknown. This study deployed the Mouse Mammary Tumor Virus (MMTV as an insertional mutagen to find both the driver genes and the networks in which they function. Using deep insertion site sequencing we identified around 31000 retroviral integration sites in 604 MMTV-induced mammary tumors from mice with mammary gland-specific deletion of Trp53, Pten heterozygous knockout mice, or wildtype strains. We identified 18 known common integration sites (CISs and 12 previously unknown CISs marking new candidate cancer genes. Members of the Wnt, Fgf, Fgfr, Rspo and Pdgfr gene families were commonly mutated in a mutually exclusive fashion. The sequence data we generated yielded also information on the clonality of insertions in individual tumors, allowing us to develop a data-driven model of MMTV-induced tumor development. Insertional mutations near Wnt and Fgf genes mark the earliest "initiating" events in MMTV induced tumorigenesis, whereas Fgfr genes are targeted later during tumor progression. Our data shows that insertional mutagenesis can be used to discover the mutational networks, the timing of mutations, and the genes that initiate and drive tumor evolution.

  18. Tumor microenvironment regulates metastasis and metastasis genes of mouse MMTV-PymT mammary cancer cells in vivo.

    Science.gov (United States)

    Werbeck, J L; Thudi, N K; Martin, C K; Premanandan, C; Yu, L; Ostrowksi, M C; Rosol, T J

    2014-07-01

    Metastasis is the primary cause of death in breast cancer patients, yet there are challenges to modeling this process in vivo. The goal of this study was to analyze the effects of injection site on tumor growth and metastasis and gene expression of breast cancer cells in vivo using the MMTV-PymT breast cancer model (Met-1 cells). Met-1 cells were injected into 5 sites (subcutaneous, mammary fat pad, tail vein, intracardiac, and intratibial), and tumors and metastases were monitored using bioluminescent imaging and confirmed with gross necropsy and histopathology. Met-1 tumors were analyzed based on morphology and changes in gene expression in each tissue microenvironment. There were 6 permissible sites of Met-1 tumor growth (mammary gland, subcutis, lung, adrenal gland, ovary, bone). Met-1 cells grew faster in the subcutis compared to mammary fat pad tumors (highest Ki-67 index). Morphologic differences were evident in each tumor microenvironment. Finally, 7 genes were differentially expressed in the Met-1 tumors in the 6 sites of growth or metastasis. This investigation demonstrates that breast cancer progression and metastasis are regulated by not only the tumor cells but also the experimental model and unique molecular signals from the tumor microenvironment.

  19. Potential reduction of contralateral second breast-cancer risks by prophylactic mammary irradiation: validation in a breast-cancer-prone mouse model.

    Directory of Open Access Journals (Sweden)

    Igor Shuryak

    Full Text Available BACKGROUND: Long-term breast-cancer survivors have a highly elevated risk (1 in 6 at 20 years of contralateral second breast cancer. This high risk is associated with the presence of multiple pre-malignant cell clones in the contralateral breast at the time of primary breast cancer diagnosis. Mechanistic analyses suggest that a moderate dose of X-rays to the contralateral breast can kill these pre-malignant clones such that, at an appropriate Prophylactic Mammary Irradiation (PMI dose, the long-term contralateral breast cancer risk in breast cancer survivors would be considerably decreased. AIMS: To test the predicted relationship between PMI dose and cancer risk in mammary glands that have a high risk of developing malignancies. METHODS: We tested the PMI concept using MMTV-PyVT mammary-tumor-prone mice. Mammary glands on one side of each mouse were irradiated with X-rays, while those on the other side were shielded from radiation. The unshielded mammary glands received doses of 0, 4, 8, 12 and 16 Gy in 4-Gy fractions. RESULTS: In high-risk mammary glands exposed to radiation doses designed for PMI (12 and 16 Gy, tumor incidence rates were respectively decreased by a factor of 2.2 (95% CI, 1.1-5.0 at 12 Gy, and a factor of 3.1 (95% CI, 1.3-8.3 at 16 Gy, compared to those in the shielded glands that were exposed to very low radiation doses. The same pattern was seen for PMI-exposed mammary glands relative to zero-dose controls. CONCLUSIONS: The pattern of cancer risk reduction by PMI was consistent with mechanistic predictions. Contralateral breast PMI may thus have promise as a spatially targeted breast-conserving option for reducing the current high risk of contralateral second breast cancers. For estrogen-receptor positive primary tumors, PMI might optimally be used concomitantly with systemically delivered chemopreventive drugs such as tamoxifen or aromatase inhibitors, while for estrogen-receptor negative tumors, PMI might be used alone.

  20. Dietary fat-dependent transcriptional architecture and copy number alterations associated with modifiers of mammary cancer metastasis

    DEFF Research Database (Denmark)

    Gordon, Ryan A; Merrill, Michele La; Hunter, Kent W

    2010-01-01

    Breast cancer is a complex disease resulting from a combination of genetic and environmental factors. Among environmental factors, body composition and intake of specific dietary components like total fat are associated with increased incidence of breast cancer and metastasis. We previously showed...... detected metastasis modifiers were identified. Additional analyses, such as eQTL by dietary fat interaction analysis, causality and database evaluations, helped to further refine the candidate loci to produce an enriched list of genes potentially involved in the pathogenesis of metastatic mammary cancer...

  1. The potential role of COX-2 in cancer stem cell-mediated canine mammary tumor initiation: an immunohistochemical study.

    Science.gov (United States)

    Huang, Jian; Zhang, Di; Xie, Fuqiang; Lin, Degui

    2015-01-01

    Increasing evidence suggests that cancer stem cells (CSCs) are responsible for tumor initiation and maintenance. Additionally, it is becoming apparent that cyclooxygenase (COX) signaling is associated with canine mammary tumor development. The goals of the present study were to investigate COX-2 expression patterns and their effect on CSC-mediated tumor initiation in primary canine mammary tissues and tumorsphere models using immunohistochemistry. Patterns of COX-2, CD44, octamer-binding transcription factor (Oct)-3/4, and epidermal growth factor receptor (EGFR) expression were examined in malignant mammary tumor (MMT) samples and analyzed in terms of clinicopathological characteristics. COX-2 and Oct-3/4 expression was higher in MMTs compared to other histological samples with heterogeneous patterns. In MMTs, COX-2 expression correlated with tumor malignancy features. Significant associations between COX-2, CD44, and EGFR were observed in low-differentiated MMTs. Comparative analysis showed that the levels of COX-2, CD44, and Oct-3/4 expression varied significantly among TSs of three histological grades. Enhanced COX-2 staining was consistently observed in TSs. Similar levels of staining intensity were found for CD44 and Oct-3/4, but EGFR expression was weak. Our findings indicate the potential role of COX-2 in CSC-mediated tumor initiation, and suggest that COX-2 inhibition may help treat canine mammary tumors by targeting CSCs.

  2. CONJUGATED LINOLEIC ACIDS (CLA) DECREASE THE BREAST CANCER RISK IN DMBA-TREATED RATS.

    Science.gov (United States)

    Białek, Agnieszka; Tokarz, Andrzej; Zagrodzki, Paweł

    2016-01-01

    The aim of this study was to investigate how supplementation of diet of female Sprague-Dawley rats with different doses of conjugated linoleic acids and for a varied period of time influences breast cancer risk, fatty acids profile and lipids peroxidation in chemically induced mammary tumors. Animals were divided into nine groups with different modifications of diet (vegetable oil, 1.0 or 2.0% of CLA) and period of supplementation, which lasted after (A), before (B) and before and after (BA) carcinogenic agent--7,12-dimethylbenz[a]anthracene administration at 50th day of life. Mammary adenocarcinomas occurred in all groups, but CLA supplementation decreased the cancer morbidity. Two percent CLA seems to be excessive because of the coexisting cachexia. Two CLA isomers (9-cis, 11-trans and 10-trans, 12-cis) were detected in tumors but content of rumenic acid was higher. Dietary supplementation significantly influenced some unsaturated fatty acids content (C18:2 n-6 trans, C20:1, C20:5 n-3, C22:2), but the anti- or prooxidant properties of CLA were not confirmed. CLA can inhibit chemically induced mammary tumors development in female rats, but their cytotoxic action seems not to be connected with lipids peroxidation. CLA isomers differ with their incorporation into cancerous tissues and they influence the content of some other fatty acids.

  3. Radiation to supraclavicular and internal mammary lymph nodes in breast cancer increases the risk of stroke.

    Science.gov (United States)

    Nilsson, G; Holmberg, L; Garmo, H; Terent, A; Blomqvist, C

    2009-03-10

    The aim of this study was to assess whether adjuvant treatment of breast cancer (BC) affects the risk of stroke, and to explore radiation targets and fraction doses regarding risk and location of stroke. In a Swedish BC cohort diagnosed during 1970-2003, we carried out a nested case-control study of stroke after BC, with relevant details extracted from medical records. The odds ratio (OR) for radiotherapy (RT) vs that of no RT did not differ between cases and controls (OR=0.85; confidence interval, CI=0.6-1.3). Radiotherapy to internal mammary chain (IMC) and supraclavicular (SCL) lymph nodes vs that of no RT was associated with a higher, although not statistically significant, risk of stroke (OR=1.3; CI=0.8-2.2). In a pooled analysis, RT to IMC and SCL vs the pooled group of no RT and RT to breast/chest wall/axilla (but not IMC and SCL), showed a significant increase of stroke (OR=1.8; CI=1.1-2.8). There were no associations between cancer laterality, targets of RT, and location of stroke. The radiation targets, IMC and SCL, showed a statistically significant trend for an increased risk of stroke with daily fraction dose. Our finding of a target-specific increased risk of stroke and a dose-response relationship for daily fraction dose, indicate that there may be a causal link between RT to the IMC and SCL and risk of stroke.

  4. Ectopic runx2 expression in mammary epithelial cells disrupts formation of normal acini structure: implications for breast cancer progression.

    Science.gov (United States)

    Pratap, Jitesh; Imbalzano, Karen M; Underwood, Jean M; Cohet, Nathalie; Gokul, Karthiga; Akech, Jacqueline; van Wijnen, Andre J; Stein, Janet L; Imbalzano, Anthony N; Nickerson, Jeffrey A; Lian, Jane B; Stein, Gary S

    2009-09-01

    The transcription factor Runx2 is highly expressed in breast cancer cells compared with mammary epithelial cells and contributes to metastasis. Here we directly show that Runx2 expression promotes a tumor cell phenotype of mammary acini in three-dimensional culture. Human mammary epithelial cells (MCF-10A) form polarized, growth-arrested, acini-like structures with glandular architecture. The ectopic expression of Runx2 disrupts acini formation, and electron microscopic ultrastructural analysis revealed the absence of lumens. Characterization of the disrupted acini structures showed increased cell proliferation (Ki-67 positive cells), decreased apoptosis (Bcl-2 induction), and loss of basement membrane formation (absence of beta(4) integrin expression). In complementary experiments, inhibition of Runx2 function in metastatic MDA-MB-231 breast cancer cells by stable expression of either short hairpin RNA-Runx2 or a mutant Runx2 deficient in subnuclear targeting resulted in reversion of acini to more normal structures and reduced tumor growth in vivo. These novel findings provide direct mechanistic evidence for the biological activity of Runx2, dependent on its subnuclear localization, in promoting early events of breast cancer progression and suggest a molecular therapeutic target.

  5. Mammary epithelial morphogenesis and early breast cancer. Evidence of involvement of basal components of the RNA Polymerase I transcription machinery.

    Science.gov (United States)

    Rossetti, Stefano; Wierzbicki, Andrzej J; Sacchi, Nicoletta

    2016-09-16

    Upregulation of RNA Polymerase (Pol I)-mediated transcription of rRNA and increased ribogenesis are hallmarks of breast cancer. According to several datasets, including The Cancer Genome Atlas (TCGA), amplification/upregulation of genes encoding for basal components of the Pol I transcriptional machinery is frequent at different breast cancer stages. Here we show that knock down of the RNA polymerase I-specific transcription initiation factor RRN3 (TIF-IA) in breast cancer cells is sufficient to reduce rRNA synthesis and inhibit cell proliferation, and second that stable ectopic expression of RRN3 in human mammary epithelial (HME1) cells, by increasing rRNA transcription, confers increased sensitivity to the anti-proliferative effects of a selective Pol I inhibitor. Further, RRN3-overexpressing HME1 cells, when grown in in vitro 3-dimensional (3D) culture, develop into morphologically aberrant acinar structures lacking a lumen and filled with proliferative cells, thus acquiring a morphology resembling in situ ductal breast cancer lesions (DCIS). Consequently, interference with RRN3 control of Pol I transcription seems capable of both compromising mammary epithelial morphogenetic processes at early breast cancer stages, and driving breast cancer progression by fostering proliferation.

  6. Stereoselective metabolism of the environmental mammary carcinogen 6-nitrochrysene to trans-1,2-dihydroxy-1,2-dihydro-6-nitrochrysene by aroclor 1254-treated rat liver microsomes and their comparative mutation profiles in a laci mammary epithelial cell line.

    Science.gov (United States)

    Sun, Yuan-Wan; Guttenplan, Joseph B; Khmelnitsky, Michael; Krzeminski, Jacek; Boyiri, Telih; Amin, Shantu; El-Bayoumy, Karam

    2009-12-01

    The environmental pollutant 6-nitrochrysene (6-NC) is a powerful mammary carcinogen and mutagen in rats. Our previous studies have shown that 6-NC is metabolized to trans-1,2-dihydroxy-1,2-dihydro-6-nitrochrysene (1,2-DHD-6-NC) in rats and in several in vitro systems, including human breast tissue, and the latter is the proximate carcinogenic form in the rat mammary gland. Because optically active enantiomers of numerous polynuclear aromatic hydrocarbon (PAH) metabolites including chrysene have different biological activities, we hypothesized that the stereochemical course of 6-NC metabolism might play a significant role in the carcinogenic/mutagenic activities of the parent 6-NC. The goal of this study is to evaluate the effect of stereochemistry on the mutagenicity of 1,2-DHD-6-NC using the cII gene of lacI mammary epithelial cells in vitro. Resolution of (+/-)-1,2-DHD-6-NC was obtained by either nonchiral or chiral stationary phase HPLC methods. We determined that the ratio of (-)-[R,R]- and (+)-[S,S]-1,2-DHD-6-NC formed in the metabolism of 6-NC by rat liver microsomes is 88:12. The mutation fractions and mutation spectra of [R,R] and [S,S]-enantiomers were examined. Our results showed that the [R,R]-isomer is a significantly (p GC, AT > TA, and GC > TA substitutions, and these are similar to those obtained from 6-NC in vivo in the mammary glands of rats treated with 6-NC. The mutation spectra of the [S,S]-isomer were similar to the [R,R]-isomer, but a higher percentage of AT > GC substitutions in the [R,R]-isomer was noted. On the basis of the results of the present study, we hypothesize that [R,R]-1,2-DHD-6-NC is the proximate carcinogen of 6-NC in the rat mammary gland in vivo and will test this hypothesis in a future study.

  7. Screening and analysis of breast cancer genes regulated by the human mammary microenvironment in a humanized mouse model

    Science.gov (United States)

    Zheng, Mingjie; Wang, Jue; Ling, Lijun; Xue, Dandan; Wang, Shui; Zhao, Yi

    2016-01-01

    Tumor microenvironments play critical regulatory roles in tumor growth. Although mouse cancer models have contributed to the understanding of human tumor biology, the effectiveness of mouse cancer models is limited by the inability of the models to accurately present humanized tumor microenvironments. Previously, a humanized breast cancer model in severe combined immunodeficiency mice was established, in which human breast cancer tissue was implanted subcutaneously, followed by injection of human breast cancer cells. It was demonstrated that breast cancer cells showed improved growth in the human mammary microenvironment compared with a conventional subcutaneous mouse model. In the present study, the novel mouse model and microarray technology was used to analyze changes in the expression of genes in breast cancer cells that are regulated by the human mammary microenvironment. Humanized breast and conventional subcutaneous mouse models were established, and orthotopic tumor cells were obtained from orthotopic tumor masses by primary culture. An expression microarray using Illumina HumanHT-12 v4 Expression BeadChip and database analyses were performed to investigate changes in gene expression between tumors from each microenvironment. A total of 94 genes were differentially expressed between the primary cells cultured from the humanized and conventional mouse models. Significant upregulation of genes that promote cell proliferation and metastasis or inhibit apoptosis, such as SH3-domain binding protein 5 (BTK-associated), sodium/chloride cotransporter 3 and periostin, osteoblast specific factor, and genes that promote angiogenesis, such as KIAA1618, was also noted. Other genes that restrain cell proliferation and accelerate cell apoptosis, including tripartite motif containing TRIM36 and NES1, were downregulated. The present results revealed differences in various aspects of tumor growth and metabolism between the two model groups and indicated the functional

  8. Interstitial laser immunotherapy for treatment of metastatic mammary tumors in rats

    Science.gov (United States)

    Figueroa, Daniel; Joshi, Chet; Wolf, Roman F.; Walla, Jonny; Goddard, Jessica; Martin, Mallory; Kosanke, Stanley D.; Broach, Fred S.; Pontius, Sean; Brown, Destiny; Li, Xiaosong; Howard, Eric; Nordquist, Robert E.; Hode, Tomas; Chen, Wei R.

    2011-03-01

    Thermal therapy has been used for cancer treatment for more than a century. While thermal effect can be direct, immediate, and controllable, it is not sufficient to completely eradicate tumors, particularly when tumors have metastasized locally or to the distant sites. Metastases are the major cause of treatment failure and cancer deaths. Current available therapies, such as surgery, radiation, and chemotherapy, only have limited curative effects in patients with late-stage, metastatic cancers. Immunotherapy has been considered as the ultimate approach for cancer treatment since a systemic, anti-tumor, immunological response can be induced. Using the combination of photothermal therapy and immunotherapy, laser immunotherapy (LIT),a novel immunotherapy modality for late-stage cancer treatment, has been developed. LIT has shown great promise in pre-clinical studies and clinical breast cancer and melanoma pilot trials. However, the skin color and the depth of the tumor have been challenges for effective treatment with LIT. To induce a thermal destruction zone of appropriate size without causing thermal damage on the skin, we have developed interstitial laser immunotherapy (ILIT) using a cylindrical diffuser. To determine the effectiveness of ILIT, we treated the DMBA-4 metastatic tumors in rats. The thermal damage in tumor tissue was studied using TTC immersion and hematoxolin and eosin (H & E) staining. Also observed was the overall survival of the treated animals. Our results demonstrated that the ILIT could impact a much larger tumor area, and it significantly reduced the surface damage compared with the early version of non-invasive LIT. The survival data also indicate that ILIT has the potential to become an effective tool for the treatment of deeper, larger, and metastatic tumors, with reduced side effects.

  9. Combination between Taxol-Encapsulated Liposomes and Eruca sativa Seed Extract Suppresses Mammary Tumors in Female Rats Induced by 7,12 Dimethylbenz(α)anthracene.

    Science.gov (United States)

    Shaban, Nadia; Abdel-Rahman, Salah; Haggag, Amany; Awad, Doaa; Bassiouny, Ahmad; Talaat, Iman

    2016-01-01

    Taxol (paclitaxel) is a powerful anti-cancer drug widely used against several types of malignant tumors. Because Taxol may exert several side effects, a variety of formulations have been developed. One of these features liposomes, regarded as one of the most promising drug carriers, biocompatible and best able to reduce drug toxicity without changing efficacy against tumor cells. Eruca sativa seed extract (SE) is considered a promising natural product from cruciferous vegetables against breast cancer, increasing chemotherapeutic and eliminating harmful side effects. The effects of Taxol-encapsulated liposomes (T) alone and in combination between Eruca sativa seed extract on nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX-2) and B-cell lymphoma-2 (Bcl-2) gene expression levels were investigated in rat mammary gland carcinogenesis induced by 7,12 dimethylbenz(α) anthracene (DMBA) using qRT-PCR. The results showed that DMBA increased NF-κB, COX-2 and Bcl-2 gene expression levels and lipid peroxidation (LP), while decreasing glutathione-S-transferase (GST) and superoxide dismutase (SOD) activities and total antioxidant concentration (TAC) compared to the control group. T and T-SE treatment reduced NF-κB, COX-2 and Bcl-2 gene expression levels and LP. Hence, T and T-SE treatment appeared to reduce inflammation and cell proliferation, while increasing apoptosis, GST and SOD activities and TAC.

  10. Characterization of cell lines derived from breast cancers and normal mammary tissues for the study of the intrinsic molecular subtypes.

    Science.gov (United States)

    Prat, Aleix; Karginova, Olga; Parker, Joel S; Fan, Cheng; He, Xiaping; Bixby, Lisa; Harrell, J Chuck; Roman, Erick; Adamo, Barbara; Troester, Melissa; Perou, Charles M

    2013-11-01

    Five molecular subtypes (luminal A, luminal B, HER2-enriched, basal-like, and claudin-low) with clinical implications exist in breast cancer. Here, we evaluated the molecular and phenotypic relationships of (1) a large in vitro panel of human breast cancer cell lines (BCCLs), human mammary fibroblasts (HMFs), and human mammary epithelial cells (HMECs); (2) in vivo breast tumors; (3) normal breast cell subpopulations; (4) human embryonic stem cells (hESCs); and (5) bone marrow-derived mesenchymal stem cells (hMSC). First, by integrating genomic data of 337 breast tumor samples with 93 cell lines we were able to identify all the intrinsic tumor subtypes in the cell lines, except for luminal A. Secondly, we observed that the cell lines recapitulate the differentiation hierarchy detected in the normal mammary gland, with claudin-low BCCLs and HMFs cells showing a stromal phenotype, HMECs showing a mammary stem cell/bipotent progenitor phenotype, basal-like cells showing a luminal progenitor phenotype, and luminal B cell lines showing a mature luminal phenotype. Thirdly, we identified basal-like and highly migratory claudin-low subpopulations of cells within a subset of triple-negative BCCLs (SUM149PT, HCC1143, and HCC38). Interestingly, both subpopulations within SUM149PT were enriched for tumor-initiating cells, but the basal-like subpopulation grew tumors faster than the claudin-low subpopulation. Finally, claudin-low BCCLs resembled the phenotype of hMSCs, whereas hESCs cells showed an epithelial phenotype without basal or luminal differentiation. The results presented here help to improve our understanding of the wide range of breast cancer cell line models through the appropriate pairing of cell lines with relevant in vivo tumor and normal cell counterparts.

  11. SNORD-host RNA Zfas1 is a regulator of mammary development and a potential marker for breast cancer.

    Science.gov (United States)

    Askarian-Amiri, Marjan E; Crawford, Joanna; French, Juliet D; Smart, Chanel E; Smith, Martin A; Clark, Michael B; Ru, Kelin; Mercer, Tim R; Thompson, Ella R; Lakhani, Sunil R; Vargas, Ana C; Campbell, Ian G; Brown, Melissa A; Dinger, Marcel E; Mattick, John S

    2011-05-01

    Long noncoding RNAs (lncRNAs) are increasingly recognized to play major regulatory roles in development and disease. To identify novel regulators in breast biology, we identified differentially regulated lncRNAs during mouse mammary development. Among the highest and most differentially expressed was a transcript (Zfas1) antisense to the 5' end of the protein-coding gene Znfx1. In vivo, Zfas1 RNA is localized within the ducts and alveoli of the mammary gland. Zfas1 intronically hosts three previously undescribed C/D box snoRNAs (SNORDs): Snord12, Snord12b, and Snord12c. In contrast to the general assumption that noncoding SNORD-host transcripts function only as vehicles to generate snoRNAs, knockdown of Zfas1 in a mammary epithelial cell line resulted in increased cellular proliferation and differentiation, while not substantially altering the levels of the SNORDs. In support of an independent function, we also found that Zfas1 is extremely stable, with a half-life >16 h. Expression analysis of the SNORDs revealed these were expressed at different levels, likely a result of distinct structures conferring differential stability. While there is relatively low primary sequence conservation between Zfas1 and its syntenic human ortholog ZFAS1, their predicted secondary structures have similar features. Like Zfas1, ZFAS1 is highly expressed in the mammary gland and is down-regulated in breast tumors compared to normal tissue. We propose a functional role for Zfas1/ ZFAS1 in the regulation of alveolar development and epithelial cell differentiation in the mammary gland, which, together with its dysregulation in human breast cancer, suggests ZFAS1 as a putative tumor suppressor gene.

  12. Lentiviral Transduction of Mammary Stem Cells for Analysis of Gene Function during Development and Cancer

    Science.gov (United States)

    Welm, Bryan E.; Dijkgraaf, Gerrit J. P.; Bledau, Anita S.; Welm, Alana L.; Werb, Zena

    2008-01-01

    SUMMARY The mouse mammary gland is the only epithelial organ capable of complete regeneration upon orthotopic transplantation, making it ideally suited for in vivo gene function studies through viral mediated gene delivery. A hurdle that has challenged the widespread adoption of this technique has been the inability to transduce mammary stem cells effectively. We have overcome this limitation by infecting total primary mammary epithelial cells in suspension with high titer lentiviruses. Transduced cells gave rise to all major cell types of the mammary gland, and were capable of clonal outgrowth and functional differentiation in serial transplants. To demonstrate that this method is a valuable alternative to developing transgenic animals, we used lentiviral-mediated Wnt-1 overexpression to replicate MMTV-Wnt-1 mammary phenotypes and used a dominant-negative Xenopus Suppressor of Hairless to reveal a requirement for Notch signaling during ductal morphogenesis. Importantly, this method is also applicable to transduction of cells from other tissues. PMID:18371425

  13. Signalling pathways implicated in early mammary gland morphogenesis and breast cancer.

    Directory of Open Access Journals (Sweden)

    Beatrice Howard

    2006-08-01

    Full Text Available Specification of mammary epithelial cell fate occurs during embryogenesis as cells aggregate to form the mammary anlage. Within the embryonic mammary bud, a population of epithelial cells exists that will subsequently proliferate to form a ductal tree filling the stromal compartment, and which can produce milk upon terminal differentiation after birth. Subsequently, these structures can be remodelled and returned to a basal state after weaning before regenerating in future pregnancies. The plasticity of the mammary epithelial cell, and its responsiveness to hormone receptors, facilitates this amazing biological feat, but aberrant signalling may also result in unintended consequences in the form of frequent malignancies. Reflecting this intimate connection, a considerable number of signalling pathways have been implicated in both mammary gland morphogenesis and carcinogenesis.

  14. Investigation into the cancer protective effect of flaxseed in Tg.NK (MMTV/c-neu) mice, a murine mammary tumor model

    DEFF Research Database (Denmark)

    Birkved, Franziska Kramer; Mortensen, Alicja; Penalvo, Jose L;

    2011-01-01

    The aim of the present study was to investigate whether low flaxseed doses relevant to human dietary exposure can prevent mammary tumors in transgenic Tg.NK mice, a model of breast cancer. Animals were exposed to flaxseed through the diet at human relevant levels. Tumor-related parameters and tumor...... to the controls. Thus, the effect of small dietary doses of flaxseed on mammary tumor development in Tg.NK mice remains to be established....

  15. Inhibitory effects of combination of lycopene and genistein on 7,12- dimethyl benz(a)anthracene-induced breast cancer in rats.

    Science.gov (United States)

    Sahin, Kazim; Tuzcu, Mehmet; Sahin, Nurhan; Akdemir, Fatih; Ozercan, Ibrahim; Bayraktar, Soley; Kucuk, Omer

    2011-11-01

    Breast cancer is one of the most common cancers in women. Carotenoids and soy isoflavones have been postulated to have breast cancer preventive effects. We investigated the potential preventive effects of lycopene and genistein, alone and in combination, on breast cancer development in female Wistar rats treated with 7,12-dimethylbenz[a]anthracene (DMBA), a carcinogen known to induce breast tumors. Mammary carcinogenesis was initiated by a single, oral gavage of DMBA (80 mg/kg body weight) at 55 days of animal age. Fifty female Wistar rats were divided into 5 experimental groups having 10 animals per group: Group 1 (normal control), Group 2 (DMBA control), Group 3 (DMBA + lycopene), Group 4 (DMBA + genistein), and Group 5 (DMBA + lycopene and genistein). Rats were fed either lycopene (20 mg /kg bw) or genistein (2 mg /kg bw) by oral gavage (3 times per week) starting 2 wk prior to DMBA injection. Treatment was continued for 20 wk. Rats treated with DMBA developed mammary tumors with 100% tumor incidence during the 20-wk study. Inhibition of mammary cancer incidence by lycopene (70%), genistein (60%) and their combination (40%) was observed. Tumor weight decreased by 48%, 61%, and 67%, and mean tumor volume decreased by 18%, 35%, and 65% with lycopene, genistein, and lycopene + genistein, respectively (P cancer development and was associated with a decrease in MDA, 8-isoprostane, and 8-OhdG levels and with an increase in serum lycopene and genistein levels. Animals administered DMBA developed breast cancer, which was associated with increased expression of Bcl-2 and decreased expression of Bax, caspase 3, and caspase 9 in mammary tissues. Administration of genistein and lycopene in combination was more effective in inhibiting DMBA-induced breast tumors and modulating the expression of apoptosis associated proteins than the administration of each agent alone. Our results suggest that lycopene and genistein are potent antioxidants and, when given in combination, offer

  16. Therapeutic effect of Semecarpus anacardium Linn. nut milk extract on carbohydrate metabolizing and mitochondrial TCA cycle and respiratory chain enzymes in mammary carcinoma rats.

    Science.gov (United States)

    Arathi, G; Sachdanandam, P

    2003-09-01

    Semecarpus anacardium Linn. of the family Anacardiaceae has many applications in the Ayurvedic and Siddha systems of medicine. We have evaluated the effect of S. anacardium nut milk extract on carbohydrate metabolizing enzymes and mitochondrial tricarboxylic acid cycle and respiratory enzymes in liver and kidney mitochondria of dimethyl benzanthracene-induced mammary carcinoma in Sprague-Dawley rats. Mammary carcinoma-bearing rats showed a significant rise in glycolytic enzymes (hexokinase, phosphoglucoisomerase and aldolase) and a simultaneous fall in gluconeogenic enzymes (glucose-6-phosphatase and fructose 1,6-diphosphatase). The activities of mitochondrial enzymes isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, NADH-dehydrogenase and cytochrome C oxidase were significantly lowered in mammary carcinoma-bearing rats when compared with control rats. S. anacardium nut extract administration to tumour-induced animals significantly lowered the glycolytic enzyme activities (hexokinase, phosphoglucoisomerase and aldolase) and there was a rise in gluconeogenic enzymes (glucose-6-phosphatase and fructose 1,6-diphosphatase), which indicated an antitumour and anticancer effect. Comparison of normal control rats and rats administered S. anacardium only as drug control animals showed no significant variations in enzyme activities. S. anacardium nut extract administration to dimethyl benzanthracene-tumour-induced animals significantly increased the activities of mitochondrial enzymes, thereby suggesting its role in mitochondrial energy production.

  17. Low-dose effects of bisphenol A on mammary gland development in rats

    DEFF Research Database (Denmark)

    Egebjerg, Karen Mandrup; Boberg, Julie; Isling, Louise Krag

    2016-01-01

    Bisphenol A (BPA) is widely used in food contact materials, toys, and other products. Several studies have indicated that effects observed at doses near human exposure levels may not be observed at higher doses. Many studies have shown effects on mammary glands at low doses of BPA, however, because...

  18. The role of maintenance proteins in the preservation of epithelial cell identity during mammary gland remodeling and breast cancer initiation

    Institute of Scientific and Technical Information of China (English)

    Danila Coradini; Saro Oriana

    2014-01-01

    During normal postnatal mammary gland development and adult remodeling related to the menstrual cycle, pregnancy, and lactation, ovarian hormones and peptide growth factors contribute to the delineation of a definite epithelial cellidentity. This identity is maintained during cellreplication in a heritable but DNA-independent manner. The preservation of cellidentity is fundamental, especialy when cels must undergo changes in response to intrinsic and extrinsic signals. The maintenance proteins, which are required for cellidentity preservation, act epigenetically by regulating gene expression through DNA methylation, histone modification, and chromatin remodeling. Among the maintenance proteins, the Trithorax (TrxG) and Polycomb (PcG) group proteins are the best characterized. In this review, we summarize the structures and activities of the TrxG and PcG complexes and describe their pivotal roles in nuclear estrogen receptor activity. In addition, we provide evidence that perturbations in these epigenetic regulators are involved in disrupting epithelial cellidentity, mammary gland remodeling, and breast cancer initiation.

  19. Role of ATP-sensitive potassium channels in modulating nociception in rat model of bone cancer pain.

    Science.gov (United States)

    Xia, Hui; Zhang, Dengwen; Yang, Shijie; Wang, Yu; Xu, Lin; Wu, Jinjing; Ren, Jing; Yao, Wenlong; Fan, Longchang; Zhang, Chuanhan; Tian, Yuke; Pan, Hui-Lin; Wang, Xueren

    2014-03-20

    Bone cancer pain is a major clinical problem and remains difficult to treat. ATP-sensitive potassium (KATP) channels may be involved in regulating nociceptive transmission at the spinal cord level. We determined the role of spinal KATP channels in the control of mechanical hypersensitivity in a rat model of bone cancer pain. The rat model of bone cancer pain was induced by implanting rat mammary gland carcinoma cells (Walker256) into the tibias. KATP modulators (pinacidil and glibenclamide) or the specific Kir6.2-siRNA were injected via an intrathecal catheter. The mechanical withdrawal threshold of rats was tested using von Frey filaments. The Kir6.2 mRNA and protein levels were measured by quantitative PCR and western blots, respectively. Intrathecal injection of pinacidil, a KATP channel opener, significantly increased the tactile withdrawal threshold of cancer cell-injected rats in a dose-dependent manner. In contrast, intrathecal delivery of glibenclamide, a KATP channel blocker, or the specific Kir6.2-siRNA significantly reduced the tactile withdrawal threshold of cancer cell-injected rats. The mRNA and protein levels of Kir6.2 in the spinal cord of cancer cell-injected rats were significantly lower than those in control rats. Our findings suggest that the KATP channel expression level in the spinal cord is reduced in bone cancer pain. Activation of KATP channels at the spinal level reduces pain hypersensitivity associated with bone cancer pain.

  20. Lymphoscintigraphy Can Select Breast Cancer Patients for Internal Mammary Chain Radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Hindie, Elif, E-mail: elif.hindie@sls.aphp.fr [Department of Nuclear Medicine, Saint-Louis Hospital, Paris 7 University, Paris (France); Department of Nuclear Medicine, CHU de Bordeaux, University of Bordeaux-Segalen, Bordeaux (France); Groheux, David [Department of Nuclear Medicine, Saint-Louis Hospital, Paris 7 University, Paris (France); Hennequin, Christophe [Department of Radiation Oncology, Saint-Louis Hospital, Paris (France); Zanotti-Fregonara, Paolo; Vercellino, Laetitia; Berenger, Nathalie; Toubert, Marie-Elisabeth [Department of Nuclear Medicine, Saint-Louis Hospital, Paris 7 University, Paris (France); Maylin, Claude [Department of Radiation Oncology, Saint-Louis Hospital, Paris (France); Vilcoq, Jacques-Robert [Department of Radiation Oncology, Hartmann Hospital, Neuilly sur Seine (France); Espie, Marc [Breast Diseases Unit, Saint-Louis Hospital, Paris (France)

    2012-07-15

    Purpose: Given the risk of undesired toxicity, prophylactic internal mammary (IM) chain irradiation should be offered only to patients at high risk of occult involvement. Lymphoscintigraphy for axillary sentinel node biopsy might help in selecting these patients. Methods and Materials: We reviewed published studies with the following selection criteria: {>=}300 breast cancer patients referred for axilla sentinel node biopsy; scintigraphy performed after peritumoral or intratumoral tracer injection; IM biopsy in the case of IM drainage; and axilla staged routinely independent of IM status. Results: Six prospective studies, for a total of 3,876 patients, fulfilled the inclusion criteria. Parasternal drainage was present in 792 patients (20.4%). IM biopsy was performed in 644 patients and was positive in 111 (17.2%). Of the positive IM biopsies, 40% were associated with tumors in the lateral breast quadrants. A major difference in the IM positivity rate was found according to the axilla sentinel node status. In patients with negative axilla, the IM biopsy was positive in 7.8% of cases. In patients with positive axilla, however, the IM biopsy was positive in 41% (p < .00001). Because biopsy of multiple IM hot nodes is difficult, the true risk could be even greater, probably close to 50%. Conclusions: Patients with IM drainage on lymphoscintigraphy and a positive axilla sentinel node have a high risk of occult IM involvement. These women should be considered for IM radiotherapy.

  1. Isoform-specific function of calpains in cell adhesion disruption: studies in postlactational mammary gland and breast cancer.

    Science.gov (United States)

    Rodríguez-Fernández, Lucía; Ferrer-Vicens, Iván; García, Concha; Oltra, Sara S; Zaragozá, Rosa; Viña, Juan R; García-Trevijano, Elena R

    2016-09-15

    Cleavage of adhesion proteins is the first step for physiological clearance of undesired cells during postlactational regression of the mammary gland, but also for cell migration in pathological states such as breast cancer. The intracellular Ca(2+)-dependent proteases, calpains (CAPNs), are known to cleave adhesion proteins. The isoform-specific function of CAPN1 and CAPN2 was explored and compared in two models of cell adhesion disruption: mice mammary gland during weaning-induced involution and breast cancer cell lines according to tumor subtype classification. In both models, E-cadherin, β-catenin, p-120, and talin-1 were cleaved as assessed by western blot analysis. Both CAPNs were able to cleave adhesion proteins from lactating mammary gland in vitro Nevertheless, CAPN2 was the only isoform found to co-localize with E-cadherin in cell junctions at the peak of lactation. CAPN2/E-cadherin in vivo interaction, analyzed by proximity ligation assay, was dramatically increased during involution. Calpain inhibitor administration prevented the cytosolic accumulation of truncated E-cadherin cleaved by CAPN2. Conversely, in breast cancer cells, CAPN2 was restricted to the nuclear compartment. The isoform-specific expression of CAPNs and CAPN activity was dependent on the breast cancer subtype. However, CAPN1 and CAPN2 knockdown cells showed that cleavage of adhesion proteins and cell migration was mediated by CAPN1, independently of the breast cancer cell line used. Data presented here suggest that the subcellular distribution of CAPN1 and CAPN2 is a major issue in target-substrate recognition; therefore, it determines the isoform-specific role of CAPNs during disruption of cell adhesion in either a physiological or a pathological context.

  2. Canine mammary tumors contain cancer stem-like cells and form spheroids with an embryonic stem cell signature.

    Science.gov (United States)

    Ferletta, Maria; Grawé, Jan; Hellmén, Eva

    2011-01-01

    We have investigated the presence of tentative stem-like cells in the canine mammary tumor cell line CMT-U229. This cell line is established from an atypical benign mixed mammary tumor, which has the property of forming duct-like structures in collagen gels. Stem cells in mammary glands are located in the epithelium; therefore we thought that the CMT-U229 cell line would be suitable for detection of tentative cancer stem-like cells. Side population (SP) analyses by flow cytometry were performed with cells that formed spheroids and with cells that did not. Flow cytometric, single sorted cells were expanded and re-cultured as spheroids. The spheroids were paraffin embedded and characterized by immunohistochemistry. SP analyses showed that spheroid forming cells (retenate) as well as single cells (filtrate) contained SP cells. Sca1 positive cells were single cell sorted and thereafter the SP population increased with repeated SP analyses. The SP cells were positively labeled with the cell surface-markers CD44 and CD49f (integrin alpha6); however the expression of CD24 was low or negative. The spheroids expressed the transcription factor and stem cell marker Sox2, as well as Oct4. Interestingly, only peripheral cells of the spheroids and single cells were positive for Oct4 expression. SP cells are suggested to correspond to stem cells and in this study, we have enriched for tentative tumor stem-like cells derived from a canine mammary tumor. All the used markers indicate that the studied CMT-U229 cell line contains SP cells, which in particular have cancer stem-like cell characteristics.

  3. Mammary epithelial cell

    DEFF Research Database (Denmark)

    Kass, Laura; Erler, Janine Terra; Dembo, Micah

    2007-01-01

    a repertoire of transmembrane receptors, of which integrins are the best characterized. Integrins modulate cell fate by reciprocally transducing biochemical and biophysical cues between the cell and the extracellular matrix, facilitating processes such as embryonic branching morphogenesis and lactation...... in the mammary gland. During breast development and cancer progression, the extracellular matrix is dynamically altered such that its composition, turnover, processing and orientation change dramatically. These modifications influence mammary epithelial cell shape, and modulate growth factor and hormonal...

  4. Pubertal Social Isolation and Hypervigilance Regulate Gene Expression Mechanisms of Mammary Differentiation and Cancer Risks

    Science.gov (United States)

    2010-08-01

    which prevent pheromonal communication within our animal colony. Fortunately, the mouse’s response to pheromonal isolation is opposite that of rats...central nervous system of mice and the peripheral blood lymphocytes of humans . To examine gene expression differences, RNA was extracted from a subset of...hexokinase 2 (Hk2). The human orthologues of mouse Acly and Acaca were previously shown to be upregulated in aggressive, metastatic breast cancer cell

  5. DBCG-IMN: A Population-Based Cohort Study on the Effect of Internal Mammary Node Irradiation in Early Node-Positive Breast Cancer

    DEFF Research Database (Denmark)

    Thorsen, Lise Bech Jellesmark; Offersen, Birgitte Vrou; Danø, Hella;

    2016-01-01

    PURPOSE: It is unknown whether irradiation of the internal mammary lymph nodes improves survival in patients with early-stage breast cancer. A possible survival benefit might be offset by radiation-induced heart disease. We assessed the effect of internal mammary node irradiation (IMNI) in patients...... pronounced in patients at high risk of internal mammary node metastasis. Equal numbers in each group died of ischemic heart disease. CONCLUSION: In this naturally allocated, population-based cohort study, IMNI increased overall survival in patients with early-stage node-positive breast cancer....... with early-stage node-positive breast cancer. PATIENTS AND METHODS: In this nationwide, prospective population-based cohort study, we included patients who underwent operation for unilateral early-stage node-positive breast cancer. Patients with right-sided disease were allocated to IMNI, whereas patients...

  6. A monograph proposing the use of canine mammary tumours as a model for the study of hereditary breast cancer susceptibility genes in humans.

    Science.gov (United States)

    Goebel, Katie; Merner, Nancy D

    2017-05-01

    Canines are excellent models for cancer studies due to their similar physiology and genomic sequence to humans, companion status and limited intra-breed heterogeneity. Due to their affliction to mammary cancers, canines can serve as powerful genetic models of hereditary breast cancers. Variants within known human breast cancer susceptibility genes only explain a fraction of familial cases. Thus, further discovery is necessary but such efforts have been thwarted by genetic heterogeneity. Reducing heterogeneity is key, and studying isolated human populations have helped in the endeavour. An alternative is to study dog pedigrees, since artificial selection has resulted in extreme homogeneity. Identifying the genetic predisposition to canine mammary tumours can translate to human discoveries - a strategy currently underutilized. To explore this potential, we reviewed published canine mammary tumour genetic studies and proposed benefits of next generation sequencing canine cohorts to facilitate moving beyond incremental advances.

  7. 地塞米松对大鼠 Walker 256乳腺癌骨转移癌痛的作用%Effect of dexamethasone on rat bone metastasis pain induced by Walker 256 mammary gland carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    张凡; 李毅; 丁杰; 张海林

    2015-01-01

    Objective To establish a rat model of bone metastasis pain induced by Walker 256 mammary gland carcinoma cells and observe the effect of dexamethasone on bone cancer pain. Methods Ascitic tumour cells were made from Walker 256 mammary gland carcinoma cells injected to tibia of rats.Then,the withdrawal threshold to mechanical stimulus and withdrawal time in response to radiant thermal stimulus were tested before and after operation.Results The withdrawal threshold to mechanical stimulus and withdrawal time in response to radiant thermal stimulus were significantly reduced in the tibia bone inoculated with Walker 256 cells.The pathology results showed the evidence of tibia bone structure was destructed by tumor.It is suggested that the model of bone metastasis pain induced by Walker 256 mammary gland carcinoma cell was successfully established.Dexamethasone (5 mg/kg ) elevated withdrawal threshold to mechanical stimulus in rat model of bone metastasis pain induced by Walker 256 mammary gland carcinoma cell.Conclusion Dexamethasone could alleviate bone cancer pain.%目的:建立大鼠 Walker 256乳腺癌骨转移癌痛模型,观察地塞米松对骨转移癌疼痛痛阈的影响。方法制备 Walker 256乳腺癌细胞的大鼠腹腔积液瘤细胞,将其注射入大鼠胫骨,测量术前及术后机械刺痛阈和辐射热痛阈。结果接种 Walker 256乳腺癌大鼠术侧机械刺激痛觉和辐射热痛觉阈值显著降低,且病理学结果显示骨质受到肿瘤破坏,提示 Walker 256大鼠乳腺癌骨转移癌疼痛模型成功建立。地塞米松(5 mg/kg)能够显著提高骨转移癌疼痛模型刺痛痛阈。结论地塞米松能够缓解大鼠骨转移癌疼痛。

  8. Effect of zinc and polyphenols supplementation on antioxidative defense mechanisms and the frequency of microsatellite instability in chemically-induced mammary carcinogenesis in the rat.

    Science.gov (United States)

    Bobrowska-Korczak, Barbara; Skrajnowska, Dorota; Tokarz, Andrzej; Bialek, Slawomir; Jezierska, Ewelina

    2015-01-01

    The aim of the present study was to assess the effect of dietary supplementation (with zinc or zinc and polyphenolic compounds - resveratrol or genistein) on antioxidant enzymes (glutathione peroxidase - GPx, catalase - CAT and superoxide dismutase - SOD) and the frequency of microsatellite instability (MSI) in a widely used model of mammary carcinogenesis induced in the rat by treatment with 7,12-dimethyl-1,2-benz[a]anthracene (DMBA). The impact of selected compounds on the intensity of DMBA-induced carcinogenesis was also assessed. Sixty four Sprague-Dawley female rats were divided into study groups which, apart from the standard diet and DMBA, were treated with zinc, zinc and resveratrol or zinc and genistein via gavage for a period ranging from 40 days to 20 weeks of age. On the basis of the obtained results it can be said that synergistic reaction between Zn(II) and genistein causes a delay in cancer development as compared with the animals treated with DMBA but with no food supplementation. Supplementation with Zn(II) and polyphenolic compounds resulted in the occurrence of microsatellite instabilities in tumors. LOH (loss of heterozygosity) was found in tumor samples at microsatellite D1Mgh6 and D3Mgh9. DMBA treatment increased significantly the glutathione peroxidase activity whereas it had no effect on the SOD and CAT activities, as compared with control rats. Diet supplementation has an effect on the activity of selected antioxidant enzymes. Diet supplementation has an effect on the occurrence of microsatellite instabilities as well as on the intensity of the neoplastic process. The intensity of occurrence of microsatellite instabilities does not depend on the activity of selected antioxidant enzymes.

  9. Determination of the functional size of oxytocin receptors in plasma membranes from mammary gland and uterine myometrium of the rat by radiation inactivation

    Energy Technology Data Exchange (ETDEWEB)

    Soloff, M.S.; Beauregard, G.; Potier, M.

    1988-05-01

    Gel filtration of detergent-solubilized oxytocin (OT) receptors in plasma membrane fractions from both regressed mammary gland and labor myometrium of the rat, showed that specific (/sup 3/H)OT binding was associated with a heterogeneously sized population of macromolecules. As radiation inactivation is the only method available to measure the apparent molecular weights of membrane proteins in situ, we used this approach to define the functional sizes of OT receptors. The results indicate that both mammary and myometrial receptors are uniform in size and of similar molecular mass. Mammary and myometrial receptors were estimated to be 57.5 +/- 3.8 (SD) and 58.8 +/- 1.6 kilodaltons, respectively. Knowledge of the functional size of OT receptors will be useful in studies involving the purification and characterization of the receptor and associated membrane components.

  10. The contrast study on the contrast-enhanced ultrasonography in the patients with mammary cancer and mammary fibroma%乳腺癌及乳腺纤维瘤超声及造影特征的对比研究

    Institute of Scientific and Technical Information of China (English)

    王淑贤; 闫国珍; 李爱华; 刘扬

    2015-01-01

    Objective:To evaluate the clinical value of contrast-enhanced ultrasonography( CEUS) in the diagnosis of mammary cancer. Methods:66 cases of mammary cancer and 85 cases of mammary fibroma from January 1st, 2013 to December 31st, 2014 in the First Affiliated Hospital of Baotou Medical College were selected to perform routine ultrasound examination and CEUS before the operation so as to observe the characteristics of breast masses. All the cases were confirmed by operation and compared with the results of pathology examination. Results:The 66 cases of mammary cancer were significantly dif-ferent from the 85 cases of mammary fibroma in the initiation time, peak time, transit time, fading time and disappearing time on CEUS ( P 0. 05);The radiocontrast agent entered slowly and came slowly out of the perforator vessel;The radiocontrast agent in the lesion was homogeneously dis-tributed and enhanced centripetally, without signs of retention. Conclusions:CEUS has important instructional value to the diagnosis of mammary cancer and mammary fibroma clinically.%目的:探讨超声及造影特征对乳腺癌的临床诊断价值. 方法:2013年1月1日至2014年12月31日在包头医学院第一附属医院住院的66例乳腺癌及85例乳腺纤维瘤患者,术前行常规超声及超声造影检查,观察肿块超声及造影特征,所有病例均经手术证实并与病理结果相对照. 结果:66例乳腺癌患者与85例乳腺纤维瘤患者超声造影的开始增强时间、达峰时间、渡越时间、开始消退时间、完全消退时间相比较均有统计学意义( P 0. 05),可见环绕血管并呈慢进快出,病灶内造影剂分布均匀,造影剂呈向心性增强,无造影剂滞留. 结论:超声及造影检查对乳腺癌和乳腺纤维瘤的鉴别诊断具有重要的指导价值.

  11. [Effect of veralipride on the estral cycle, genital tract, mammary gland and pituitary gland in female rats (author's transl)].

    Science.gov (United States)

    Tuchmann-Duplessis, H

    1980-10-15

    A study of the potential biological effects of veralipride was conducted in female rats. A definite stimulating action on the mammary gland was noted, but doses of 5 to 20 mg/kg/day are required to produce secretion, which is varying from one animal to another. Follicular maturation is preserved, though there is an increase in the number of corpora lutea with more marked development in some of them. Progesterone impregnation of the uterus occurs in a variable way and then only at doses of 5 + 0 20 mg/kg/day. Vaginal mucification, from a reduction in estrogen in relation to progesterone impregnation, is noted after 1 mg/kg/day (though 25 p. cent of the animals still demonstrate vaginal keratinization after 20 mg/kg/day). Finally, degranulation of the carminophile cells of the anterior pituitary gland, occurs after 5 mg/kg/day.

  12. No association between Epstein-Barr Virus and Mouse Mammary Tumor Virus with Breast Cancer in Mexican Women

    Science.gov (United States)

    Morales-Sánchez, Abigail; Molina-Muñoz, Tzindilú; Martínez-López, Juan L. E.; Hernández-Sancén, Paulina; Mantilla, Alejandra; Leal, Yelda A.; Torres, Javier; Fuentes-Pananá, Ezequiel M.

    2013-10-01

    Breast cancer is the most frequent malignancy affecting women worldwide. It has been suggested that infection by Epstein Barr Virus (EBV), Mouse Mammary Tumor Virus or a similar virus, MMTV-like virus (MMTV-LV), play a role in the etiology of the disease. However, studies looking at the presence of these viruses in breast cancer have produced conflicting results, and this possible association remains controversial. Here, we used polymerase chain reaction assay to screen specific sequences of EBV and MMTV-LV in 86 tumor and 65 adjacent tissues from Mexican women with breast cancer. Neither tumor samples nor adjacent tissue were positive for either virus in a first round PCR and only 4 tumor samples were EBV positive by a more sensitive nested PCR. Considering the study's statistical power, these results do not support the involvement of EBV and MMTV-LV in the etiology of breast cancer.

  13. Profile of Steroid Receptors and Increased Aromatase Immunoexpression in Canine Inflammatory Mammary Cancer as a Potential Therapeutic Target.

    Science.gov (United States)

    De Andrés, P J; Cáceres, S; Clemente, M; Pérez-Alenza, M D; Illera, J C; Peña, L

    2016-04-01

    Canine inflammatory mammary cancer (IMC) has been proposed as a model for the study of human inflammatory breast cancer (IBC). The aims of this study were to compare the immunohistochemical expression of aromatase (Arom) and several hormone receptors [estrogen receptor α (ERα), estrogen receptor β (ERβ), progesterone receptor (PR) and androgen receptor (AR)], in 21 IMC cases vs 19 non-IMC; and to study the possible effect of letrozole on canine IMC and human inflammatory breast cancer (IBC) in vitro using IPC-366 and SUM-149 cell lines. Significant elevations of the means of Arom Total Score (TS), ERβ TS and PR TS were found in the IMC group (p = 0.025, p = 0.038 and p = 0.037, respectively). Secondary IMC tumours expressed higher levels of Arom than primary IMC (p = 0.029). Non-IMC PR- tumours contained higher levels of Arom than non-IMC PR+ tumours (p = 0.007). After the addition of letrozole, the number of IMC and IBC cells dropped drastically. The overexpression of Arom found and the results obtained in vitro further support canine IMC as a model for the study of IBC and future approaches to the treatment of dogs with mammary cancer, and especially IMC, using Arom inhibitors.

  14. Internal Mammary Recipient Site Breast Cancer Recurrence Following Delayed Microvascular Breast Reconstruction

    OpenAIRE

    Rosich-Medina, Anais; Wang, Susan; Erel, Ertan; Malata, Charles M.

    2013-01-01

    Objective: The internal mammary vessels are a popular recipient site for microsurgical anastomoses of free flap breast reconstructions. We, however, observed 3 patients undergoing internal mammary vessel delayed free flap breast reconstruction that subsequently developed tumor recurrence at this site. We reviewed their characteristics to determine whether there was a correlation between delayed microsurgical reconstruction and local recurrence. Methods: A retrospective review of a single surg...

  15. Effect of Withania somnifera root extract on spontaneous estrogen receptor-negative mammary cancer in MMTV/Neu mice.

    Science.gov (United States)

    Khazal, Kamel F; Hill, Donald L; Grubbs, Clinton J

    2014-11-01

    The cancer-preventive activity of an extract of Withania somnifera (WS) roots was examined in female transgenic (MMTV/Neu) mice that received a diet containing the extract (750 mg/kg of diet) for 10 months. Mice in the treated group (n=35) had an average of 1.66 mammary carcinomas, and mice in the control group (n=33) had 2.48, showing a reduction of 33%. The average weights of the carcinomas were 2.36 g for mice in the treated group and 2.63 g for the controls, a difference of 10%. Labeling indices for Ki67 and proliferating cell nuclear antigen marker in mammary carcinomas of the treated group were 35% and 30% lower, respectively, than those of the corresponding control group. Expression of the chemokine was reduced by 50%. These results indicate that the root extract reduced the number of mammary carcinomas that developed and reduced the rate of cell division in the carcinomas.

  16. Internal Mammary Recipient Site Breast Cancer Recurrence Following Delayed Microvascular Breast Reconstruction

    Science.gov (United States)

    Rosich-Medina, Anais; Wang, Susan; Erel, Ertan; Malata, Charles M.

    2013-01-01

    Objective: The internal mammary vessels are a popular recipient site for microsurgical anastomoses of free flap breast reconstructions. We, however, observed 3 patients undergoing internal mammary vessel delayed free flap breast reconstruction that subsequently developed tumor recurrence at this site. We reviewed their characteristics to determine whether there was a correlation between delayed microsurgical reconstruction and local recurrence. Methods: A retrospective review of a single surgeon's delayed free flap breast reconstructions using the internal mammary vessels was conducted over a 7-year period to identify the time intervals between mastectomy and delayed breast reconstruction and between delayed breast reconstruction and recurrence. Results: Three patients developed local recurrence at the site of the microvascular anastomoses following delayed breast reconstruction. All patients had been disease-free following mastectomy. The median time interval between mastectomy and delayed breast reconstruction was 28 months (range = 20-120 months) while that between delayed breast reconstruction and local recurrence was 7 months (range = 4-10 months). Two patients died from metastatic disease, 36 and 72 months following their local recurrence. One patient remains alive 44 months after reconstruction. Conclusions: Local tumor recurrence at the internal mammary vessel dissection site following delayed breast reconstruction raises the question whether these 2 events may be related. Specifically, could internal mammary vessel dissection undertaken for delayed microsurgical reconstruction predispose to recurrence in the internal mammary lymph nodes? Further research is needed to ascertain whether delayed breast reconstruction increases the risk of local recurrence in this patient group. PMID:23383360

  17. Inhibition of NF-κB, Bcl-2 and COX-2 Gene Expression by an Extract of Eruca sativa Seeds during Rat Mammary Gland Carcinogenesis.

    Science.gov (United States)

    Abdel-Rahman, Salah; Shaban, Nadia; Haggag, Amany; Awad, Doaa; Bassiouny, Ahmad; Talaat, Iman

    2015-01-01

    The effect of Eruca sativa seed extract (SE) on nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX-2) and B-cell lymphoma-2 (Bcl-2) gene expression levels was investigated in rat mammary gland carcinogenesis induced by 7,12 dimethylbenz(α)anthracene (DMBA). DMBA increased NF-κB, COX-2 and Bcl-2 gene expression levels and lipid peroxidation (LP), while, decreased glutathione-S-transferase (GST) and superoxide dismutase (SOD) activities and total antioxidant concentration (TAC) compared to the control group. After DMBA administration, SE treatment reduced NF-κB, COX-2 and Bcl-2 gene expression levels and LP. Hence, SE treatment reduced inflammation and cell proliferation, while increasing apoptosis, GST and SOD activities and TAC. Analysis revealed that SE has high concentrations of total flavonoids, triterpenoids, alkaloids and polyphenolic compounds such as gallic, chlorogenic, caffeic, 3,4-dicaffeoyl quinic, 3,5-dicaffeoyl quinic, tannic, cinnamic acids, catechin and phloridzin. These findings indicate that SE may be considered a promising natural product from cruciferous vegetables against breast cancer, especially given its high antioxidant properties.

  18. The Proliferative Activity of Mammary Epithelial Cells in Normal Tissue Predicts Breast Cancer Risk in Premenopausal Women.

    Science.gov (United States)

    Huh, Sung Jin; Oh, Hannah; Peterson, Michael A; Almendro, Vanessa; Hu, Rong; Bowden, Michaela; Lis, Rosina L; Cotter, Maura B; Loda, Massimo; Barry, William T; Polyak, Kornelia; Tamimi, Rulla M

    2016-04-01

    The frequency and proliferative activity of tissue-specific stem and progenitor cells are suggested to correlate with cancer risk. In this study, we investigated the association between breast cancer risk and the frequency of mammary epithelial cells expressing p27, estrogen receptor (ER), and Ki67 in normal breast tissue. We performed a nested case-control study of 302 women (69 breast cancer cases, 233 controls) who had been initially diagnosed with benign breast disease according to the Nurses' Health Studies. Immunofluorescence for p27, ER, and Ki67 was performed on tissue microarrays constructed from benign biopsies containing normal mammary epithelium and scored by computational image analysis. We found that the frequency of Ki67(+) cells was positively associated with breast cancer risk among premenopausal women [OR = 10.1, 95% confidence interval (CI) = 2.12-48.0]. Conversely, the frequency of ER(+) or p27(+) cells was inversely, but not significantly, associated with subsequent breast cancer risk (ER(+): OR = 0.70, 95% CI, 0.33-1.50; p27(+): OR = 0.89, 95% CI, 0.45-1.75). Notably, high Ki67(+)/low p27(+) and high Ki67(+)/low ER(+) cell frequencies were significantly associated with a 5-fold higher risk of breast cancer compared with low Ki67(+)/low p27(+) and low Ki67(+)/low ER(+) cell frequencies, respectively, among premenopausal women (Ki67(hi)/p27(lo): OR = 5.08, 95% CI, 1.43-18.1; Ki67(hi)/ER(lo): OR = 4.68, 95% CI, 1.63-13.5). Taken together, our data suggest that the fraction of actively cycling cells in normal breast tissue may represent a marker for breast cancer risk assessment, which may therefore impact the frequency of screening procedures in at-risk women. Cancer Res; 76(7); 1926-34. ©2016 AACR.

  19. Anticancer activity of fungal taxol derived from Botryodiplodia theobromae Pat., an endophytic fungus, against 7, 12 dimethyl benz(a)anthracene (DMBA)-induced mammary gland carcinogenesis in Sprague Dawley rats.

    Science.gov (United States)

    Pandi, M; Manikandan, R; Muthumary, J

    2010-01-01

    Breast cancer is the second most prevalent cancer worldwide and their incidence increases gradually. Taxol (paclitaxel), a potent anticancer drug, is naturally isolated from the bark of the Pacific yew. Taxol is widely used in the treatment of ovarian, lung and breast cancer. The increased demand for taxol, coupled with its limited availability from the protected Pacific yew, has had researchers scrambling for alternate sources. The purpose of the present study is to investigate chemopreventive effect of fungal taxol derived from a novel endophytic fungus Botryodiplodia theobromae Pat., isolated from a medicinal plant Morinda citrifolia Linn. The fungal taxol is found to be active against the 7, 12 dimethyl benz(a)anthracene (DMBA)-induced mammary gland carcinogenesis in Sprague dawley rats. The enzymic and non-enzymic antioxidants i.e. superoxide dismutase (SOD), catalase (CAT), glutatione peroxidase (GPx), glutatione-S-transferase (GST), reduced glutathione (GSH), vitamin C and vitamin E were evaluated in control and experimental groups. Lipid peroxides levels (LPO) were also tested. Histological analysis of breast tissue was analyzed by haematoxylin and eosin staining to assess the cytoprotective role of fungal taxol active against breast cancer. Immunohistochemical analyses were also performed to evaluate the effect of fungal taxol on the inflammatory marker such as Cyclooxygenase-2 (COX-2) in control and experimental groups. The results showed that the fungal taxol significantly suppresses the DMBA-induced breast cancer in Sprague dawley rats.

  20. Effect of primrose oil and corn oil diets on eicosanoid synthesis by rat mammary tumor induced by dimethylbenzanthracene (DMBA)

    Energy Technology Data Exchange (ETDEWEB)

    El-Ela, S.H.A.; Bunce, O.R.

    1986-03-01

    Evening primrose oil (PO) contains 9% gamma-linolenic acid (GLA) and 75% linoleic acid (LA) each of which are prostaglandin precursors. Corn oil (CO) contains 60% linoleic acid. Fifty day old virgin female rats were given DMBA (5 mg, intragastric). Three weeks post DMBA the rats were separated into two dietary groups of 20% PO and 20% CO, respectively. At 16 weeks post DMBA the rats were killed and mammary tumors analyzed by RIA for PGE/sub 1/, PGE/sub 2/, and 6-keto F/sub 1..cap alpha... PGE/sub 1/ levels in PO fed animals were increased two fold over those fed CO indicating that it is possible to shunt GLA toward monoenoic eicosanoid synthesis. However PGE/sub 2/ and 6 keto F/sub 1..cap alpha../ levels were 5x higher in PO compared to CO. Although this could be attributed to higher cis linoleic acid content of PO, more subtle mechanisms may be responsible.

  1. KISS1R induces invasiveness of estrogen receptor-negative human mammary epithelial and breast cancer cells.

    Science.gov (United States)

    Cvetkovic, Donna; Dragan, Magdalena; Leith, Sean J; Mir, Zuhaib M; Leong, Hon S; Pampillo, Macarena; Lewis, John D; Babwah, Andy V; Bhattacharya, Moshmi

    2013-06-01

    Kisspeptins (KPs), peptide products of the KISS1 metastasis-suppressor gene, are endogenous ligands for a G protein-coupled receptor (KISS1R). KISS1 acts as a metastasis suppressor in numerous human cancers. However, recent studies have demonstrated that an increase in KISS1 and KISS1R expression in patient breast tumors correlates with higher tumor grade and metastatic potential. We have shown that KP-10 stimulates invasion of estrogen receptor α (ERα)-negative MDA-MB-231 breast cancer cells via transactivation of the epidermal growth factor receptor (EGFR). Here, we report that either KP-10 treatment of ERα-negative nonmalignant mammary epithelial MCF10A cells or expression of KISS1R in MCF10A cells induced a mesenchymal phenotype and stimulated invasiveness. Similarly, exogenous expression of KISS1R in ERα-negative SKBR3 breast cancer cells was sufficient to trigger invasion and induced extravasation in vivo. In contrast, KP-10 failed to transactivate EGFR or stimulate invasiveness in the ERα-positive MCF7 and T47D breast cancer cells. This suggested that ERα negatively regulates KISS1R-dependent breast cancer cell migration, invasion, and EGFR transactivation. In support of this, we found that these KP-10-induced effects were ablated upon exogenous expression of ERα in the MDA-MB-231 cells, by down-regulating KISS1R expression. Lastly, we have identified IQGAP1, an actin cytoskeletal binding protein as a novel binding partner of KISS1R, and have shown that KISS1R regulates EGFR transactivation in breast cancer cells in an IQGAP1-dependent manner. Overall, our data strongly suggest that the ERα status of mammary cells dictates whether KISS1R may be a novel clinical target for treating breast cancer metastasis.

  2. Vitamin D and the mammary gland: a review on its role in normal development and breast cancer.

    Science.gov (United States)

    Lopes, Nair; Paredes, Joana; Costa, José Luis; Ylstra, Bauke; Schmitt, Fernando

    2012-05-31

    Breast cancer is a heterogeneous disease associated with diverse biological behaviours and clinical outcome. Although some molecular subgroups of breast cancer have a targeted therapy, the most aggressive tumours still lack a molecular target. Despite vitamin D being classically associated with the physiological role of calcium regulation and phosphate transport in bone metabolism, several studies have demonstrated a wide range of functions for this hormone, which are particularly important in the field of cancer. The mechanisms underlying the protective actions of vitamin D in cancer development are only sparsely understood, but evidence shows that vitamin D participates in cell growth regulation, apoptosis and cell differentiation. In addition, it has been implicated in the suppression of cancer cell invasion, angiogenesis and metastasis. Most of vitamin D biological actions are mediated by the vitamin D receptor and the synthesis and catabolism of this hormone are regulated by the enzymes CYP27B1 and CYP24A1. In the present review we highlight research data concerning the function of this hormone in the mammary gland, with a special focus on breast carcinogenesis. Hence, and although the available data are controversial, we consider not only updated information on the epidemiology of vitamin D in breast cancer and its potential value as a therapeutic agent or prophylactic (with an emphasis on molecular mechanisms and effectors of vitamin D action), but include data on its role in other stages of breast cancer progression as well. Accordingly, we review data on the influence of vitamin D in the development of normal breast and the expression of vitamin D-related proteins (VDR, CYP27B1 and CYP24A21) in benign mammary lesions and ductal carcinomas in situ.

  3. The gene desert mammary carcinoma susceptibility locus Mcs1a regulates Nr2f1 modifying mammary epithelial cell differentiation and proliferation.

    Directory of Open Access Journals (Sweden)

    Bart M G Smits

    2013-06-01

    Full Text Available Genome-wide association studies have revealed that many low-penetrance breast cancer susceptibility loci are located in non-protein coding genomic regions; however, few have been characterized. In a comparative genetics approach to model such loci in a rat breast cancer model, we previously identified the mammary carcinoma susceptibility locus Mcs1a. We now localize Mcs1a to a critical interval (277 Kb within a gene desert. Mcs1a reduces mammary carcinoma multiplicity by 50% and acts in a mammary cell-autonomous manner. We developed a megadeletion mouse model, which lacks 535 Kb of sequence containing the Mcs1a ortholog. Global gene expression analysis by RNA-seq revealed that in the mouse mammary gland, the orphan nuclear receptor gene Nr2f1/Coup-tf1 is regulated by Mcs1a. In resistant Mcs1a congenic rats, as compared with susceptible congenic control rats, we found Nr2f1 transcript levels to be elevated in mammary gland, epithelial cells, and carcinoma samples. Chromatin looping over ∼820 Kb of sequence from the Nr2f1 promoter to a strongly conserved element within the Mcs1a critical interval was identified. This element contains a 14 bp indel polymorphism that affects a human-rat-mouse conserved COUP-TF binding motif and is a functional Mcs1a candidate. In both the rat and mouse models, higher Nr2f1 transcript levels are associated with higher abundance of luminal mammary epithelial cells. In both the mouse mammary gland and a human breast cancer global gene expression data set, we found Nr2f1 transcript levels to be strongly anti-correlated to a gene cluster enriched in cell cycle-related genes. We queried 12 large publicly available human breast cancer gene expression studies and found that the median NR2F1 transcript level is consistently lower in 'triple-negative' (ER-PR-HER2- breast cancers as compared with 'receptor-positive' breast cancers. Our data suggest that the non-protein coding locus Mcs1a regulates Nr2f1, which is a candidate

  4. Quantitative Assessment of Mammary Gland Density in Rodents Using Digital Image Analysis

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    Thompson Henry J

    2011-06-01

    Full Text Available Abstract Background Rodent models have been used extensively to study mammary gland development and for studies of toxicology and carcinogenesis. Mammary gland gross morphology can visualized via the excision of intact mammary gland chains following fixation and staining with carmine using a tissue preparation referred to as a whole mount. Methods are described for the automated collection of digital images from an entire mammary gland whole mount and for the interrogation of digital data using a "masking" technique available with Image-Pro® plus image analysis software (Mediacybernetics. Silver Spring, MD. Results Parallel to mammographic analysis in humans, measurements of rodent mammary gland density were derived from area-based or volume-based algorithms and included: total circumscribed mammary fat pad mass, mammary epithelial mass, and epithelium-free fat pad mass. These values permitted estimation of absolute mass of mammary epithelium as well as breast density. The biological plausibility of these measurements was evaluated in mammary whole mounts from rats and mice. During mammary gland development, absolute epithelial mass increased linearly without significant changes in mammographic density. Treatment of rodents with tamoxifen, 9-cis-retinoic acid, or ovariectomy, and occurrence of diet induced obesity decreased both absolute epithelial mass and mammographic density. The area and volumetric methods gave similar results. Conclusions Digital image analysis can be used for screening agents for potential impact on reproductive toxicity or carcinogenesis as well as for mechanistic studies, particularly for cumulative effects on mammary epithelial mass as well as translational studies of mechanisms that explain the relationship between epithelial mass and cancer risk.

  5. Tangeretin, a citrus pentamethoxyflavone, exerts cytostatic effect via p53/p21 up-regulation and suppresses metastasis in 7,12-dimethylbenz(α)anthracene-induced rat mammary carcinoma.

    Science.gov (United States)

    Arivazhagan, Lakshmi; Sorimuthu Pillai, Subramanian

    2014-11-01

    Breast cancer is the most commonly diagnosed cancer among women worldwide, which is characterized by unregulated cell growth and metastasis. Many bioactive compounds of plant origin such as tangeretin have been shown to possess potent antioxidant and anticancerous properties. In the present study we have investigated the chemotherapeutic effect of tangeretin against 7,12-dimethylbenz(α)anthracene (DMBA)-induced rat mammary carcinogenesis and studied its underlying mechanism of action. Breast cancer was induced by "air pouch technique" with a single dose of 25mg/kg of DMBA. Tangeretin (50 mg/kg) was administered orally for four weeks. Remarkably, tangeretin treatment controlled the growth of cancer cells which was clearly evidenced by morphological and histological analysis. Also, serum levels of estradiol, progesterone and prolactin; lipid bound sialic acid and total sialic acid and the tissue levels of nitric oxide and protein carbonyls of cancer induced animals were decreased upon tangeretin treatment. Staining of breast tissues for nucleolar organizer regions, mast cells, glycoproteins, lipids and collagen showed that tangeretin treatment to breast cancer induced rats significantly reduced tumorigenesis. Oral tangeretin treatment also effectively reduced the tumor cell proliferation markers such as PCNA, COX-2 and Ki-67. Further, tangeretin treatment arrested the cancer cell division at the G1/S phase via p53/p21 up-regulation and inhibited metastasis by suppressing matrix metalloproteinase (MMP)-2, MMP-9 and vascular endothelial growth factor. Taken together, the data provides new evidence on the mechanism of action of tangeretin in breast cancer and hence extends the hypothesis supporting its potential use in chemotherapy.

  6. In-Silico Genomic Approaches To Understanding Lactation, Mammary Development, And Breast Cancer

    Science.gov (United States)

    Lactation-related traits are influenced by genetics. From a quantitative standpoint, these traits have been well studied in dairy species, but there has also been work on the genetics of lactation in humans and mice. In addition, there is evidence to support the notion that other mammary gland trait...

  7. Tumor-induced inflammation in mammary adipose tissue stimulates a vicious cycle of autotaxin expression and breast cancer progression.

    Science.gov (United States)

    Benesch, Matthew G K; Tang, Xiaoyun; Dewald, Jay; Dong, Wei-Feng; Mackey, John R; Hemmings, Denise G; McMullen, Todd P W; Brindley, David N

    2015-09-01

    Compared to normal tissues, many cancer cells overexpress autotaxin (ATX). This secreted enzyme produces extracellular lysophosphatidate, which signals through 6 GPCRs to drive cancer progression. Our previous work showed that ATX inhibition decreases 4T1 breast tumor growth in BALB/c mice by 60% for about 11 d. However, 4T1 cells do not produce significant ATX. Instead, the ATX is produced by adjacent mammary adipose tissue. We investigated the molecular basis of this interaction in human and mouse breast tumors. Inflammatory mediators secreted by breast cancer cells increased ATX production in adipose tissue. The increased lysophosphatidate signaling further increased inflammatory mediator production in adipose tissue and tumors. Blocking ATX activity in mice bearing 4T1 tumors with 10 mg/kg/d ONO-8430506 (a competitive ATX inhibitor, IC90 = 100 nM; Ono Pharma Co., Ltd., Osaka, Japan) broke this vicious inflammatory cycle by decreasing 20 inflammatory mediators by 1.5-8-fold in cancer-inflamed adipose tissue. There was no significant decrease in inflammatory mediator levels in fat pads that did not bear tumors. ONO-8430506 also decreased plasma TNF-α and G-CSF cytokine levels by >70% and leukocyte infiltration in breast tumors and adjacent adipose tissue by >50%. Hence, blocking tumor-driven inflammation by ATX inhibition is effective in decreasing tumor growth in breast cancers where the cancer cells express negligible ATX.

  8. Study on 41Ca-AMS for diagnosis and assessment of cancer bone metastasis in rats

    Science.gov (United States)

    Shen, Hongtao; Pang, Fangfang; Jiang, Shan; He, Ming; Dong, Kejun; Dou, Liang; Pang, Yijun; Yang, Xianlin; Ruan, Xiangdong; Liu, Manjun; Xia, Chunbo

    2015-10-01

    The annual incidence of new cancer patients in China is about 2 million, 30-40% of which will end up with bone metastasis. Profound study on the preclinical model and early diagnosis of cancer bone metastasis in rats are very significant for the drug development, better understanding and treatment of bone metastases. In order to monitor the process of bone metabolism and early detection of bone metastasis of cancer cells, a technique of 41Ca isotope tracer combined with AMS has been developed and applied in the study on the bone metastasis of cancer cells by rat model. In this work, 3-month-old female Sprague-Dawley (SD) rats were randomly divided into different groups, and tumor cells injected respectively into the tail vein, femoral artery, femoral cavity and the thigh muscle to establish the rat models for bone metastases. The most appropriate model, i.e., the thigh muscle group, was finally adopted in our real metastases experiment. Each rat in this group was intramuscularly (i.m.) injected with 250 μl CaCl2 solution (containing 1.4 mg Ca and 5nCi 41Ca). About 40 days later, the rat mammary gland carcinoma cells (Walker 256) were injected into these rats following the established protocol. After bone metastasis, medicine interventions were performed. The sequential urine and blood samples were collected and analyzed for 41Ca (by AMS) and N-terminal telopeptide (Ntx), respectively. Bone Mineral Density (BMD) values in the femur and the tibia were measured by CT scan. The results of 41Ca/Ca in longitudinal urinary samples can sensitively reveal the skeletal perturbations caused by bone metastasis of rats, suggests that 41Ca might be similarly developed for human use and improve clinical management through the assessment of the curative effect and non-invasive detection of the earliest stages of cancer growth in bone.

  9. Epstein-Barr virus, human papillomavirus and mouse mammary tumour virus as multiple viruses in breast cancer.

    Directory of Open Access Journals (Sweden)

    Wendy K Glenn

    Full Text Available BACKGROUND: The purpose of this investigation is to determine if Epstein Barr virus (EBV, high risk human papillomavirus (HPV, and mouse mammary tumour viruses (MMTV co-exist in some breast cancers. MATERIALS AND METHODS: All the specimens were from women residing in Australia. For investigations based on standard PCR, we used fresh frozen DNA extracts from 50 unselected invasive breast cancers. For normal breast specimens, we used DNA extracts from epithelial cells from milk donated by 40 lactating women. For investigations based on in situ PCR we used 27 unselected archival formalin fixed breast cancer specimens and 18 unselected archival formalin fixed normal breast specimens from women who had breast reduction surgery. Thirteen of these fixed breast cancer specimens were ductal carcinoma in situ (dcis and 14 were predominantly invasive ductal carcinomas (idc. RESULTS: EBV sequences were identified in 68%, high risk HPV sequences in 50%, and MMTV sequences in 78% of DNA extracted from 50 invasive breast cancer specimens. These same viruses were identified in selected normal and breast cancer specimens by in situ PCR. Sequences from more than one viral type were identified in 72% of the same breast cancer specimens. Normal controls showed these viruses were also present in epithelial cells in human milk - EBV (35%, HPV, 20% and MMTV (32% of 40 milk samples from normal lactating women, with multiple viruses being identified in 13% of the same milk samples. CONCLUSIONS: We conclude that (i EBV, HPV and MMTV gene sequences are present and co-exist in many human breast cancers, (ii the presence of these viruses in breast cancer is associated with young age of diagnosis and possibly an increased grade of breast cancer.

  10. CA 15–3 cell lines and tissue expression in canine mammary cancer and the correlation between serum levels and tumour histological grade

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    Manuali Elisabetta

    2012-06-01

    Full Text Available Abstract Background Mammary tumours are the most common malignancy diagnosed in female dogs and a significant cause of mortality and morbidity in this species. Carbohydrate antigen (CA 15–3 is a mucinous glycoprotein aberrantly over-expressed in human mammary neoplasms and one of the most widely used serum tumour markers in women with breast cancer. The aim of this study was to investigate the antigenic analogies of human and canine CA 15–3 and to assess its expression in canine mammary cancer tissues and cell lines. Immunohistochemical expression of CA 15–3 was evaluated in 7 canine mammary cancer cell lines and 50 malignant mammary tumours. As a positive control, the human breast carcinoma cell line MCF7 and tissue were used. To assess CA 15–3 staining, a semi-quantitative method was applied. To confirm the specificity and cross-reactivity of an anti-human CA 15–3 antibody to canine tissues, an immunoblot analysis was performed. We also investigated serum CA 15–3 activity to establish whether its expression could be assigned to several tumour characteristics to evaluate its potential use as a serum tumour marker in the canine mammary oncology field. Results Immunocytochemical analysis revealed CA 15–3 expression in all examined canine mammary cancer cell lines, whereas its expression was confirmed by immunoblot only in the most invasive cells (CMT-W1, CMT-W1M, CMT-W2 and CMT-W2M. In the tissue, an immunohistochemical staining pattern was observed in 34 (68% of the malignant tumours. A high statistical correlation (p = 0.0019 between serum CA 15–3 levels and the degree of tumour proliferation and differentiation was shown, which indicates that the values of this serum marker increase as the tumour stage progresses. Conclusions The results of this study reveal that CA 15–3 is expressed in both canine mammary tumour cell lines and tissues and that serum levels significantly correlate with the histological grade of the

  11. Chemopreventive efficacy and anti-lipid peroxidative potential of Jasminum grandiflorum Linn. on 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinogenesis.

    Science.gov (United States)

    Kolanjiappan, K; Manoharan, S

    2005-12-01

    The aim of this study was to investigate the chemopreventive efficacy and anti-lipid peroxidative potential of Jasminum grandiflorum Linn. on 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary carcinogenesis. Mammary tumors were developed by a single subcutaneous injection of 25 mg DMBA in 1 mL emulsion of sunflower oil and physiological saline. The tumor incidence and tumor volume that formed in the breast were determined. Oral administration of ethanolic extract of J. grandiflorum flowers (JgEt) at a dose of 300 mg/kg body weight for 14 weeks to DMBA-injected animals completely prevented the formation of tumors in the pre-initiation period. JgEt also exerted significant anti-lipid peroxidative effect and improved the antioxidant defense system in DMBA-treated rats. The results of this study clearly indicate that JgEt has potent chemopreventive efficacy in experimental mammary carcinogenesis and further studies are warranted to isolate and characterize the bioactive principle from JgEt.

  12. The role of maintenance proteins in the preservation of epithelial cell identity during mammary gland remodeling and breast cancer initiation.

    Science.gov (United States)

    Coradini, Danila; Oriana, Saro

    2014-02-01

    During normal postnatal mammary gland development and adult remodeling related to the menstrual cycle, pregnancy, and lactation, ovarian hormones and peptide growth factors contribute to the delineation of a definite epithelial cell identity. This identity is maintained during cell replication in a heritable but DNA-independent manner. The preservation of cell identity is fundamental, especially when cells must undergo changes in response to intrinsic and extrinsic signals. The maintenance proteins, which are required for cell identity preservation, act epigenetically by regulating gene expression through DNA methylation, histone modification, and chromatin remodeling. Among the maintenance proteins, the Trithorax (TrxG) and Polycomb (PcG) group proteins are the best characterized. In this review, we summarize the structures and activities of the TrxG and PcG complexes and describe their pivotal roles in nuclear estrogen receptor activity. In addition, we provide evidence that perturbations in these epigenetic regulators are involved in disrupting epithelial cell identity, mammary gland remodeling, and breast cancer initiation.

  13. Endogenous Mouse Mammary Tumor Viruses (Mtv: New Roles for an Old Virus in Cancer, Infection and Immunity

    Directory of Open Access Journals (Sweden)

    Michael eHolt

    2013-11-01

    Full Text Available Mouse Mammary Tumor Viruses are beta-retroviruses that exist in both exogenous (MMTV and endogenous (Mtv forms. Exogenous MMTV is transmitted via the milk of lactating animals and is capable of inducing mammary gland tumors later in life. MMTV has provided a number of critical models for studying both viral infection as well as human breast cancer. In addition to the horizontally transmitted MMTV, most inbred mouse strains contain permanently integrated Mtv proviruses within their genome that are remnants of MMTV infection and vertically transmitted. Historically, Mtv have been appreciated for their role in shaping the T cell repertoire during thymic development via negative selection. In addition, more recent work has demonstrated a larger role for Mtv in modulating host immune responses due to its peripheral expression. The influence of Mtv on host response has been observed during experimental murine models of Polyomavirus- and ESb-induced lymphoma as well as Leishmania major and Plasmodium berghei ANKA infection. Decreased susceptibility to bacterial pathogens and virus-induced tumors has been observed among mice lacking all Mtv. We have also demonstrated a role for Mtv Sag in the expansion of regulatory T cells following chronic viral infection. The aim of this review is to summarize the latest research in the field regarding peripheral expression of Mtv with a particular focus on their role and influence on the immune system, infectious disease outcome, and potential involvement in tumor formation.

  14. Validation study of the modified injection technique for internal mammary sentinel lymph node biopsy in breast cancer

    Directory of Open Access Journals (Sweden)

    Cong BB

    2015-09-01

    Full Text Available Bin-Bin Cong,1,2,* Xiao-Shan Cao,1,2,* Peng-Fei Qiu,1 Yan-Bing Liu,1 Tong Zhao,1 Peng Chen,1 Chun-Jian Wang,1 Zhao-Peng Zhang,1 Xiao Sun,1 Yong-Sheng Wang1 1Breast Cancer Center, Shandong Cancer Hospital and Institute, 2School of Medicine and Life Sciences, Jinan University-Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China *These authors contributed equally to this study Abstract: According to the hypothesis of internal mammary sentinel lymph node (IM-SLN lymphatic drainage pattern, a modified radiotracer injection technique (periareolar intraparenchyma, high volume, and ultrasonographic guidance was established. To verify the accuracy of the hypothesis and validate the modified radiotracer injection technique and to observe whether the lymphatic drainage of the whole breast parenchyma could reach to the same IM-SLN, different tracers were injected into different locations of the breast. The validation study results showed that the correlation and the agreement of the radiotracer and the fluorescence tracer are significant (case-base, rs =0.808, P<0.001; Kappa =0.79, P<0.001. It proved that the lymphatic drainage from different location of the breast (the primary tumor, the subareolar plexus reached the same IM-SLNs and the hypothesis of IM-SLN lymphatic drainage pattern (ie, IM-SLN receives lymphatic drainage from not only the primary tumor area, but also the entire breast parenchyma. In other words, it validated the accuracy of our modified radiotracer injection technique. Keywords: breast cancer, internal mammary, sentinel lymph node biopsy, visualization rate

  15. The Balance of Cell Surface and Soluble Type III TGF-β Receptor Regulates BMP Signaling in Normal and Cancerous Mammary Epithelial Cells

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    Catherine E. Gatza

    2014-06-01

    Full Text Available Bone morphogenetic proteins (BMPs are members of the TGF-β superfamily that are over-expressed in breast cancer, with context dependent effects on breast cancer pathogenesis. The type III TGF-β receptor (TβRIII mediates BMP signaling. While TβRIII expression is lost during breast cancer progression, the role of TβRIII in regulating BMP signaling in normal mammary epithelium and breast cancer cells has not been examined. Restoring TβRIII expression in a 4T1 murine syngeneic model of breast cancer suppressed Smad1/5/8 phosphorylation and inhibited the expression of the BMP transcriptional targets, Id1 and Smad6, in vivo. Similarly, restoring TβRIII expression in human breast cancer cell lines or treatment with sTβRIII inhibited BMP-induced Smad1/5/8 phosphorylation and BMP-stimulated migration and invasion. In normal mammary epithelial cells, shRNA-mediated silencing of TβRIII, TβRIII over-expression, or treatment with sTβRIII inhibited BMP-mediated phosphorylation of Smad1/5/8 and BMP induced migration. Inhibition of TβRIII shedding through treatment with TAPI-2 or expression of a non-shedding TβRIII mutant rescued TβRIII mediated inhibition of BMP induced Smad1/5/8 phosphorylation and BMP induced migration and/or invasion in both in normal mammary epithelial cells and breast cancer cells. Conversely, expression of a TβRIII mutant, which exhibited increased shedding, significantly reduced BMP-mediated Smad1/5/8 phosphorylation, migration, and invasion. These data demonstrate that TβRIII regulates BMP-mediated signaling and biological effects, primarily through the ligand sequestration effects of sTβRIII in normal and cancerous mammary epithelial cells and suggest that the ratio of membrane bound versus sTβRIII plays an important role in mediating these effects.

  16. A prognosis classifier for breast cancer based on conserved gene regulation between mammary gland development and tumorigenesis: a multiscale statistical model.

    Science.gov (United States)

    Tian, Yingpu; Chen, Baozhen; Guan, Pengfei; Kang, Yujia; Lu, Zhongxian

    2013-01-01

    Identification of novel cancer genes for molecular therapy and diagnosis is a current focus of breast cancer research. Although a few small gene sets were identified as prognosis classifiers, more powerful models are still needed for the definition of effective gene sets for the diagnosis and treatment guidance in breast cancer. In the present study, we have developed a novel statistical approach for systematic analysis of intrinsic correlations of gene expression between development and tumorigenesis in mammary gland. Based on this analysis, we constructed a predictive model for prognosis in breast cancer that may be useful for therapy decisions. We first defined developmentally associated genes from a mouse mammary gland epithelial gene expression database. Then, we found that the cancer modulated genes were enriched in this developmentally associated genes list. Furthermore, the developmentally associated genes had a specific expression profile, which associated with the molecular characteristics and histological grade of the tumor. These result suggested that the processes of mammary gland development and tumorigenesis share gene regulatory mechanisms. Then, the list of regulatory genes both on the developmental and tumorigenesis process was defined an 835-member prognosis classifier, which showed an exciting ability to predict clinical outcome of three groups of breast cancer patients (the predictive accuracy 64∼72%) with a robust prognosis prediction (hazard ratio 3.3∼3.8, higher than that of other clinical risk factors (around 2.0-2.8)). In conclusion, our results identified the conserved molecular mechanisms between mammary gland development and neoplasia, and provided a unique potential model for mining unknown cancer genes and predicting the clinical status of breast tumors. These findings also suggested that developmental roles of genes may be important criteria for selecting genes for prognosis prediction in breast cancer.

  17. Funded Projects | Division of Cancer Prevention

    Science.gov (United States)

    Breast Cancer (vaccines)Plac1 vaccine for breast cancer preventionEfficacy of a multi-antigen vaccine in the prevention of methynitrosourea-induced mammary cancers (ER+) in female Sprague-Dawley rats Breast Cancer (small molecules and biomarkers)Chemopreventive effects in both standard chow diets and high-fat diets of known positive- and negative-chemopreventive agents employing both high-risk (but histologically normal) mammary epithelium and mammary cancers including correlative biomarkers | Breast Cancer (vaccines) Cervical Cancer (small molecule) Colon Cancer (small molecules, vaccine, biomarker) Lung Cancer (small molecules, vaccine, biomarker, vaccine) Pancreatic Cancer (small molecule) Prostate Cancer (small molecule) Oral Cancer (small molecule) Skin Cancer (small molecule)

  18. Mammary gland development.

    Science.gov (United States)

    Macias, Hector; Hinck, Lindsay

    2012-01-01

    The mammary gland develops through several distinct stages. The first transpires in the embryo as the ectoderm forms a mammary line that resolves into placodes. Regulated by epithelial–mesenchymal interactions, the placodes descend into the underlying mesenchyme and produce the rudimentary ductal structure of the gland present at birth. Subsequent stages of development—pubertal growth, pregnancy, lactation, and involution—occur postnatally under the regulation of hormones. Puberty initiates branching morphogenesis, which requires growth hormone (GH) and estrogen, as well as insulin-like growth factor 1 (IGF1), to create a ductal tree that fills the fat pad. Upon pregnancy, the combined actions of progesterone and prolactin generate alveoli, which secrete milk during lactation. Lack of demand for milk at weaning initiates the process of involution whereby the gland is remodeled back to its prepregnancy state. These processes require numerous signaling pathways that have distinct regulatory functions at different stages of gland development. Signaling pathways also regulate a specialized subpopulation of mammary stem cells that fuel the dramatic changes in the gland occurring with each pregnancy. Our knowledge of mammary gland development and mammary stem cell biology has significantly contributed to our understanding of breast cancer and has advanced the discovery of therapies to treat this disease.

  19. Peroxisome proliferator-activated receptors: role of isoform gamma in the antineoplastic effect of iodine in mammary cancer.

    Science.gov (United States)

    Nunez-Anita, R E; Cajero-Juarez, M; Aceves, C

    2011-09-01

    Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors. Three subtypes--PPAR alpha, PPAR beta, and PPAR gamma--have been identified and are differentially expressed in tissues. Originally, they were described as molecular regulators of lipid metabolism; recently, it has been shown that they are also involved in regulating the cell cycle and apoptosis in both normal and tumoral cells. In fact, some synthetic PPAR ligands are used to treat dyslipidemia, metabolic diseases, and type 2 diabetes. Here, we review the role of PPAR gamma (PPARγ) in tumor initiation and progression, emphasizing the relationship between this isoform and the cellular and molecular mechanisms involved in the antineoplastic effect of iodine on mammary cancer.

  20. Histopathological and in vivo evidence of regucalcin as a protective molecule in mammary gland carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Marques, Ricardo; Vaz, Cátia V.; Maia, Cláudio J. [CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã (Portugal); Gomes, Madalena [IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto (Portugal); Gama, Adelina [Department of Veterinary Sciences, Animal and Veterinary Science Research Center (CECAV), University of Trás-os-Montes and Alto Douro (UTAD) (Portugal); Alves, Gilberto; Santos, Cecília R. [CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã (Portugal); Schmitt, Fernando [IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto (Portugal); Medical Faculty, University of Porto, Porto (Portugal); Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto (Canada); Department of Pathology, University Health Network, Toronto (Canada); Socorro, Sílvia, E-mail: ssocorro@fcsaude.ubi.pt [CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã (Portugal)

    2015-01-15

    Regucalcin (RGN) is a calcium-binding protein, which has been shown to be underexpressed in cancer cases. This study aimed to determine the association of RGN expression with clinicopathological parameters of human breast cancer. In addition, the role of RGN in malignancy of mammary gland using transgenic rats overexpressing the protein (Tg-RGN) was investigated. Wild-type (Wt) and Tg-RGN rats were treated with 7,12-dimethylbenz[α]anthracene (DMBA). Carcinogen-induced tumors were histologically classified and the Ki67 proliferation index was estimated. Immunohistochemistry analysis showed that RGN immunoreactivity was negatively correlated with the histological grade of breast infiltrating ductal carcinoma suggesting that progression of breast cancer is associated with loss of RGN. Tg-RGN rats displayed lower incidence of carcinogen-induced mammary gland tumors, as well as lower incidence of invasive forms. Moreover, higher proliferation was observed in non-invasive tumors of Wt animals comparatively with Tg-RGN. Overexpression of RGN was associated with diminished expression of cell-cycle inhibitors and increased expression of apoptosis inducers. Augmented activity of apoptosis effector caspase-3 was found in the mammary gland of Tg-RGN. RGN overexpression protected from carcinogen-induced mammary gland tumor development and was linked with reduced proliferation and increased apoptosis. These findings indicated the protective role of RGN in the carcinogenesis of mammary gland. - Highlights: • RGN immunoreactivity was negatively correlated with breast cancer differentiation. • Transgenic overexpression of RGN diminished incidence of carcinogen-induced tumors. • Transgenic overexpression of RGN restricted proliferation and fostered apoptosis. • RGN has a protective role in the carcinogenesis of mammary gland.

  1. Spontaneously immortalised bovine mammary epithelial cells exhibit a distinct gene expression pattern from the breast cancer cells

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    Li Qianqian

    2010-10-01

    Full Text Available Abstract Background Spontaneous immortalisation of cultured mammary epithelial cells (MECs is an extremely rare event, and the molecular mechanism behind spontaneous immortalisation of MECs is unclear. Here, we report the establishment of a spontaneously immortalised bovine mammary epithelial cell line (BME65Cs and the changes in gene expression associated with BME65Cs cells. Results BME65Cs cells maintain the general characteristics of normal mammary epithelial cells in morphology, karyotype and immunohistochemistry, and are accompanied by the activation of endogenous bTERT (bovine Telomerase Reverse Transcriptase and stabilisation of the telomere. Currently, BME65Cs cells have been passed for more than 220 generations, and these cells exhibit non-malignant transformation. The expression of multiple genes was investigated in BME65Cs cells, senescent BMECs (bovine MECs cells, early passage BMECs cells and MCF-7 cells (a human breast cancer cell line. In comparison with early passage BMECs cells, the expression of senescence-relevant apoptosis-related gene were significantly changed in BME65Cs cells. P16INK4a was downregulated, p53 was low expressed and Bax/Bcl-2 ratio was reversed. Moreover, a slight upregulation of the oncogene c-Myc, along with an undetectable level of breast tumor-related gene Bag-1 and TRPS-1, was observed in BME65Cs cells while these genes are all highly expressed in MCF-7. In addition, DNMT1 is upregulated in BME65Cs. These results suggest that the inhibition of both senescence and mitochondrial apoptosis signalling pathways contribute to the immortality of BME65Cs cells. The expression of p53 and p16INK4a in BME65Cs was altered in the pattern of down-regulation but not "loss", suggesting that this spontaneous immortalization is possibly initiated by other mechanism rather than gene mutation of p53 or p16INK4a. Conclusions Spontaneously immortalised BME65Cs cells maintain many characteristics of normal BMEC cells and

  2. ΔNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signalling.

    Science.gov (United States)

    Chakrabarti, Rumela; Wei, Yong; Hwang, Julie; Hang, Xiang; Andres Blanco, Mario; Choudhury, Abrar; Tiede, Benjamin; Romano, Rose-Anne; DeCoste, Christina; Mercatali, Laura; Ibrahim, Toni; Amadori, Dino; Kannan, Nagarajan; Eaves, Connie J; Sinha, Satrajit; Kang, Yibin

    2014-10-01

    Emerging evidence suggests that cancer is populated and maintained by tumour-initiating cells (TICs) with stem-like properties similar to those of adult tissue stem cells. Despite recent advances, the molecular regulatory mechanisms that may be shared between normal and malignant stem cells remain poorly understood. Here we show that the ΔNp63 isoform of the Trp63 transcription factor promotes normal mammary stem cell (MaSC) activity by increasing the expression of the Wnt receptor Fzd7, thereby enhancing Wnt signalling. Importantly, Fzd7-dependent enhancement of Wnt signalling by ΔNp63 also governs tumour-initiating activity of the basal subtype of breast cancer. These findings establish ΔNp63 as a key regulator of stem cells in both normal and malignant mammary tissues and provide direct evidence that breast cancer TICs and normal MaSCs share common regulatory mechanisms.

  3. Extracellular vesicles from women with breast cancer promote an epithelial-mesenchymal transition-like process in mammary epithelial cells MCF10A.

    Science.gov (United States)

    Galindo-Hernandez, Octavio; Gonzales-Vazquez, Cristina; Cortes-Reynosa, Pedro; Reyes-Uribe, Emmanuel; Chavez-Ocaña, Sonia; Reyes-Hernandez, Octavio; Sierra-Martinez, Mónica; Salazar, Eduardo Perez

    2015-12-01

    Extracellular vesicles (EVs) mediate many stages of tumor progression including angiogenesis, escape from immune surveillance, and extracellular matrix degradation. We studied whether EVs from plasma of women with breast cancer are able to induce an epithelial-mesenchymal transition (EMT) process in mammary epithelial cells MCF10A. Our findings demonstrate that EVs from plasma of breast cancer patients induce a downregulation of E-cadherin expression and an increase of vimentin and N-cadherin expression. Moreover, EVs induce migration and invasion, as well as an increase of NFκB-DNA binding activity and MMP-2 and MMP-9 secretions. In summary, our findings demonstrate, for the first time, that EVs from breast cancer patients induce an EMT-like process in human mammary non-tumorigenic epithelial cells MCF10A.

  4. Examining the pathogenesis of breast cancer using a novel agent-based model of mammary ductal epithelium dynamics.

    Directory of Open Access Journals (Sweden)

    Joaquin Chapa

    Full Text Available The study of the pathogenesis of breast cancer is challenged by the long time-course of the disease process and the multi-factorial nature of generating oncogenic insults. The characterization of the longitudinal pathogenesis of malignant transformation from baseline normal breast duct epithelial dynamics may provide vital insight into the cascading systems failure that leads to breast cancer. To this end, extensive information on the baseline behavior of normal mammary epithelium and breast cancer oncogenesis was integrated into a computational model termed the Ductal Epithelium Agent-Based Model (DEABM. The DEABM is composed of computational agents that behave according to rules established from published cellular and molecular mechanisms concerning breast duct epithelial dynamics and oncogenesis. The DEABM implements DNA damage and repair, cell division, genetic inheritance and simulates the local tissue environment with hormone excretion and receptor signaling. Unrepaired DNA damage impacts the integrity of the genome within individual cells, including a set of eight representative oncogenes and tumor suppressors previously implicated in breast cancer, with subsequent consequences on successive generations of cells. The DEABM reproduced cellular population dynamics seen during the menstrual cycle and pregnancy, and demonstrated the oncogenic effect of known genetic factors associated with breast cancer, namely TP53 and Myc, in simulations spanning ∼40 years of simulated time. Simulations comparing normal to BRCA1-mutant breast tissue demonstrated rates of invasive cancer development similar to published epidemiologic data with respect to both cumulative incidence over time and estrogen-receptor status. Investigation of the modeling of ERα-positive (ER+ tumorigenesis led to a novel hypothesis implicating the transcription factor and tumor suppressor RUNX3. These data suggest that the DEABM can serve as a potentially valuable framework to

  5. Examining the pathogenesis of breast cancer using a novel agent-based model of mammary ductal epithelium dynamics.

    Science.gov (United States)

    Chapa, Joaquin; Bourgo, Ryan J; Greene, Geoffrey L; Kulkarni, Swati; An, Gary

    2013-01-01

    The study of the pathogenesis of breast cancer is challenged by the long time-course of the disease process and the multi-factorial nature of generating oncogenic insults. The characterization of the longitudinal pathogenesis of malignant transformation from baseline normal breast duct epithelial dynamics may provide vital insight into the cascading systems failure that leads to breast cancer. To this end, extensive information on the baseline behavior of normal mammary epithelium and breast cancer oncogenesis was integrated into a computational model termed the Ductal Epithelium Agent-Based Model (DEABM). The DEABM is composed of computational agents that behave according to rules established from published cellular and molecular mechanisms concerning breast duct epithelial dynamics and oncogenesis. The DEABM implements DNA damage and repair, cell division, genetic inheritance and simulates the local tissue environment with hormone excretion and receptor signaling. Unrepaired DNA damage impacts the integrity of the genome within individual cells, including a set of eight representative oncogenes and tumor suppressors previously implicated in breast cancer, with subsequent consequences on successive generations of cells. The DEABM reproduced cellular population dynamics seen during the menstrual cycle and pregnancy, and demonstrated the oncogenic effect of known genetic factors associated with breast cancer, namely TP53 and Myc, in simulations spanning ∼40 years of simulated time. Simulations comparing normal to BRCA1-mutant breast tissue demonstrated rates of invasive cancer development similar to published epidemiologic data with respect to both cumulative incidence over time and estrogen-receptor status. Investigation of the modeling of ERα-positive (ER+) tumorigenesis led to a novel hypothesis implicating the transcription factor and tumor suppressor RUNX3. These data suggest that the DEABM can serve as a potentially valuable framework to augment the

  6. Decreased autocrine EGFR signaling in metastatic breast cancer cells inhibits tumor growth in bone and mammary fat pad.

    Science.gov (United States)

    Nickerson, Nicole K; Mohammad, Khalid S; Gilmore, Jennifer L; Crismore, Erin; Bruzzaniti, Angela; Guise, Theresa A; Foley, John

    2012-01-01

    Breast cancer metastasis to bone triggers a vicious cycle of tumor growth linked to osteolysis. Breast cancer cells and osteoblasts express the epidermal growth factor receptor (EGFR) and produce ErbB family ligands, suggesting participation of these growth factors in autocrine and paracrine signaling within the bone microenvironment. EGFR ligand expression was profiled in the bone metastatic MDA-MB-231 cells (MDA-231), and agonist-induced signaling was examined in both breast cancer and osteoblast-like cells. Both paracrine and autocrine EGFR signaling were inhibited with a neutralizing amphiregulin antibody, PAR34, whereas shRNA to the EGFR was used to specifically block autocrine signaling in MDA-231 cells. The impact of these was evaluated with proliferation, migration and gene expression assays. Breast cancer metastasis to bone was modeled in female athymic nude mice with intratibial inoculation of MDA-231 cells, and cancer cell-bone marrow co-cultures. EGFR knockdown, but not PAR34 treatment, decreased osteoclasts formed in vitro (p<0.01), reduced osteolytic lesion tumor volume (p<0.01), increased survivorship in vivo (p<0.001), and resulted in decreased MDA-231 growth in the fat pad (p<0.01). Fat pad shEGFR-MDA-231 tumors produced in nude mice had increased necrotic areas and decreased CD31-positive vasculature. shEGFR-MDA-231 cells also produced decreased levels of the proangiogenic molecules macrophage colony stimulating factor-1 (MCSF-1) and matrix metalloproteinase 9 (MMP9), both of which were decreased by EGFR inhibitors in a panel of EGFR-positive breast cancer cells. Thus, inhibiting autocrine EGFR signaling in breast cancer cells may provide a means for reducing paracrine factor production that facilitates microenvironment support in the bone and mammary gland.

  7. Decreased autocrine EGFR signaling in metastatic breast cancer cells inhibits tumor growth in bone and mammary fat pad.

    Directory of Open Access Journals (Sweden)

    Nicole K Nickerson

    Full Text Available Breast cancer metastasis to bone triggers a vicious cycle of tumor growth linked to osteolysis. Breast cancer cells and osteoblasts express the epidermal growth factor receptor (EGFR and produce ErbB family ligands, suggesting participation of these growth factors in autocrine and paracrine signaling within the bone microenvironment. EGFR ligand expression was profiled in the bone metastatic MDA-MB-231 cells (MDA-231, and agonist-induced signaling was examined in both breast cancer and osteoblast-like cells. Both paracrine and autocrine EGFR signaling were inhibited with a neutralizing amphiregulin antibody, PAR34, whereas shRNA to the EGFR was used to specifically block autocrine signaling in MDA-231 cells. The impact of these was evaluated with proliferation, migration and gene expression assays. Breast cancer metastasis to bone was modeled in female athymic nude mice with intratibial inoculation of MDA-231 cells, and cancer cell-bone marrow co-cultures. EGFR knockdown, but not PAR34 treatment, decreased osteoclasts formed in vitro (p<0.01, reduced osteolytic lesion tumor volume (p<0.01, increased survivorship in vivo (p<0.001, and resulted in decreased MDA-231 growth in the fat pad (p<0.01. Fat pad shEGFR-MDA-231 tumors produced in nude mice had increased necrotic areas and decreased CD31-positive vasculature. shEGFR-MDA-231 cells also produced decreased levels of the proangiogenic molecules macrophage colony stimulating factor-1 (MCSF-1 and matrix metalloproteinase 9 (MMP9, both of which were decreased by EGFR inhibitors in a panel of EGFR-positive breast cancer cells. Thus, inhibiting autocrine EGFR signaling in breast cancer cells may provide a means for reducing paracrine factor production that facilitates microenvironment support in the bone and mammary gland.

  8. Loss of monocyte chemoattractant protein-1 expression delays mammary tumorigenesis and reduces localized inflammation in the C3(1)/SV40Tag triple negative breast cancer model.

    Science.gov (United States)

    Cranford, Taryn L; Velázquez, Kandy T; Enos, Reilly T; Bader, Jackie E; Carson, Meredith S; Chatzistamou, Ioulia; Nagarkatti, Mitzi; Murphy, E Angela

    2017-02-01

    Monocyte chemoattractant protein 1 (MCP-1) has been implicated as a major modulator in the progression of mammary tumorigenesis, largely due to its ability to recruit macrophages to the tumor microenvironment. Macrophages are key mediators in the connection between inflammation and cancer progression and have been shown to play an important role in tumorigenesis. Thus, MCP-1 may be a potential therapeutic target in inflammatory and difficult-to-treat cancers such as triple negative breast cancer (TNBC). We examined the effect of MCP-1 depletion on mammary tumorigenesis in a model of TNBC. Tumor measurements were conducted weekly (until 22 weeks of age) and at sacrifice (23 weeks of age) in female C3(1)/SV40Tag and C3(1)/SV40Tag MCP-1 deficient mice to determine tumor numbers and tumorvolumes. Histopathological scoring was performed at 12 weeks of age and 23 weeks of age. Gene expression of macrophage markers and inflammatory mediators were measured in the mammary gland and tumor microenvironment at sacrifice. As expected, MCP-1 depletion resulted in decreased tumorigenesis, indicated by reduced primary tumor volume and multiplicity, and a delay in tumor progression represented by histopathological scoring (12 weeks of age). Deficiency in MCP-1 significantly downregulated expression of macrophage markers in the mammary gland (Mertk and CD64) and the tumor microenvironment (CD64), and also reduced expression of inflammatory cytokines in the mammary gland (TNFα and IL-1β) and the tumor microenvironment (IL-6). These data support the hypothesis that MCP-1 expression contributes to increased tumorigenesis in a model of TNBC via recruitment of macrophages and subsequent increase in inflammatory mediators.

  9. Bisphenol A (BPA) Exposure In Utero Leads to Immunoregulatory Cytokine Dysregulation in the Mouse Mammary Gland: A Potential Mechanism Programming Breast Cancer Risk.

    Science.gov (United States)

    Fischer, Catha; Mamillapalli, Ramanaiah; Goetz, Laura G; Jorgenson, Elisa; Ilagan, Ysabel; Taylor, Hugh S

    2016-08-01

    Bisphenol-A (BPA) is a ubiquitous estrogen-like endocrine disrupting compound (EDC). BPA exposure in utero has been linked to breast cancer and abnormal mammary gland development in mice. The recent rise in incidence of human breast cancer and decreased age of first detection suggests a possible environmental etiology. We hypothesized that developmental programming of carcinogenesis may involve an aberrant immune response. Both innate and adaptive immunity play a role in tumor suppression through cytolytic CD8, NK, and Th1 T-cells. We hypothesized that BPA exposure in utero would lead to dysregulation of both innate and adaptive immunity in the mammary gland. CD1 mice were exposed to BPA in utero during gestation (days 9-21) via osmotic minipump. At 6 weeks, the female offspring were ovariectomized and estradiol was given at 8 weeks. RNA and protein were extracted from the posterior mammary glands, and the mRNA and protein levels were measured by PCR array, qRT-PCR, and western blot. In mouse mammary tissue, BPA exposure in utero significantly decreased the expression of members of the chemokine CXC family (Cxcl2, Cxcl4, Cxcl14, and Ccl20), interleukin 1 (Il1) gene family (Il1β and Il1rn), interleukin 2 gene family (Il7 receptor), and interferon gene family (interferon regulatory factor 9 (Irf9), as well as immune response gene 1 (Irg1). Additionally, BPA exposure in utero decreased Esr1 receptor gene expression and increased Esr2 receptor gene expression. In utero exposure of BPA resulted in significant changes to inflammatory modulators within mammary tissue. We suggest that dysregulation of inflammatory cytokines, both pro-inflammatory and anti-inflammatory, leads to a microenvironment that may promote disordered cell growth through inhibition of the immune response that targets cancer cells.

  10. High-Fat, High-Calorie Diet Enhances Mammary Carcinogenesis and Local Inflammation in MMTV-PyMT Mouse Model of Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Cowen, Sarah [Department of Surgery, West Virginia University Health Sciences Center, Morgantown, WV 26506 (United States); Mary Babb Randolph Cancer Center, West Virginia University Health Sciences Center, Morgantown, WV 26506 (United States); McLaughlin, Sarah L. [Mary Babb Randolph Cancer Center, West Virginia University Health Sciences Center, Morgantown, WV 26506 (United States); Hobbs, Gerald [Mary Babb Randolph Cancer Center, West Virginia University Health Sciences Center, Morgantown, WV 26506 (United States); Department of Statistics, West Virginia University, Morgantown, WV 26506 (United States); Coad, James [Department of Pathology, West Virginia University Health Sciences Center, Morgantown, WV 26506 (United States); Martin, Karen H. [Mary Babb Randolph Cancer Center, West Virginia University Health Sciences Center, Morgantown, WV 26506 (United States); Department of Neurobiology and Anatomy, West Virginia University Health Sciences Center, Morgantown, WV 26506 (United States); Olfert, I. Mark [Mary Babb Randolph Cancer Center, West Virginia University Health Sciences Center, Morgantown, WV 26506 (United States); Department of Human Performance and Exercise Physiology, West Virginia University Health Sciences Center, Morgantown, WV 26506 (United States); Vona-Davis, Linda, E-mail: lvdavis@hsc.wvu.edu [Department of Surgery, West Virginia University Health Sciences Center, Morgantown, WV 26506 (United States); Mary Babb Randolph Cancer Center, West Virginia University Health Sciences Center, Morgantown, WV 26506 (United States)

    2015-06-26

    Epidemiological studies provide strong evidence that obesity and the associated adipose tissue inflammation are risk factors for breast cancer; however, the molecular mechanisms are poorly understood. We evaluated the effect of a high-fat/high-calorie diet on mammary carcinogenesis in the immunocompetent MMTV-PyMT murine model. Four-week old female mice (20/group) were randomized to receive either a high-fat (HF; 60% kcal as fat) or a low-fat (LF; 16% kcal) diet for eight weeks. Body weights were determined, and tumor volumes measured by ultrasound, each week. At necropsy, the tumors and abdominal visceral fat were weighed and plasma collected. The primary mammary tumors, adjacent mammary fat, and lungs were preserved for histological and immunohistochemical examination and quantification of infiltrating macrophages, crown-like structure (CLS) formation, and microvessel density. The body weight gains, visceral fat weights, the primary mammary tumor growth rates and terminal weights, were all significantly greater in the HF-fed mice. Adipose tissue inflammation in the HF group was indicated by hepatic steatosis, pronounced macrophage infiltration and CLS formation, and elevations in plasma monocyte chemoattractant protein-1 (MCP-1), leptin and proinflammatory cytokine concentrations. HF intake was also associated with higher tumor-associated microvascular density and the proangiogenic factor MCP-1. This study provides preclinical evidence in a spontaneous model of breast cancer that mammary adipose tissue inflammation induced by diet, enhances the recruitment of macrophages and increases tumor vascular density suggesting a role for obesity in creating a microenvironment favorable for angiogenesis in the progression of breast cancer.

  11. High-Fat, High-Calorie Diet Enhances Mammary Carcinogenesis and Local Inflammation in MMTV-PyMT Mouse Model of Breast Cancer

    Directory of Open Access Journals (Sweden)

    Sarah Cowen

    2015-06-01

    Full Text Available Epidemiological studies provide strong evidence that obesity and the associated adipose tissue inflammation are risk factors for breast cancer; however, the molecular mechanisms are poorly understood. We evaluated the effect of a high-fat/high-calorie diet on mammary carcinogenesis in the immunocompetent MMTV-PyMT murine model. Four-week old female mice (20/group were randomized to receive either a high-fat (HF; 60% kcal as fat or a low-fat (LF; 16% kcal diet for eight weeks. Body weights were determined, and tumor volumes measured by ultrasound, each week. At necropsy, the tumors and abdominal visceral fat were weighed and plasma collected. The primary mammary tumors, adjacent mammary fat, and lungs were preserved for histological and immunohistochemical examination and quantification of infiltrating macrophages, crown-like structure (CLS formation, and microvessel density. The body weight gains, visceral fat weights, the primary mammary tumor growth rates and terminal weights, were all significantly greater in the HF-fed mice. Adipose tissue inflammation in the HF group was indicated by hepatic steatosis, pronounced macrophage infiltration and CLS formation, and elevations in plasma monocyte chemoattractant protein-1 (MCP-1, leptin and proinflammatory cytokine concentrations. HF intake was also associated with higher tumor-associated microvascular density and the proangiogenic factor MCP-1. This study provides preclinical evidence in a spontaneous model of breast cancer that mammary adipose tissue inflammation induced by diet, enhances the recruitment of macrophages and increases tumor vascular density suggesting a role for obesity in creating a microenvironment favorable for angiogenesis in the progression of breast cancer.

  12. High-Fat, High-Calorie Diet Enhances Mammary Carcinogenesis and Local Inflammation in MMTV-PyMT Mouse Model of Breast Cancer.

    Science.gov (United States)

    Cowen, Sarah; McLaughlin, Sarah L; Hobbs, Gerald; Coad, James; Martin, Karen H; Olfert, I Mark; Vona-Davis, Linda

    2015-06-26

    Epidemiological studies provide strong evidence that obesity and the associated adipose tissue inflammation are risk factors for breast cancer; however, the molecular mechanisms are poorly understood. We evaluated the effect of a high-fat/high-calorie diet on mammary carcinogenesis in the immunocompetent MMTV-PyMT murine model. Four-week old female mice (20/group) were randomized to receive either a high-fat (HF; 60% kcal as fat) or a low-fat (LF; 16% kcal) diet for eight weeks. Body weights were determined, and tumor volumes measured by ultrasound, each week. At necropsy, the tumors and abdominal visceral fat were weighed and plasma collected. The primary mammary tumors, adjacent mammary fat, and lungs were preserved for histological and immunohistochemical examination and quantification of infiltrating macrophages, crown-like structure (CLS) formation, and microvessel density. The body weight gains, visceral fat weights, the primary mammary tumor growth rates and terminal weights, were all significantly greater in the HF-fed mice. Adipose tissue inflammation in the HF group was indicated by hepatic steatosis, pronounced macrophage infiltration and CLS formation, and elevations in plasma monocyte chemoattractant protein-1 (MCP-1), leptin and proinflammatory cytokine concentrations. HF intake was also associated with higher tumor-associated microvascular density and the proangiogenic factor MCP-1. This study provides preclinical evidence in a spontaneous model of breast cancer that mammary adipose tissue inflammation induced by diet, enhances the recruitment of macrophages and increases tumor vascular density suggesting a role for obesity in creating a microenvironment favorable for angiogenesis in the progression of breast cancer.

  13. Anti-tumor response induced by immunologically modified carbon nanotubes and laser irradiation using rat mammary tumor model

    Science.gov (United States)

    Acquaviva, Joseph T.; Hasanjee, Aamr M.; Bahavar, Cody F.; Zhou, Fefian; Liu, Hong; Howard, Eric W.; Bullen, Liz C.; Silvy, Ricardo P.; Chen, Wei R.

    2015-03-01

    Laser immunotherapy (LIT) is being developed as a treatment modality for metastatic cancer which can destroy primary tumors and induce effective systemic anti-tumor responses by using a targeted treatment approach in conjunction with the use of a novel immunoadjuvant, glycated chitosan (GC). In this study, Non-invasive Laser Immunotherapy (NLIT) was used as the primary treatment mode. We incorporated single-walled carbon nanotubes (SWNTs) into the treatment regimen to boost the tumor-killing effect of LIT. SWNTs and GC were conjugated to create a completely novel, immunologically modified carbon nanotube (SWNT-GC). To determine the efficacy of different laser irradiation durations, 5 minutes or 10 minutes, a series of experiments were performed. Rats were inoculated with DMBA-4 cancer cells, a highly aggressive metastatic cancer cell line. Half of the treatment group of rats receiving laser irradiation for 10 minutes survived without primary or metastatic tumors. The treatment group of rats receiving laser irradiation for 5 minutes had no survivors. Thus, Laser+SWNT-GC treatment with 10 minutes of laser irradiation proved to be effective at reducing tumor size and inducing long-term anti-tumor immunity.

  14. Global gene expression profiles of canine macrophages and canine mammary cancer cells grown as a co-culture in vitro

    Directory of Open Access Journals (Sweden)

    Król Magdalena

    2012-02-01

    Full Text Available Abstract Background Solid tumours comprise various cells, including cancer cells, resident stromal cells, migratory haemopoietic cells and other. These cells regulate tumour growth and metastasis. Macrophages constitute probably the most important element of all interactions within the tumour microenvironment. However, the molecular mechanism, that guides tumour environment, still remains unknown. Exploring the underlying molecular mechanisms that orchestrate these phenomena has been the aim of our study. A co-culture of canine mammary cancer cells and macrophages was established and maintained for 72 hrs. Having sorted the cells, gene expression in cancer cells and macrophages, using DNA microarrays, was examined. The results were confirmed using real-time qPCR and confocal microscopy. Moreover, their ability for migration and invasion has been assessed. Results Microarray analysis showed that the up-regulated genes in the cancer cell lines are involved in 15 highly over-manifested pathways. The pathways that drew our diligent attention included: the inflammation pathway mediated by chemokine and cytokine, the Toll receptor signalling pathway and the B cell activation. The up-regulated genes in the macrophages were involved in only 18 significantly over-manifested pathways: the angiogenesis, the p53 pathway feedback loops2 and the Wnt signalling pathway. The microarray analysis revealed that co-culturing of cancer cells with macrophages initiated the myeloid-specific antigen expression in cancer cells, as well as cytokine/chemokine genes expression. This finding was confirmed at mRNA and protein level. Moreover, we showed that macrophages increase cancer migration and invasion. Conclusions The presence of macrophages in the cancer environment induces acquisition of the macrophage phenotype (specific antigens and chemokines/cytokines expression in cancer cells. We presumed that cancer cells also acquire other myeloid features, such as

  15. Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk

    Science.gov (United States)

    Samuelson, David J.; Hesselson, Stephanie E.; Aperavich, Beth A.; Zan, Yunhong; Haag, Jill D.; Trentham-Dietz, Amy; Hampton, John M.; Mau, Bob; Chen, Kai-Shun; Baynes, Caroline; Khaw, Kay-Tee; Luben, Robert; Perkins, Barbara; Shah, Mitul; Pharoah, Paul D.; Dunning, Alison M.; Easton, Doug F.; Ponder, Bruce A.; Gould, Michael N.

    2007-01-01

    Breast cancer risk is a polygenic trait. To identify breast cancer modifier alleles that have a high population frequency and low penetrance we used a comparative genomics approach. Quantitative trait loci (QTL) were initially identified by linkage analysis in a rat mammary carcinogenesis model followed by verification in congenic rats carrying the specific QTL allele under study. The Mcs5a locus was identified by fine-mapping Mcs5 in a congenic model. Here we characterize the Mcs5a locus, which when homozygous for the Wky allele, reduces mammary cancer risk by 50%. The Mcs5a locus is a compound QTL with at least two noncoding interacting elements: Mcs5a1 and Mcs5a2. The resistance phenotype is only observed in rats carrying at least one copy of the Wky allele of each element on the same chromosome. Mcs5a1 is located within the ubiquitin ligase Fbxo10, whereas Mcs5a2 includes the 5′ portion of Frmpd1. Resistant congenic rats show a down-regulation of Fbxo10 in the thymus and an up-regulation of Frmpd1 in the spleen. The association of the Mcs5a1 and Mcs5a2 human orthologs with breast cancer was tested in two population-based breast cancer case-control studies (≈12,000 women). The minor alleles of rs6476643 (MCS5A1) and rs2182317 (MCS5A2) were independently associated with breast cancer risk. The minor allele of rs6476643 increases risk, whereas the rs2182317 minor allele decreases risk. Both alleles have a high population frequency and a low penetrance toward breast cancer risk. PMID:17404222

  16. Reproductive experience influences grooming behavior during pregnancy in rats

    OpenAIRE

    A.P. Serafim; Felicio,L.F.

    2002-01-01

    The pregnancy-induced increase in self-licking observed in rats is important for mammary gland development and lactation. Reproductive experience has epidemiologial implications such as a decrease in the incidence of mammary gland cancer in women and it also influences various behavioral, neurochemical and endocrine parameters. The aim of the present study was to investigate the influence of reproductive experience on grooming behavior patterns during pregnancy in rats. Self-grooming behavior...

  17. A nomogram based on mammary ductoscopic indicators for evaluating the risk of breast cancer in intraductal neoplasms with nipple discharge.

    Science.gov (United States)

    Lian, Zhen-Qiang; Wang, Qi; Zhang, An-Qin; Zhang, Jiang-Yu; Han, Xiao-Rong; Yu, Hai-Yun; Xie, Si-Mei

    2015-04-01

    Mammary ductoscopy (MD) is commonly used to detect intraductal lesions associated with nipple discharge. This study investigated the relationships between ductoscopic image-based indicators and breast cancer risk, and developed a nomogram for evaluating breast cancer risk in intraductal neoplasms with nipple discharge. A total of 879 consecutive inpatients (916 breasts) with nipple discharge who underwent selective duct excision for intraductal neoplasms detected by MD from June 2008 to April 2014 were analyzed retrospectively. A nomogram was developed using a multivariate logistic regression model based on data from a training set (687 cases) and validated in an independent validation set (229 cases). A Youden-derived cut-off value was assigned to the nomogram for the diagnosis of breast cancer. Color of discharge, location, appearance, and surface of neoplasm, and morphology of ductal wall were independent predictors for breast cancer in multivariate logistic regression analysis. A nomogram based on these predictors performed well. The P value of the Hosmer-Lemeshow test for the prediction model was 0.36. Area under the curve values of 0.812 (95 % confidence interval (CI) 0.763-0.860) and 0.738 (95 % CI 0.635-0.841) was obtained in the training and validation sets, respectively. The accuracies of the nomogram for breast cancer diagnosis were 71.2 % in the training set and 75.5 % in the validation set. We developed a nomogram for evaluating breast cancer risk in intraductal neoplasms with nipple discharge based on MD image findings. This model may aid individual risk assessment and guide treatment in clinical practice.

  18. The Immune System as a New Possible Cell Target for AFP 464 in a Spontaneous Mammary Cancer Mouse Model.

    Science.gov (United States)

    Callero, Mariana A; Rodriguez, Cristina E; Sólimo, Aldana; Bal de Kier Joffé, Elisa; Loaiza Perez, Andrea I

    2017-02-16

    Aminoflavone (AFP 464, NSC 710464), an antitumor agent which recently entered phase II clinical trials, acts against estrogen-positive breast cancer (ER +). AFP 464, which has a unique mechanism of action by activating aryl hydrocarbon receptor (AhR) signaling pathway, decreased tumor size and growth rate in the estrogen dependent, Tamoxifen-sensitive spontaneous M05 mouse model. Considering that AhR has recently emerged as a physiological regulator of the innate and adaptive immune responses, we investigated whether AFP 464 modulates the immune response in our mouse model. Studies on the effect of AFP 464 on the immune system were carried in BALB/c mice bearing M05 semi-differentiated mammary adenocarcinomas that express estrogen and progesterone receptors. Splenic cells and tumor inflammatory infiltrates were studied by cytometric analyses. The modulation of splenocytes cytotoxic activity by AFP 464 was also evaluated. We further investigated the effects of AFP 464 on peritoneal macrophages by evaluating metalloproteinase, arginase and iNOS activities. We found that AFP 464 increased splenic cytotoxic activity, diminished the number of systemic and local Treg lymphocytes and MDSCs, and induced a M1 phenotype in peritoneal macrophages of M05 tumor bearing mice. Therefore, we conclude that AFP 464 modulates immune response which collaborates with its anti-tumor activity. Our results place the immune system as a novel target for this anti-cancer agent to strengthen the rationale for its inclusion in breast cancer treatment regimens. This article is protected by copyright. All rights reserved.

  19. Molecular profiling of human mammary gland links breast cancer risk to a p27(+) cell population with progenitor characteristics.

    Science.gov (United States)

    Choudhury, Sibgat; Almendro, Vanessa; Merino, Vanessa F; Wu, Zhenhua; Maruyama, Reo; Su, Ying; Martins, Filipe C; Fackler, Mary Jo; Bessarabova, Marina; Kowalczyk, Adam; Conway, Thomas; Beresford-Smith, Bryan; Macintyre, Geoff; Cheng, Yu-Kang; Lopez-Bujanda, Zoila; Kaspi, Antony; Hu, Rong; Robens, Judith; Nikolskaya, Tatiana; Haakensen, Vilde D; Schnitt, Stuart J; Argani, Pedram; Ethington, Gabrielle; Panos, Laura; Grant, Michael; Clark, Jason; Herlihy, William; Lin, S Joyce; Chew, Grace; Thompson, Erik W; Greene-Colozzi, April; Richardson, Andrea L; Rosson, Gedge D; Pike, Malcolm; Garber, Judy E; Nikolsky, Yuri; Blum, Joanne L; Au, Alfred; Hwang, E Shelley; Tamimi, Rulla M; Michor, Franziska; Haviv, Izhak; Liu, X Shirley; Sukumar, Saraswati; Polyak, Kornelia

    2013-07-03

    Early full-term pregnancy is one of the most effective natural protections against breast cancer. To investigate this effect, we have characterized the global gene expression and epigenetic profiles of multiple cell types from normal breast tissue of nulliparous and parous women and carriers of BRCA1 or BRCA2 mutations. We found significant differences in CD44(+) progenitor cells, where the levels of many stem cell-related genes and pathways, including the cell-cycle regulator p27, are lower in parous women without BRCA1/BRCA2 mutations. We also noted a significant reduction in the frequency of CD44(+)p27(+) cells in parous women and showed, using explant cultures, that parity-related signaling pathways play a role in regulating the number of p27(+) cells and their proliferation. Our results suggest that pathways controlling p27(+) mammary epithelial cells and the numbers of these cells relate to breast cancer risk and can be explored for cancer risk assessment and prevention.

  20. A hypoxic signature marks tumors formed by disseminated tumor cells in the BALB-neuT mammary cancer model.

    Science.gov (United States)

    Msaki, Aichi; Pastò, Anna; Curtarello, Matteo; Arigoni, Maddalena; Barutello, Giuseppina; Calogero, Raffaele Adolfo; Macagno, Marco; Cavallo, Federica; Amadori, Alberto; Indraccolo, Stefano

    2016-05-31

    Metastasis is the final stage of cancer progression. Some evidence indicates that tumor cell dissemination occurs early in the natural history of cancer progression. Disseminated tumor cells (DTC) have been described in the bone marrow (BM) of cancer patients as well as in experimental models, where they correlate with later development of metastasis. However, little is known about the tumorigenic features of DTC obtained at different time points along tumor progression. Here, we found that early DTC isolated from BM of 15-17 week-old Her2/neu transgenic (BALB-neuT) mice were not tumorigenic in immunodeficient mice. In contrast, DTC-derived tumors were easily detectable when late DTC obtained from 19-22 week-old BALB-neuT mice were injected. Angiogenesis, which contributes to regulate tumor dormancy, appeared dispensable to reactivate late DTC, although it accelerated growth of secondary DTC tumors. Compared with parental mammary tumors, gene expression profiling disclosed a distinctive transcriptional signature of late DTC tumors which was enriched for hypoxia-related transcripts and was maintained in ex-vivo cell culture. Altogether, these findings highlight a different tumorigenic potential of early and late DTC in the BALB-neuT model and describe a HIF-1α-related transcriptional signature in DTC tumors, which may render DTC angiogenesis-competent, when placed in a favourable environment.

  1. Identifying breast cancer risk loci by global differential allele-specific expression (DASE analysis in mammary epithelial transcriptome

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    Gao Chuan

    2012-10-01

    Full Text Available Abstract Background The significant mortality associated with breast cancer (BCa suggests a need to improve current research strategies to identify new genes that predispose women to breast cancer. Differential allele-specific expression (DASE has been shown to contribute to phenotypic variables in humans and recently to the pathogenesis of cancer. We previously reported that nonsense-mediated mRNA decay (NMD could lead to DASE of BRCA1/2, which is associated with elevated susceptibility to breast cancer. In addition to truncation mutations, multiple genetic and epigenetic factors can contribute to DASE, and we propose that DASE is a functional index for cis-acting regulatory variants and pathogenic mutations, and that global analysis of DASE in breast cancer precursor tissues can be used to identify novel causative alleles for breast cancer susceptibility. Results To test our hypothesis, we employed the Illumina® Omni1-Quad BeadChip in paired genomic DNA (gDNA and double-stranded cDNA (ds-cDNA samples prepared from eight BCa patient-derived normal mammary epithelial lines (HMEC. We filtered original array data according to heterozygous genotype calls and calculated DASE values using the Log ratio of cDNA allele intensity, which was normalized to the corresponding gDNA. We developed two statistical methods, SNP- and gene-based approaches, which allowed us to identify a list of 60 candidate DASE loci (DASE ≥ 2.00, P ≤ 0.01, FDR ≤ 0.05 by both methods. Ingenuity Pathway Analysis of DASE loci revealed one major breast cancer-relevant interaction network, which includes two known cancer causative genes, ZNF331 (DASE = 2.31, P = 0.0018, FDR = 0.040 and USP6 (DASE = 4.80, P = 0.0013, FDR = 0.013, and a breast cancer causative gene, DMBT1 (DASE=2.03, P = 0.0017, FDR = 0.014. Sequence analysis of a 5′ RACE product of DMBT1 demonstrated that rs2981745, a putative breast cancer risk locus, appears to be one of the causal variants leading to DASE

  2. Canine mammary gland tumors.

    Science.gov (United States)

    Sorenmo, Karin

    2003-05-01

    The National Consensus Group recommends that all women with tumors larger than 1 cm be offered chemotherapy regardless of tumor histology of lymph node status. This recommendation is to ensure that everyone at risk for failing, even though the risk may be low in women with relatively small tumors and favorable histology, has a choice and receives the benefit of adjuvant chemotherapy. This type of treatment recommendation may also be made in dogs based on recognized, well-accepted prognostic factors such as tumor size, stage, type, and histologic differentiation. Based on the limited clinical information available in veterinary medicine, the drugs that are effective in human breast cancer, such as cyclophosphamide, 5-fluorouracil, and doxorubicin, may also have a role in the treatment of malignant mammary gland tumors in dogs. Randomized prospective studies are needed, however, to evaluate the efficacy of chemotherapy in dogs with high-risk mammary gland tumors and to determine which drugs and protocols are the most efficacious. Until such studies are performed, the treatment of canine mammary gland tumors will be based on the individual oncologist's understanding of tumor biology, experience, interpretation of the available studies, and a little bit of gut-feeling. Table 2 is a proposal for treatment guidelines for malignant canine mammary gland tumors according to established prognostic factors, results from published veterinary studies, and current recommendations for breast cancer treatment in women.

  3. Transforming growth factor-alpha abrogates glucocorticoid-stimulated tight junction formation and growth suppression in rat mammary epithelial tumor cells.

    Science.gov (United States)

    Buse, P; Woo, P L; Alexander, D B; Cha, H H; Reza, A; Sirota, N D; Firestone, G L

    1995-03-24

    The glucocorticoid and transforming growth factor-alpha (TGF-alpha) regulation of growth and cell-cell contact was investigated in the Con8 mammary epithelial tumor cell line derived from a 7,12-dimethylbenz(alpha)anthracene-induced rat mammary adenocarcinoma. In Con8 cell monolayers cultured on permeable filter supports, the synthetic glucocorticoid, dexamethasone, coordinately suppressed [3H]thymidine incorporation, stimulated monolayer transepithelial electrical resistance (TER), and decreased the paracellular leakage of [3H]inulin or [14C]mannitol across the monolayer. These processes dose dependently correlated with glucocorticoid receptor occupancy and function. Constitutive production of TGF-alpha in transfected cells or exogenous treatment with TGF-alpha prevented the glucocorticoid growth suppression response and disrupted tight junction formation without affecting glucocorticoid responsiveness. Treatment with hydroxyurea or araC demonstrated that de novo DNA synthesis is not a requirement for the growth factor disruption of tight junctions. Immunofluorescence analysis revealed that the ZO-1 tight junction protein is localized exclusively at the cell periphery in dexamethasone-treated cells and that TGF-alpha caused-ZO-1 to relocalize from the cell periphery back to a cytoplasmic compartment. Taken together, our results demonstrate that glucocorticoids can coordinately regulate growth inhibition and cell-cell contact of mammary tumor cells and that TGF-alpha, can override both effects of glucocorticoids. These results have uncovered a novel functional "cross-talk" between glucocorticoids and TGF-alpha which potentially regulates the proliferation and differentiation of mammary epithelial cells.

  4. Induction of NAD(P)H-quinone oxidoreductase 1 by antioxidants in female ACI rats is associated with decrease in oxidative DNA damage and inhibition of estrogen-induced breast cancer

    Science.gov (United States)

    Singh, Bhupendra; Bhat, Hari K.

    2012-01-01

    Exact mechanisms underlying the initiation and progression of estrogen-related cancers are not clear. Literature, evidence and our studies strongly support the role of estrogen metabolism-mediated oxidative stress in estrogen-induced breast carcinogenesis. We have recently demonstrated that antioxidants vitamin C and butylated hydroxyanisole (BHA) or estrogen metabolism inhibitor α-naphthoflavone (ANF) inhibit 17β-estradiol (E2)-induced mammary tumorigenesis in female ACI rats. The objective of the current study was to identify the mechanism of antioxidant-mediated protection against E2-induced DNA damage and mammary tumorigenesis. Female ACI rats were treated with E2 in the presence or absence of vitamin C or BHA or ANF for up to 240 days. Nuclear factor erythroid 2-related factor 2 (NRF2) and NAD(P)H-quinone oxidoreductase 1 (NQO1) were suppressed in E2-exposed mammary tissue and in mammary tumors after treatment of rats with E2 for 240 days. This suppression was overcome by co-treatment of rats with E2 and vitamin C or BHA. Time course studies indicate that NQO1 levels tend to increase after 4 months of E2 treatment but decrease on chronic exposure to E2 for 8 months. Vitamin C and BHA significantly increased NQO1 levels after 120 days. 8-Hydroxydeoxyguanosine (8-OHdG) levels were higher in E2-exposed mammary tissue and in mammary tumors compared with age-matched controls. Vitamin C or BHA treatment significantly decreased E2-mediated increase in 8-OHdG levels in the mammary tissue. In vitro studies using silencer RNA confirmed the role of NQO1 in prevention of oxidative DNA damage. Our studies further demonstrate that NQO1 upregulation by antioxidants is mediated through NRF2. PMID:22072621

  5. Ink4a/Arf(-/-) and HRAS(G12V) transform mouse mammary cells into triple-negative breast cancer containing tumorigenic CD49f(-) quiescent cells.

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    Kai, K; Iwamoto, T; Kobayashi, T; Arima, Y; Takamoto, Y; Ohnishi, N; Bartholomeusz, C; Horii, R; Akiyama, F; Hortobagyi, G N; Pusztai, L; Saya, H; Ueno, N T

    2014-01-23

    Intratumoral heterogeneity within individual breast tumors is a well-known phenomenon that may contribute to drug resistance. This heterogeneity is dependent on several factors, such as types of oncogenic drivers and tumor precursor cells. The purpose of our study was to engineer a mouse mammary tumor model with intratumoral heterogeneity by using defined genetic perturbations. To achieve this, we used mice with knockout (-/-) of Ink4a/Arf, a tumor suppressor locus; these mice are known to be susceptible to non-mammary tumors such as fibrosarcoma. To induce mammary tumors, we retrovirally introduced an oncogene, HRAS(G12V), into Ink4a/Arf(-/-) mammary cells in vitro, and those cells were inoculated into syngeneic mice mammary fat pads. We observed 100% tumorigenesis. The tumors formed were negative for estrogen receptor, progesterone receptor and HER2. Further, they had pathological features similar to those of human triple-negative breast cancer (TNBC) (for example, pushing borders, central necrosis). The tumors were found to be heterogeneous and included two subpopulations: CD49f(-) quiescent cells and CD49f(+)cells. Contrary to our expectation, CD49f(-) quiescent cells had high tumor-initiating potential and CD49f(+)cells had relatively low tumor-initiating potential. Gene expression analysis revealed that CD49f(-) quiescent cells overexpressed epithelial-to-mesenchymal transition-driving genes, reminiscent of tumor-initiating cells and claudin-low breast cancer. Our animal model with intratumoral heterogeneity, derived from defined genetic perturbations, allows us to test novel molecular targeted drugs in a setting that mimics the intratumoral heterogeneity of human TNBC.

  6. Can Breast Tumors Affect the Oxidative Status of the Surrounding Environment? A Comparative Analysis among Cancerous Breast, Mammary Adjacent Tissue, and Plasma.

    Science.gov (United States)

    Panis, C; Victorino, V J; Herrera, A C S A; Cecchini, A L; Simão, A N C; Tomita, L Y; Cecchini, R

    2015-01-01

    In this paper, we investigated the oxidative profile of breast tumors in comparison with their normal adjacent breast tissue. Our study indicates that breast tumors present enhanced oxidative/nitrosative stress, with concomitant augmented antioxidant capacity when compared to the adjacent normal breast. These data indicate that breast cancers may be responsible for the induction of a prooxidant environment in the mammary gland, in association with enhanced TNF-α and nitric oxide.

  7. High Fat Diet-induced Breast Cancer Model in Rat

    OpenAIRE

    Wu, Meng-Ju; Chang, Chun-Ju

    2016-01-01

    Obesity has been linked to breast cancer progression but the underlying mechanisms remain obscure. Being overweight or obese for a woman at the time she is diagnosed with breast cancer is linked to a high risk of recurrence regardless of treatment factors. In rodents, high body weight is also associated with increased incidence of spontaneous and chemically induced tumors. To study the complex interaction between the mammary epithelia and the microenvironment, with a focus on the mechanism un...

  8. Efeito da trimegestona sobre o tecido mamário de ratas castradas Effect of trimegestone on mammary gland of castrated rats

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    Luciana de Oliveira Marques

    2011-07-01

    Full Text Available OBJETIVO: Avaliar o efeito da trimegestona sobre a proliferação celular do tecido mamário de ratas castradas. MÉTODOS: Foram utilizadas 45 ratas adultas e virgens, da linhagem Wistar, submetidas à castração. Após o 60º dia da castração, confirmado o hipoestrogenismo, os animais foram divididos aleatoriamente em três grupos, conforme o tratamento proposto: controle (n=15 recebeu soro fisiológico 0,9%; estrogênio (n=15 recebeu 17 beta-estradiol; e combinado (n=15 recebeu 17 beta-estradiol associado à trimegestona, todos por 60 dias consecutivos. Após o término do tratamento, procedeu-se a exérese das mamas inguinais, destinadas a análise morfométrica pela coloração de hematoxilina e eosina (HE e imuno-histoquímica pela quantificação do anticorpo anti-PCNA no tecido mamário, seguido de eutanásia. Os parâmetros morfométricos avaliados foram: proliferação celular epitelial, atividade secretora e alteração do estroma mamário. Ocorreram nove óbitos durante o experimento. As variáveis foram submetidas à análise estatística adotando-se como significante pPURPOSE: To evaluate the efect of trimegestone on the histological changes of the mammary tissue of castrated rats. METHODS: Forty-five virgin female Wistar rats were used after oophorectomy. Sixty days after surgery, with hypoestrogenisms confirmed, the experimental rats were randomly assigned to three groups of 15 animals each, when then the specific treatment for each group was started. The control group (C and experimental groups 1 and 2 respectively received 0.9% saline solution, 17-beta-estradiol and 17-beta-estradiol in combination with trimegestone for 60 consecutive days. After the end of treatment , the inguinal mammary glands were removed, stained with hematoxylin and eosin (HE for morphometry and examined by immunohistochemistry for the quantification of anti-PCNA antibody in the mammary tissue, followed by euthanasia. The morphometric parameters

  9. Outcomes of patients with breast cancer who present with ipsilateral supraclavicular or internal mammary lymph node metastases.

    Science.gov (United States)

    Dellapasqua, Silvia; Bagnardi, Vincenzo; Balduzzi, Alessandra; Iorfida, Monica; Rotmensz, Nicole; Santillo, Barbara; Viale, Giuseppe; Ghisini, Raffaella; Veronesi, Paolo; Luini, Alberto; Morra, Anna; Goldhirsch, Aron; Colleoni, Marco

    2014-02-01

    The prognostic implications of internal mammary (IM) and supraclavicular (SC) node involvement in locally advanced breast cancer is still unclear. We evaluated 107 patients with IM (n = 65) or SC (n = 42) node involvement who underwent operation at the European Institute of Oncology between 1997 and 2009 to assess their prognostic features. We subsequently analyzed matched cohorts, using the 107 patients as cases and another group of patients as a control cohort, to evaluate prognostic differences between patients with and those without IM or SC node involvement. Five-year disease-free survival (DFS) was 84% in IM vs. 38.8% in SC node involvement (P node vs. 57.1% in SC node involvement (P node involvement. Conversely, a statistically significant difference in DFS and locoregional recurrence was observed in patients with SC node involvement compared with controls without SC node involvement. SC node involvement correlated with a significantly poorer outcome in patients with locally advanced breast cancer. Adequate staging, including biopsy of suspicious locoregional ipsilateral lymph nodes, is mandatory in these patients. Patients with IM or SC node involvement should be treated with curative intent using combined-modality treatments. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Hypothyroidism advances mammary involution in lactating rats through inhibition of PRL signaling and induction of LIF/STAT3 mRNAs.

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    Campo Verde Arboccó, Fiorella; Sasso, Corina V; Actis, Esteban A; Carón, Rubén W; Hapon, María Belén; Jahn, Graciela A

    2016-01-01

    Thyroid diseases have deleterious effects on lactation, litter growth and survival, and hinder the suckling-induced hormone release, leading in the case of hyperthyroidism, to premature mammary involution. To determine the effects of hypothyroidism (HypoT) on late lactation, we analyzed the effect of chronic 6-propyl-2-thiouracil (PTU)-induced HypoT on mammary histology and the expression of members of the JAK/STAT/SOCS signaling pathway, milk proteins, prolactin (PRLR), estrogen (ER), progesterone (PR) and thyroid hormone (TR) receptors, markers of involution (such as stat3, lif, bcl2, BAX and PARP) on lactation (L) day 21. HypoT mothers showed increased histological markers of involution compared with control rats, such as adipose/epithelial ratio, inactive alveoli, picnotic nuclei and numerous detached apoptotic cells within the alveolar lumina. We also found decreased PRLR, β-casein and α-lactoalbumin mRNAs, but increased SOCS1, SOCS3, STAT3 and LIF mRNAs, suggesting a decrease in PRL signaling and induction of involution markers. Furthermore, Caspase-3 and 8 and PARP labeled cells and the expression of structural proteins such as β-Actin, α-Tubulin and Lamin B were increased, indicating the activation of apoptotic pathways and tissue remodelation. HypoT also increased PRA (mRNA and protein) and erβ and decreased erα mRNAs, and increased strongly TRα1, TRβ1, PRA and ERα protein levels. These results show that lactating HypoT rats have premature mammary involution, most probably induced by the inhibition of prolactin signaling along with the activation of the LIF-STAT3 pathway.

  11. Selection of chemotherapy for metastatic mammary cancer by effect on cesium-131 uptake.

    Science.gov (United States)

    Ferguson, D J; Harper, P V

    1977-09-01

    Cesium-131 was administered intravenously to 39 patients with superficial metastases of mammary carcinoma and the concentration in tumor was compared with that in normal tissue by application of a detector in vivo, before and after 1 to 5 days of chemotherapy with cyclophosphamide (CP), 5-fluorouracil (FU), or diethylstilbestrol. A change of the cesium concentration ratio (tumor/normal tissue) greater than 15% after brief treatment correctly predicted the therapeutic effect after 1 to 39 months on the tumors that were tested in 30 of 33 tests. No reliable correlation could be made in the remaining 21 tests in which the change of ratio was less than 15%. The concentration of cesium-131 in the skin, fat, and skeletal muscle of mice was not appreciably altered by treatment for 5 days with CP or FU.

  12. Collagen induced arthritis increases secondary metastasis in MMTV-PyV MT mouse model of mammary cancer

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    Gruber Helen E

    2011-08-01

    Full Text Available Abstract Background Several studies have demonstrated that sites of chronic inflammation are often associated with the establishment and growth of various malignancies. A common inflammatory condition in humans is autoimmune arthritis (AA. Although AA and cancer are different diseases, many of the underlying processes that contribute to the disorders of the joints and connective tissue that characterize AA also affect cancer progression and metastasis. Systemically, AA can lead to cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge being available, there has been minimal research linking breast cancer, arthritis, and metastasis associated with breast cancer. Notably both diseases are extremely prevalent in older post-menopausal women. Methods To establish the novel link between arthritis induced inflammation and secondary metastasis associated with breast cancer, PyV MT mice that spontaneously develop mammary gland carcinoma were injected with Type II collagen (CII to induce arthritis at 9 and 18 weeks of age for pre-metastatic and metastatic condition. The sites of secondary metastasis and the associated inflammatory microenvironment were evaluated. Results A significant increase in breast cancer-associated secondary metastasis to the lungs and bones was observed in the arthritic versus the non-arthritic PyV MT mice along with an increase in primary tumor burden. We report significant increases in the levels of interstitial cellular infiltrates and pro-inflammatory cytokines such as interleukin-17 (IL-17, interleukin-6 (IL-6, Pro- Matrix metallopeptidase 9 (Pro-MMP9, insulin like growth factor-II (GF-II and macrophage colony stimulating factor (M-CSF in the arthritic lung and bone milieu as well as in the circulation. These pro-inflammatory cytokines along with the inflammatory microenvironment may be the underlying factors

  13. RUNX2 correlates with subtype-specific breast cancer in a human tissue microarray, and ectopic expression of Runx2 perturbs differentiation in the mouse mammary gland

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    Laura McDonald

    2014-05-01

    Full Text Available RUNX2, a master regulator of osteogenesis, is oncogenic in the lymphoid lineage; however, little is known about its role in epithelial cancers. Upregulation of RUNX2 in cell lines correlates with increased invasiveness and the capacity to form osteolytic disease in models of breast and prostate cancer. However, most studies have analysed the effects of this gene in a limited number of cell lines and its role in primary breast cancer has not been resolved. Using a human tumour tissue microarray, we show that high RUNX2 expression is significantly associated with oestrogen receptor (ER/progesterone receptor (PR/HER2-negative breast cancers and that patients with high RUNX2 expression have a poorer survival rate than those with negative or low expression. We confirm RUNX2 as a gene that has a potentially important functional role in triple-negative breast cancer. To investigate the role of this gene in breast cancer, we made a transgenic model in which Runx2 is specifically expressed in murine mammary epithelium under the control of the mouse mammary tumour virus (MMTV promoter. We show that ectopic Runx2 perturbs normal development in pubertal and lactating animals, delaying ductal elongation and inhibiting lobular alveolar differentiation. We also show that the Runx2 transgene elicits age-related, pre-neoplastic changes in the mammary epithelium of older transgenic animals, suggesting that elevated RUNX2 expression renders such tissue more susceptible to oncogenic changes and providing further evidence that this gene might have an important, context-dependent role in breast cancer.

  14. RUNX2 correlates with subtype-specific breast cancer in a human tissue microarray, and ectopic expression of Runx2 perturbs differentiation in the mouse mammary gland.

    Science.gov (United States)

    McDonald, Laura; Ferrari, Nicola; Terry, Anne; Bell, Margaret; Mohammed, Zahra M; Orange, Clare; Jenkins, Alma; Muller, William J; Gusterson, Barry A; Neil, James C; Edwards, Joanne; Morris, Joanna S; Cameron, Ewan R; Blyth, Karen

    2014-05-01

    RUNX2, a master regulator of osteogenesis, is oncogenic in the lymphoid lineage; however, little is known about its role in epithelial cancers. Upregulation of RUNX2 in cell lines correlates with increased invasiveness and the capacity to form osteolytic disease in models of breast and prostate cancer. However, most studies have analysed the effects of this gene in a limited number of cell lines and its role in primary breast cancer has not been resolved. Using a human tumour tissue microarray, we show that high RUNX2 expression is significantly associated with oestrogen receptor (ER)/progesterone receptor (PR)/HER2-negative breast cancers and that patients with high RUNX2 expression have a poorer survival rate than those with negative or low expression. We confirm RUNX2 as a gene that has a potentially important functional role in triple-negative breast cancer. To investigate the role of this gene in breast cancer, we made a transgenic model in which Runx2 is specifically expressed in murine mammary epithelium under the control of the mouse mammary tumour virus (MMTV) promoter. We show that ectopic Runx2 perturbs normal development in pubertal and lactating animals, delaying ductal elongation and inhibiting lobular alveolar differentiation. We also show that the Runx2 transgene elicits age-related, pre-neoplastic changes in the mammary epithelium of older transgenic animals, suggesting that elevated RUNX2 expression renders such tissue more susceptible to oncogenic changes and providing further evidence that this gene might have an important, context-dependent role in breast cancer.

  15. Dehydroepiandrosterone (DHEA Feeding Protects Liver Steatosis in Obese Breast Cancer Rat Model

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    Reza Hakkak

    2017-03-01

    Full Text Available Obesity is a major health problem in the US and globally. Obesity is associated with the risk of cardiovascular disease, type 2 diabetes, cancers, hyperlipidemia, and liver steatosis development. Dehydroepiandrosterone (DHEA is a dietary supplement used as an anti-obesity supplement. Previously, we reported that DHEA feeding protects 7,12-dimethylbenz(aanthracene (DMBA-induced mammary tumors. The objectives of this study were to investigate the effects of obesity and DHEA feeding on liver steatosis, body weight gain, and serum DHEA, DHEA sulfate (DHEA-S, insulin-like growth factor-1 (IGF-1, and insulin-like growth factor binding protein-3 (IGFBP-3 levels. Female Zucker rats were randomly assigned to either a control diet or a control diet with DHEA supplementation for 155 days. Livers were collected for histological examination. Serum was collected to measure DHEA, DHEA-S, IGF-1, and IGFBP-3. Our results show that DHEA-fed rats had significantly less liver steatosis (p < 0.001 than control-fed rats and gained less weight (p < 0.001. DHEA feeding caused significant decreases (p < 0.001 in the serum levels of IGF-1 and IGFBP-3 and significantly increased (p < 0.001 serum levels of DHEA and DHEA-S. Our results suggest that DHEA feeding can protect against liver steatosis by reducing body weight gain and modulating serum IGF-1 and IGFBP-3 levels in an obese breast cancer rat model.

  16. Antineoplastic effect of iodine and iodide in dimethylbenz[a]anthracene-induced mammary tumors: association between lactoperoxidase and estrogen-adduct production.

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    Soriano, Ofelia; Delgado, Guadalupe; Anguiano, Brenda; Petrosyan, Pavel; Molina-Servín, Edith D; Gonsebatt, Maria E; Aceves, Carmen

    2011-08-01

    Several groups, including ours, have reported that iodine exhibited antiproliferative and apoptotic effects in various cancer cells only if this element is supplemented as molecular iodine, or as iodide, to cells that are able to oxidize it with the enzyme thyroperoxidase. In this study, we analyzed the effect of various concentrations of iodine and/or iodide in the dimethylbenz[a]anthracene (DMBA) mammary cancer model in rats. The results show that 0.1% iodine or iodide increases the expression of peroxisome proliferator-activated receptor type γ (PPARγ), triggering caspase-mediated apoptosis pathways in damaged mammary tissue (DMBA-treated mammary gland) as well as in frank mammary tumors, but not in normal mammary gland. DMBA treatment induces the expression of lactoperoxidase, which participates in the antineoplastic effect of iodide and could be involved in the pro-neoplastic effect of estrogens, increasing the formation of DNA adducts. In conclusion, our results show that a supplement of 0.1% molecular iodine/potassium iodide (0.05/0.05%) exert antineoplastic effects, preventing estrogen-induced DNA adducts and inducing apoptosis through PPARγ/caspases in pre-cancer and cancerous cells. Since this iodine concentration does not modify the cytology (histology, apoptosis rate) or physiology (triiodothyronine and thyrotropin) of the thyroid gland, we propose that it be considered as an adjuvant treatment for premenopausal mammary cancer.

  17. Signs of proinflammatory/genotoxic switch (adipogenotoxicosis) in mammary fat of breast cancer patients: role of menopausal status, estrogens and hyperglycemia.

    Science.gov (United States)

    Berstein, Lev M; Kovalevskij, Anatolij Y; Poroshina, Tatjana E; Kotov, Alexander V; Kovalenko, Irina G; Tsyrlina, Evgenia V; Leenman, Elena E; Revskoy, Sergey Y; Semiglazov, Vladimir F; Pozharisski, Kazimir M

    2007-08-01

    The abundance of fat tissue surrounding normal and malignant epithelial mammary cells raises the questions whether such "adipose milieu" is important in the local proinflammatory/genotoxic shift, which apparently promotes tumor development and worsens prognosis, and what conditions stimulate this shift, or "adipogenotoxicosis." We studied 95 mammary fat samples from 70 postmenopausal and 25 premenopausal breast cancer (BC) patients at a distance of 1.5-2.0 cm from tumors. The levels of leptin, adiponectin, TNFalpha and IL-6 release after 4-hr incubation of the samples were evaluated with ELISA, nitric oxide (NO) production by Griess reaction and lipid peroxidation by determination of thiobarbiturate-reactive products (TBRP). Infiltration of fat with macrophages (CD68-positive cells) and expression of cytochrome P450 1B1/estrogen 4-hydroxylase (CYP1B1) were detected by immunohistochemistry. Aromatase (CYP19) activity in mammary fat was measured by (3)H(2)O release from (3)H-1beta-androstenedione. In the postmenopausal BC patients, NO and TNFalpha production by adipose tissue explants increased independent of BMI and in parallel with decreasing leptin and, especially, adiponectin release. In the premenopausal patients, higher CYP1B1 expression and TBRP level were found in mammary fat, while higher aromatase activity was combined with higher CYP1B1 expression as well as NO and IL-6 production. In the postmenopausal group, impaired glucose tolerance was associated with higher IL-6 release production by fat and with higher IL-6/adiponectin ratio. Thus, signs of adipogenotoxicosis in mammary fat can be found in both pre- and postmenopausal BC patients. This condition is likely being maintained through estrogen- and glucose-related factors and mechanisms presumably associated with less favorable types of hormonal carcinogenesis.

  18. Comparison of the Adipose and Luminal Mammary Gland Compartment as Orthotopic Inoculation Sites in a 4T1-Based Immunocompetent Preclinical Model for Triple-Negative Breast Cancer.

    Science.gov (United States)

    Steenbrugge, Jonas; Breyne, Koen; Denies, Sofie; Dekimpe, Melissa; Demeyere, Kristel; De Wever, Olivier; Vermeulen, Peter; Van Laere, Steven; Sanders, Niek N; Meyer, Evelyne

    2016-12-01

    Breast tumorigenesis is classically studied in mice by inoculating tumor cells in the fat pad, the adipose compartment of the mammary gland. Alternatively, the mammary ducts, which constitute the luminal mammary gland compartment, also provide a suitable inoculation site to induce breast cancer in murine models. The microenvironments in these compartments influence tumor cell progression, yet this effect has not been investigated in an immunocompetent context. Here, we compared both mammary gland compartments as distinct inoculation sites, taking into account the immunological aspect by inoculating 4T1 tumor cells in immunocompetent mice. Following tumor cell inoculation in the adipose compartment of non-pretreated/naive, hormonally pretreated/naive and non-pretreated/lactating mice, the primary tumors developed similarly. However, a slower onset of primary tumor growth was found after inoculations in the luminal compartment of non-pretreated/lactating mice. Despite this difference in tumor development rate, metastasis to the liver and lungs was equally observed and was accompanied by lymphatic spreading of tumor cells and progressive splenomegaly with both inoculation types. Chitinase 3-like 1 (CHI3L1) and lipocalin 2 (LCN2) served as innovative biomarkers for disease progression showing increased levels in primary tumors and sera of the non-pretreated/lactating inoculation groups. A slower increase in circulating CHI3L1 but not LCN2 levels, was observed after inoculations in the luminal compartment which corroborated the slower tumor development at this inoculation site. Our results highlight the critical impact of different mammary gland compartments on tumor development in syngeneic murine models and support the use of novel tumor progression biomarkers in an immune-competent environment.

  19. Neem leaf extract inhibits mammary carcinogenesis by altering cell proliferation, apoptosis, and angiogenesis.

    Science.gov (United States)

    Arumugam, Arunkumar; Agullo, Pamela; Boopalan, Thiyagarajan; Nandy, Sushmita; Lopez, Rebecca; Gutierrez, Christina; Narayan, Mahesh; Rajkumar, Lakshmanaswamy

    2014-01-01

    Plant-based medicines are useful in the treatment of cancer. Many breast cancer patients use complementary and alternative medicine in parallel with conventional treatments. Neem is historically well known in Asia and Africa as a versatile medicinal plant with a wide spectrum of biological activities. The experiments reported herein determined whether the administration of an ethanolic fraction of Neem leaf (EFNL) inhibits progression of chemical carcinogen-induced mammary tumorigenesis in rat models. Seven-week-old female Sprague Dawley rats were given a single intraperitoneal injection of N-methyl-N-nitrosourea (MNU). Upon the appearance of palpable mammary tumors, the rats were divided into vehicle-treated control groups and EFNL-treated groups. Treatment with EFNL inhibited MNU-induced mammary tumor progression. EFNL treatment was also highly effective in reducing mammary tumor burden and in suppressing mammary tumor progression even after the cessation of treatment. Further, we found that EFNL treatment effectively upregulated proapoptotic genes and proteins such as p53, B cell lymphoma-2 protein (Bcl-2)-associated X protein (Bax), Bcl-2-associated death promoter protein (Bad) caspases, phosphatase and tensin homolog gene (PTEN), and c-Jun N-terminal kinase (JNK). In contrast, EFNL treatment caused downregulation of anti-apoptotic (Bcl-2), angiogenic proteins (angiopoietin and vascular endothelial growth factor A [VEGF-A]), cell cycle regulatory proteins (cyclin D1, cyclin-dependent kinase 2 [Cdk2], and Cdk4), and pro-survival signals such as NFκB, mitogen-activated protein kinase 1 (MAPK1). The data obtained in this study demonstrate that EFNL exert a potent anticancer effect against mammary tumorigenesis by altering key signaling pathways.

  20. Mammary gland morphology and gene expression differ in female rats treated with 17β-estradiol or fed soy protein isolate.

    Science.gov (United States)

    Ronis, Martin J J; Shankar, Kartik; Gomez-Acevedo, Horacio; Hennings, Leah; Singhal, Rohit; Blackburn, Michael L; Badger, Thomas M

    2012-12-01

    Soy foods have been suggested to have both positive health benefits and potentially adverse effects as a result of their content of phytoestrogens. However, studies on the estrogenicity of soy foods are lacking. Here we directly compared the effects of soy protein isolate (SPI), the protein in soy infant formula, with those of 17β-estradiol (E2), on global gene expression profiles and morphology in the female rat mammary gland. Rats were fed AIN-93G diets containing casein or SPI beginning on postnatal d 30. Rats were ovariectomized on postnatal d 50 and treated with 5 μg/kg/d E2 or vehicle for 14 d. Microarray analysis revealed that E2 treatment altered expression of 780 genes more than or equal to 2-fold (P < 0.05), whereas SPI feeding altered expression of only 53 genes more than or equal to 2-fold. Moreover, the groups had only 10 genes in common to increase more than or equal to 2-fold. The combination of SPI feeding and E2 altered expression of 422 genes and reversed E2 effects on many mRNAs, including those involved in the c-myc signaling pathway, cyclin D1, and Ki67. ERα binding to its response element on the Tie-2/Tek and progesterone receptor promoters was increased by E2, but not SPI, and this promoter binding was suppressed by the combination of E2 + SPI for the Tie-2/Tek promoter but increased for the progesterone receptor promoter (P < 0.05). SPI reduced the ratio of epithelial to fat pad area and E2 + SPI reduced both epithelial and fat pad area (P < 0.05). These data suggest that SPI is only minimally estrogenic in the rat mammary gland even in the absence of endogenous estrogens.

  1. Generation of breast cancer stem cells by steroid hormones in irradiated human mammary cell lines.

    Directory of Open Access Journals (Sweden)

    Guillaume Vares

    Full Text Available Exposure to ionizing radiation was shown to result in an increased risk of breast cancer. There is strong evidence that steroid hormones influence radiosensitivity and breast cancer risk. Tumors may be initiated by a small subpopulation of cancer stem cells (CSCs. In order to assess whether the modulation of radiation-induced breast cancer risk by steroid hormones could involve CSCs, we measured by flow cytometry the proportion of CSCs in irradiated breast cancer cell lines after progesterone and estrogen treatment. Progesterone stimulated the expansion of the CSC compartment both in progesterone receptor (PR-positive breast cancer cells and in PR-negative normal cells. In MCF10A normal epithelial PR-negative cells, progesterone-treatment and irradiation triggered cancer and stemness-associated microRNA regulations (such as the downregulation of miR-22 and miR-29c expression, which resulted in increased proportions of radiation-resistant tumor-initiating CSCs.

  2. Resveratrol enhances the chemopreventive effect of celecoxib in chemically induced breast cancer in rats.

    Science.gov (United States)

    Kisková, Terézia; Jendželovský, Rastislav; Rentsen, Erdenetsetsek; Maier-Salamon, Alexandra; Kokošová, Natália; Papčová, Zuzana; Mikeš, Jaromír; Orendáš, Peter; Bojková, Bianka; Kubatka, Peter; Svoboda, Martin; Kajo, Karol; Fedoročko, Peter; Jäger, Walter; Ekmekcioglu, Cem; Kassayová, Monika; Thalhammer, Theresia

    2014-11-01

    Resveratrol and celecoxib were used as chemopreventive agents in animal models of carcinogenesis, and exert antiproliferative and proapoptotic effects on cancer cells. Therefore, the aim of this study was to evaluate whether combining resveratrol with celecoxib may exert more potent anticarcinogenic effects than the single agents. Mammary carcinogenesis was initiated in 70 female Sprague-Dawley rats with N-methyl-N-nitrosourea (NMU). The chemoprevention with resveratrol, celecoxib, and their combination started 2 weeks before the first carcinogen dose and lasted until the end of the experiment. Tumor incidence and frequency, latency period, tumor volume, the expression of cyclooxygenase 2 (COX2) and growth differentiation factor 15 (GDF15), and also the formation of reactive oxygen species were analyzed using different methods. In addition, the levels of resveratrol and its metabolites in blood and selected tumor tissues were determined by high-performance liquid chromatography. Finally, the anticancer effects of the reagents were studied in the human breast cancer cell line MCF-7. Celecoxib as a single agent significantly decreased tumor frequency, prolonged tumor latency, and decreased the total number of malignant tumors compared with the NMU conditions. Tumor volume was nonsignificantly reduced (0.68±0.25 vs. 0.93±0.28 cm3). Importantly, the addition of resveratrol to celecoxib reduced tumor volume by 60% compared with celecoxib alone (from 0.68±0.25 to 0.27±0.07 cm3, Pcancer-preventive effects of this application. This study showed that in NMU-induced mammary cancer in rats, the combination of resveratrol and celecoxib led to a significant reduction in all tumor parameters. In addition, in terms of tumor volume, the combination was more efficient than celecoxib as a single agent.

  3. Robust spinal neuroinflammation mediates mechanical allodynia in Walker 256 induced bone cancer rats.

    Science.gov (United States)

    Mao-Ying, Qi-Liang; Wang, Xiao-Wei; Yang, Chang-Jiang; Li, Xiu; Mi, Wen-Li; Wu, Gen-Cheng; Wang, Yan-Qing

    2012-05-20

    It has been reported that remarkable and sustained activation of astrocytes and/or microglia occurs in cancer induced pain (CIP), which is different from neuropathic and inflammatory pain. The present study was designed to investigate the role of spinal Toll-like receptor 4 (TLR4) induced glial neuroinflammation in cancer induced pain using a modified rat model of bone cancer. The rat model of CIP consisted of unilateral intra-tibial injection with Walker 256 mammary gland carcinoma. Nine days after Walker 256 inoculation, a robust activation of both astrocytes and microglia in bilateral spinal dorsal horn was observed together with significant bilateral mechanical allodynia. This neuroinflammation was characterized by enhanced immunostaining of both glial fibrillary acidic protein (GFAP, astrocyte marker) and OX-42 (microglia marker), and an elevated level of IL-1β, IL-6 and TNF-α mRNA. I.t. administration of fluorocitrate (an inhibitor of glial metabolism, 1 nmol) or minocycline (an inhibitor of microglia, 100 μg) has significant anti-allodynic effects on day 12 after Walker 256 inoculation. Naloxone (a nonstereoselective TLR4 signaling blocker, 60 μg, i.t.) also significantly alleviated mechanical allodynia and simultaneously blocked the increased inflammatory cytokine mRNA. The results suggested that spinal TLR4 might play an important role in the sustained glial activation that critically contributed to the robust and sustained spinal neuroinflammation in CIP. This result could potentially help clinicians and researchers to better understand the mechanism of complicated cancer pain.

  4. Study on {sup 41}Ca-AMS for diagnosis and assessment of cancer bone metastasis in rats

    Energy Technology Data Exchange (ETDEWEB)

    Shen, Hongtao; Pang, Fangfang [College of Physics and Technology, Guangxi Normal University, Guilin 541004 (China); China Institute of Atomic Energy, P.O. Box 275-50, Beijing 102413 (China); Jiang, Shan; He, Ming; Dong, Kejun; Dou, Liang [China Institute of Atomic Energy, P.O. Box 275-50, Beijing 102413 (China); Pang, Yijun [College of Physics and Technology, Guangxi Normal University, Guilin 541004 (China); China Institute of Atomic Energy, P.O. Box 275-50, Beijing 102413 (China); Yang, Xianlin [College of Physics and Technology, Guangxi Normal University, Guilin 541004 (China); Ruan, Xiangdong [College of Physics, Guangxi University, Nanning 530004 (China); Liu, Manjun; Xia, Chunbo [Guiin Medical University, Guilin 541004 (China)

    2015-10-15

    The annual incidence of new cancer patients in China is about 2 million, 30–40% of which will end up with bone metastasis. Profound study on the preclinical model and early diagnosis of cancer bone metastasis in rats are very significant for the drug development, better understanding and treatment of bone metastases. In order to monitor the process of bone metabolism and early detection of bone metastasis of cancer cells, a technique of {sup 41}Ca isotope tracer combined with AMS has been developed and applied in the study on the bone metastasis of cancer cells by rat model. In this work, 3-month-old female Sprague–Dawley (SD) rats were randomly divided into different groups, and tumor cells injected respectively into the tail vein, femoral artery, femoral cavity and the thigh muscle to establish the rat models for bone metastases. The most appropriate model, i.e., the thigh muscle group, was finally adopted in our real metastases experiment. Each rat in this group was intramuscularly (i.m.) injected with 250 μl CaCl{sub 2} solution (containing 1.4 mg Ca and 5nCi {sup 41}Ca). About 40 days later, the rat mammary gland carcinoma cells (Walker 256) were injected into these rats following the established protocol. After bone metastasis, medicine interventions were performed. The sequential urine and blood samples were collected and analyzed for {sup 41}Ca (by AMS) and N-terminal telopeptide (Ntx), respectively. Bone Mineral Density (BMD) values in the femur and the tibia were measured by CT scan. The results of {sup 41}Ca/Ca in longitudinal urinary samples can sensitively reveal the skeletal perturbations caused by bone metastasis of rats, suggests that {sup 41}Ca might be similarly developed for human use and improve clinical management through the assessment of the curative effect and non-invasive detection of the earliest stages of cancer growth in bone.

  5. Role of dietary fatty acids in mammary gland development and breast cancer

    NARCIS (Netherlands)

    MacLennan, Mira; Ma, David W. L.

    2010-01-01

    Breast cancer is the most common cancer among women worldwide. Estimates suggest up to 35% of cases may be preventable through diet and lifestyle modification. Growing research on the role of fats in human health suggests that early exposure in life to specific fatty acids, when tissues are particul

  6. Developing a Novel Mouse Model for Breast Cancer by Targeting Oncogenes to Mammary Progenitor Cells

    Science.gov (United States)

    2005-04-01

    1260. Swope D, Harrell JC, Mahato D and Korach KS. (2002). Pietras RJ, Arboleda J, Reese DM, Wongvipat N, Pegram Gene, 294, 239-247. MD, Ramos L...sporadic cancers. Nat Rev Cancer 2004;4:814-19. (28) Paladini RD, Takahashi K, Bravo NS, Coulombe PA. On- (45) Andrechek ER, Hardy WR, Laing MA, Muller WJ

  7. Control of TCF-4 expression by VDR and vitamin D in the mouse mammary gland and colorectal cancer cell lines.

    Directory of Open Access Journals (Sweden)

    Marcy E Beildeck

    Full Text Available BACKGROUND: The vitamin D receptor (VDR pathway is important in the prevention and potentially in the treatment of many cancers. One important mechanism of VDR action is related to its interaction with the Wnt/beta-catenin pathway. Agonist-bound VDR inhibits the oncogenic Wnt/beta-catenin/TCF pathway by interacting directly with beta-catenin and in some cells by increasing cadherin expression which, in turn, recruits beta-catenin to the membrane. Here we identify TCF-4, a transcriptional regulator and beta-catenin binding partner as an indirect target of the VDR pathway. METHODOLOGY/PRINCIPAL FINDINGS: In this work, we show that TCF-4 (gene name TCF7L2 is decreased in the mammary gland of the VDR knockout mouse as compared to the wild-type mouse. Furthermore, we show 1,25(OH2D3 increases TCF-4 at the RNA and protein levels in several human colorectal cancer cell lines, the effect of which is completely dependent on the VDR. In silico analysis of the human and mouse TCF7L2 promoters identified several putative VDR binding elements. Although TCF7L2 promoter reporters responded to exogenous VDR, and 1,25(OH2D3, mutation analysis and chromatin immunoprecipitation assays, showed that the increase in TCF7L2 did not require recruitment of the VDR to the identified elements and indicates that the regulation by VDR is indirect. This is further confirmed by the requirement of de novo protein synthesis for this up-regulation. CONCLUSIONS/SIGNIFICANCE: Although it is generally assumed that binding of beta-catenin to members of the TCF/LEF family is cancer-promoting, recent studies have indicated that TCF-4 functions instead as a transcriptional repressor that restricts breast and colorectal cancer cell growth. Consequently, we conclude that the 1,25(OH2D3/VDR-mediated increase in TCF-4 may have a protective role in colon cancer as well as diabetes and Crohn's disease.

  8. The methyltransferase EZH2 is not required for mammary cancer development, although high EZH2 and low H3K27me3 correlate with poor prognosis of ER-positive breast cancers.

    Science.gov (United States)

    Bae, Woo Kyun; Yoo, Kyung Hyun; Lee, Ji Shin; Kim, Young; Chung, Ik-Joo; Park, Min Ho; Yoon, Jung Han; Furth, Priscilla A; Hennighausen, Lothar

    2015-10-01

    Enhancer of zeste homolog 2 (EZH2) catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) and its demethylation is catalyzed by UTX. EZH2 levels are frequently elevated in breast cancer and have been proposed to control gene expression through regulating repressive H3K27me3 marks. However, it is not fully established whether breast cancers with different levels of H3K27me3, EZH2 and UTX exhibit different biological behaviors. Levels of H3K27me3, EZH2 and UTX and their prognostic significance were evaluated in 146 cases of breast cancer. H3K27me3 levels were higher in HER2-negative samples. EZH2 expression was higher in cancers that were LN+, size > 20mm, and with higher tumor grade and stage. Using a Cox regression model, H3K27me3 levels and EZH2 expression were identified as independent prognostic factors for overall survival for all the breast cancers studied as well as the ER-positive subgroup. The combination of low H3K27me3 and high EZH2 expression levels were significantly associated with shorter survival. UTX expression was not significantly associated with prognosis and there were no correlations between H3K27me3 levels and EZH2/UTX expression. To determine if EZH2 is required to establish H3K27me3 marks in mammary cancer, Brca1 and Ezh2 were deleted in mammary stem cells in mice. Brca1-deficient mammary cancers with unaltered H3K27me3 levels developed in the absence of EZH2, demonstrating that EZH2 is not a mandatory H3K27 methyltransferase in mammary neoplasia and providing genetic evidence for biological independence between H3K27me3 and EZH2 in this tissue.

  9. Reproductive experience influences grooming behavior during pregnancy in rats

    Directory of Open Access Journals (Sweden)

    Serafim A.P.

    2002-01-01

    Full Text Available The pregnancy-induced increase in self-licking observed in rats is important for mammary gland development and lactation. Reproductive experience has epidemiologial implications such as a decrease in the incidence of mammary gland cancer in women and it also influences various behavioral, neurochemical and endocrine parameters. The aim of the present study was to investigate the influence of reproductive experience on grooming behavior patterns during pregnancy in rats. Self-grooming behavior was measured in age-matched virgin, primi- and multigravid (days 7, 8, 9, 19, and 20 of pregnancy rats. General grooming (head, forelimbs and shoulders was not significantly different among virgin, primi- and multigravid rats during pregnancy. Confirming previous work, pregnant rats spent significantly more time in specific grooming (mammary glands, nipple lines, genital and pelvic regions than did virgin animals. In addition, self- licking of mammary glands was significantly increased in multi- as compared to primigravid rats on days 8, 9, 19 and 20 of pregnancy. The increase in mammary gland grooming observed in multigravid rats appears to be a consequence of previous reproductive experience. These data show that reproductive experience modulates mammary gland grooming during pregnancy, possibly contributing to successful reproduction.

  10. Evaluation of internal mammary lymph nodes dissection combined with selective postoperative radiotherapy in patients with medial breast cancers

    Energy Technology Data Exchange (ETDEWEB)

    Yokota, Toru; Roppongi, Takashi; Kanno, Keiichi; Sakamoto, Ichiro; Fujii, Takanao; Mitomo, Osamu [Numata National Hospital, Gunma (Japan)

    1998-08-01

    In the reason that internal mammary lymph nodes (IMN) dissection of extended radical mastectomy (EXT) did not influence overall survival rates in patients with medial or central breast cancers, this procedure is seldom practiced in the European countries and the United States. But in the thought that IMN dissection combined with selective postoperative radiotherapy might increase disease-free or overall survival in these patients, this combined therapy in patients with medial breast cancers was evaluated. Thirty-five patients submitted to IMN dissection with extrapleural method and 114 patients submitted to non-dissection were evaluated in this study. Postoperative prophylactic radiotherapy (to IMN and supraclavicular lymph nodes) was administered to patients with histologically positive IMN or more than 4 of axillary lymph nodes. The dose of irradiation was 5000 to 5100 cGy given in 5 to 6 weeks. Patient characteristics in the two groups did not reveal any significant difference statistically. Statistical analysis was carried out both on disease-free survival and overall survival, computed from the date of radical surgery, by use of the Kaplan-Meier method. Both groups of survival were compared, using the Logrank test. The frequency of IMN metastasis is significantly associated with the one of axillary lymph nodes metastasis (p=0.03). The analysis of the percent disease-free survival related to the presence or absence of IMN dissection failed to reveal any significant difference (10 years of disease-free survival rate 56.1% and 74.5%, respectively). In the same way, the analysis of the percent overall survival failed to reveal any significant difference (10 years overall survival rate 58.8% and 80.4%, respectively). (author)

  11. Mammary gland stem cells

    DEFF Research Database (Denmark)

    Fridriksdottir, Agla J R; Petersen, Ole W; Rønnov-Jessen, Lone

    2011-01-01

    Distinct subsets of cells, including cells with stem cell-like properties, have been proposed to exist in normal human breast epithelium and breast carcinomas. The cellular origins of epithelial cells contributing to gland development, tissue homeostasis and cancer are, however, still poorly...... understood. The mouse is a widely used model of mammary gland development, both directly by studying the mouse mammary epithelial cells themselves and indirectly, by studying development, morphogenesis, differentiation and carcinogenesis of xenotransplanted human breast epithelium in vivo. While in early...... studies, human or mouse epithelium was implanted as fragments into the mouse gland, more recent technical progress has allowed the self-renewal capacity and differentiation potential of distinct cell populations or even individual cells to be interrogated. Here, we review and discuss similarities...

  12. Dehydroepiandrosterone (DHEA) Feeding Protects Liver Steatosis in Obese Breast Cancer Rat Model.

    Science.gov (United States)

    Hakkak, Reza; Bell, Andrea; Korourian, Soheila

    2017-03-20

    Obesity is a major health problem in the US and globally. Obesity is associated with the risk of cardiovascular disease, type 2 diabetes, cancers, hyperlipidemia, and liver steatosis development. Dehydroepiandrosterone (DHEA) is a dietary supplement used as an anti-obesity supplement. Previously, we reported that DHEA feeding protects 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors. The objectives of this study were to investigate the effects of obesity and DHEA feeding on liver steatosis, body weight gain, and serum DHEA, DHEA sulfate (DHEA-S), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-3) levels. Female Zucker rats were randomly assigned to either a control diet or a control diet with DHEA supplementation for 155 days. Livers were collected for histological examination. Serum was collected to measure DHEA, DHEA-S, IGF-1, and IGFBP-3. Our results show that DHEA-fed rats had significantly less liver steatosis (p DHEA feeding caused significant decreases (p DHEA and DHEA-S. Our results suggest that DHEA feeding can protect against liver steatosis by reducing body weight gain and modulating serum IGF-1 and IGFBP-3 levels in an obese breast cancer rat model.

  13. Novel Cytochrome P45OlBl as a Mammary Cancer Risk Factor.

    Science.gov (United States)

    1998-07-01

    Transfor apparatus (Hoeffer Scientific, San Francisco, CA) at 250 mA for 2 h. The membranes were blocked with 5% Carnation nonfat dry milk in PBST (PBS...Jordan and John Pink (Northwestern University, University of Wisconsin Comprehensive Cancer Center)(23, 24). ICI 182,780 was obtained from Dr. Alan...responsiveness in MDA-MB-231 human breast cancer cells is associated with ARNT expression. Fund. Appl. Toxicol, 36, 130. (23) Pink , J.J., Bilimoria

  14. NY-BR-1 protein expression in breast carcinoma: a mammary gland differentiation antigen as target for cancer immunotherapy.

    Science.gov (United States)

    Theurillat, Jean-Philippe; Zürrer-Härdi, Ursina; Varga, Zsuzsanna; Storz, Martina; Probst-Hensch, Nicole M; Seifert, Burkhardt; Fehr, Mathias K; Fink, Daniel; Ferrone, Soldano; Pestalozzi, Bernhard; Jungbluth, Achim A; Chen, Yao-Tseng; Jäger, Dirk; Knuth, Alexander; Moch, Holger

    2007-11-01

    NY-BR-1 is a recently identified differentiation antigen of the mammary gland. To use NY-BR-1 for T-cell-based immunotherapy, analysis of its co-expression with HLA class I antigens is required. In the present tissue microarray study, primary breast cancers (n = 1,444), recurrences (n = 88), lymph node (n = 525) and distant metastases (n = 91) were studied for NY-BR-1 expression using a novel monoclonal antibody. NY-BR-1 expression was compared with prognosis, estrogen receptor, HER2-status, EGFR and HLA class I antigen expression. NY-BR-1 was more frequently expressed in grade 1 (82%) than in grade 2 (69%) and grade 3 (46%) carcinomas (P < 0.0001). Moreover, NY-BR-1 expression correlated directly with estrogen receptor expression (P < 0.0001) and inversely correlated with HER2-status and EGFR expression (P < 0.0001 for both). Considering high expression level of co-expression, 198/1,321 (15%) primary breast carcinomas and 4/65 (6%) distant metastases expressed NY-BR-1 and HLA class I, suggesting that active immunotherapy can be applied to about 10% of breast cancer patients. Survival analysis showed an association of NY-BR-1 expression with better patient outcome (P = 0.015). No difference between NY-BR-1 expression of primary tumors and metastases could be found, indicating that the presence of NY-BR-1 in metastases can be deduced from their corresponding primary. Forty-three paired biopsies taken from patients before and after chemotherapy suggest that NY-BR-1 expression is not influenced by preceding chemotherapy (kappa = 0.89, P < 0.0001). In summary, the co-expression of NY-BR-1 with HLA class I antigens and its expression in metastases without modification by chemotherapy suggest that NY-BR-1 targeted immunotherapy represents a viable strategy in addition to other targeted cancer drug therapies of breast cancer.

  15. Role of PTPase LAR in EGF Receptor in the Mammary Gland

    Science.gov (United States)

    2003-06-01

    A.T.C.C. Ln 3 rat mammary adenocarcinoma cells were a Western blotting as described above. generous gift from Dr Carl McGary (University of Rochester... Whitaker Cardiovascular Institute at the Boston University School of Medicine and Dr. Young Whang from the Lineberger Comprehensive Cancer Center at...targeting in therapy -resistant human tumors. Drug Resist. Updat. 5, 11-18. 8. Liu, Y., and Rohrschneider, L. R. (2002). The gift of Gab. FEBS Lett. 515, 1

  16. Behavioral, medical imaging and histopathological features of a new rat model of bone cancer pain.

    Directory of Open Access Journals (Sweden)

    Louis Doré-Savard

    Full Text Available Pre-clinical bone cancer pain models mimicking the human condition are required to respond to clinical realities. Breast or prostate cancer patients coping with bone metastases experience intractable pain, which affects their quality of life. Advanced monitoring is thus required to clarify bone cancer pain mechanisms and refine treatments. In our model of rat femoral mammary carcinoma MRMT-1 cell implantation, pain onset and tumor growth were monitored for 21 days. The surgical procedure performed without arthrotomy allowed recording of incidental pain in free-moving rats. Along with the gradual development of mechanical allodynia and hyperalgesia, behavioral signs of ambulatory pain were detected at day 14 by using a dynamic weight-bearing apparatus. Osteopenia was revealed from day 14 concomitantly with disorganization of the trabecular architecture (µCT. Bone metastases were visualized as early as day 8 by MRI (T(1-Gd-DTPA before pain detection. PET (Na(18F co-registration revealed intra-osseous activity, as determined by anatomical superimposition over MRI in accordance with osteoclastic hyperactivity (TRAP staining. Pain and bone destruction were aggravated with time. Bone remodeling was accompanied by c-Fos (spinal and ATF3 (DRG neuronal activation, sustained by astrocyte (GFAP and microglia (Iba1 reactivity in lumbar spinal cord. Our animal model demonstrates the importance of simultaneously recording pain and tumor progression and will allow us to better characterize therapeutic strategies in the future.

  17. Expression of prolactin receptors in normal canine mammary tissue, canine mammary adenomas and mammary adenocarcinomas

    Directory of Open Access Journals (Sweden)

    Michel Erika

    2012-05-01

    Full Text Available Abstract Background Mammary tumors represent the most common neoplastic disease in female dogs. Recently, the promoting role of prolactin (PRL in the development of human breast carcinoma has been shown. Possible proliferative, anti-apoptotic, migratory and angiogenic effects of PRL on human mammary cancer cells in vitro and in vivo were suggested. The effects of PRL are mediated by its receptor, and alterations in receptor expression are likely to play a role in tumor development. Currently, not much data is available about prolactin receptor (PRLR expression in canine mammary tumors. To set the basis for investigations on the role of PRL in mammary tumorigenesis in this species, prolactin receptor expression was evaluated by semi-quantitative real time PCR and immunohistochemistry on 10 formalin-fixed, paraffin-embedded samples each of canine non-neoplastic mammary tissue, mammary adenomas and adenocarcinomas. Results The highest PRLR expression levels were found in normal mammary tissue, while adenomas, and to an even higher degree adenocarcinomas, showed a significant decrease in prolactin receptor expression. Compared to normal tissue, PRLR mRNA was reduced 2.4 fold (p = 0.0261 in adenomas and 4.8 fold (p = 0.008 in adenocarcinomas. PRLR mRNA expression was significantly lower in malignant than in benign lesions (p = 0.0165. Immunohistochemistry demonstrated PRLR expression in all three tissue types with signals mostly limited to epithelial cells. Conclusions Malignant transformation of mammary tissue was associated with a decline in prolactin receptor expression. Further studies are warranted to address the functional significance of this finding.

  18. CO-induction of rat intestinal cancers with 7,12-dimethylbenz(a)anthracene and medroxyprogesterone acetate

    Energy Technology Data Exchange (ETDEWEB)

    Hass, G.; Galt, R.; Coogan, P.; Friese, J.

    1986-03-01

    Medroxy progesterone acetate (P) is a progestin used for treatment of sex hormone-dependent human cancers. In a study of its action, 7,12-dimethyl-benz(a)anthracene (DMBA) was given, i.g., to 50-52 day old intact or gonadectomized Sprague-Dawley rats of both sexes. Groups were given 0, 5, 25 or 100 mg of P +/- 2, .5, .1, .01 or .001 mg of 17 beta estradiol (E2), s.c., each week for 12-36 weeks. Those given P often developed, independent of sex or gonadectomy, multiple intestinal adenomas and carcinomas, especially in the jejunum. At doses of P tumor incidence was as follows: 0 mg, 2/63; 5 mg, 18/96; 25 mg, 35/57; 100 mg, 72/155. Combinations of P with doses of E2 at 2, .5 or .1 mg reduced tumor incidence 65%. At 25 or 100 mg doses of P, DMBA induction of mammary tumors was inhibited, while atrophy of ovaries and adrenal cortex was impressive. Hence, this is the only progestin, which favors DMBA induction of tumors of the rat intestine, while extinguishing mammary tumors. This matter may bear on presence of hormone receptors in human colo-rectal cancers.

  19. Distinct stem cells contribute to mammary gland development and maintenance.

    Science.gov (United States)

    Van Keymeulen, Alexandra; Rocha, Ana Sofia; Ousset, Marielle; Beck, Benjamin; Bouvencourt, Gaëlle; Rock, Jason; Sharma, Neha; Dekoninck, Sophie; Blanpain, Cédric

    2011-10-09

    The mammary epithelium is composed of several cell lineages including luminal, alveolar and myoepithelial cells. Transplantation studies have suggested that the mammary epithelium is maintained by the presence of multipotent mammary stem cells. To define the cellular hierarchy of the mammary gland during physiological conditions, we performed genetic lineage-tracing experiments and clonal analysis of the mouse mammary gland during development, adulthood and pregnancy. We found that in postnatal unperturbed mammary gland, both luminal and myoepithelial lineages contain long-lived unipotent stem cells that display extensive renewing capacities, as demonstrated by their ability to clonally expand during morphogenesis and adult life as well as undergo massive expansion during several cycles of pregnancy. The demonstration that the mammary gland contains different types of long-lived stem cells has profound implications for our understanding of mammary gland physiology and will be instrumental in unravelling the cells at the origin of breast cancers.

  20. Dietary Regulation of PTEN Signaling and Mammary Tumor Initiating Cells: Implications for Breast Cancer Prevention

    Science.gov (United States)

    2012-07-01

    the end stages of at least two different lines of genetic evolution. J Pathol 2001;194:165–70. [9] Polyak K. Is breast tumor progression really...Gupta GP, Massague J. Cancer metastasis: building a framework. Cell 2006;127: 679–95. [18] Polyak K, Haviv I, Campbell IG. Co-evolution of tumor cells...409–418. 7. Polyak ,K. (2007) Breast cancer: origins and evolution. J. Clin. Invest., 117, 3155–3163. 8. Troisi,R. et al. (2007) Exploring the

  1. Growth hormone and insulin-like growth factor-I in the transition from normal mammary development to preneoplastic mammary lesions.

    Science.gov (United States)

    Kleinberg, David L; Wood, Teresa L; Furth, Priscilla A; Lee, Adrian V

    2009-02-01

    Adult female mammary development starts at puberty and is controlled by tightly regulated cross-talk between a group of hormones and growth factors. Although estrogen is the initial driving force and is joined by luteal phase progesterone, both of these hormones require GH-induced IGF-I in the mammary gland in order to act. The same group of hormones, when experimentally perturbed, can lead to development of hyperplastic lesions and increase the chances, or be precursors, of mammary carcinoma. For example, systemic administration of GH or IGF-I causes mammary hyperplasia, and overproduction of IGF-I in transgenic animals can cause the development of usual or atypical hyperplasias and sometimes carcinoma. Although studies have clearly demonstrated the transforming potential of both GH and IGF-I receptor in cell culture and in animals, debate remains as to whether their main role is actually instructive or permissive in progression to cancer in vivo. Genetic imprinting has been shown to occur in precursor lesions as early as atypical hyperplasia in women. Thus, the concept of progression from normal development to cancer through precursor lesions sensitive to hormones and growth factors discussed above is gaining support in humans as well as in animal models. Indeed, elevation of estrogen receptor, GH, IGF-I, and IGF-I receptor during progression suggests a role for these pathways in this process. New agents targeting the GH/IGF-I axis may provide a novel means to block formation and progression of precursor lesions to overt carcinoma. A novel somatostatin analog has recently been shown to prevent mammary development in rats via targeted IGF-I action inhibition at the mammary gland. Similarly, pegvisomant, a GH antagonist, and other IGF-I antagonists such as IGF binding proteins 1 and 5 also block mammary gland development. It is, therefore, possible that inhibition of IGF-I action, or perhaps GH, in the mammary gland may eventually play a role in breast cancer

  2. Isolation of Estrogen Regulated Genes from MCF-7 Human Mammary Cancer Cells

    Science.gov (United States)

    1990-07-13

    dramatic example of an anri-oncogene. The neoplastic phenotype of retinoblastoma, prostate cancer, or osteosarcoma can be suppressed by introducing an...which is down-regulated by esttogen tteattnent), and was kindly made avaUable by Dr Carl Dieffenbach and Dr. Robert Silverman (Department of Radiology

  3. Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells

    Science.gov (United States)

    Wang, Yuan Yuan; Attané, Camille; Milhas, Delphine; Dirat, Béatrice; Dauvillier, Stéphanie; Guerard, Adrien; Gilhodes, Julia; Lazar, Ikrame; Alet, Nathalie; Laurent, Victor; Le Gonidec, Sophie; Hervé, Caroline; Bost, Frédéric; Ren, Guo Sheng; Bono, Françoise; Escourrou, Ghislaine; Prentki, Marc; Nieto, Laurence; Valet, Philippe

    2017-01-01

    In breast cancer, a key feature of peritumoral adipocytes is their loss of lipid content observed both in vitro and in human tumors. The free fatty acids (FFAs), released by adipocytes after lipolysis induced by tumor secretions, are transferred and stored in tumor cells as triglycerides in lipid droplets. In tumor cell lines, we demonstrate that FFAs can be released over time from lipid droplets through an adipose triglyceride lipase–dependent (ATGL-dependent) lipolytic pathway. In vivo, ATGL is expressed in human tumors where its expression correlates with tumor aggressiveness and is upregulated by contact with adipocytes. The released FFAs are then used for fatty acid β-oxidation (FAO), an active process in cancer but not normal breast epithelial cells, and regulated by coculture with adipocytes. However, in cocultivated cells, FAO is uncoupled from ATP production, leading to AMPK/acetyl-CoA carboxylase activation, a circle that maintains this state of metabolic remodeling. The increased invasive capacities of tumor cells induced by coculture are completely abrogated by inhibition of the coupled ATGL-dependent lipolysis/FAO pathways. These results show a complex metabolic symbiosis between tumor-surrounding adipocytes and cancer cells that stimulate their invasiveness, highlighting ATGL as a potential therapeutic target to impede breast cancer progression. PMID:28239646

  4. Rosiglitazone synergizes anticancer activity of cisplatin and reduces its nephrotoxicity in 7, 12-dimethyl benz{a}anthracene (DMBA induced breast cancer rats

    Directory of Open Access Journals (Sweden)

    Tikoo Kulbhushan

    2009-04-01

    Full Text Available Abstract Background Antineoplastic drug cisplatin remains the drug of choice for various solid tumours including breast cancer. But dose dependent nephrotoxicity is the major drawback in majority of platinum based chemotherapy regimens. Recent reports have shown that inflammatory pathways are the main offender for cisplatin induced nephrotoxicity. The present study was undertaken to assess the effect of rosiglitazone, a PPARγ agonist and an anti-inflammatory agent, on cisplatin induced nephrotoxicity, and its anticancer activity in DMBA induced breast cancer rats. Methods Mammary tumours were induced in female Sprague-Dawley rats by feeding orally with dimethylbenz [a]anthracene (DMBA (60 mg/kg. Cisplatin induced nephropathy was assessed by measurements of blood urea nitrogen, albumin and creatinine levels. Posttranslational modifications of histone H3, mitogen-activated protein (MAP kinase p38 expression and PPAR-γ expression were examined by western blotting. Results Our data shows involvement of TNF-α in preventing cisplatin induced nephrotoxicity by rosiglitazone. Rosiglitazone pre-treatment to cisplatin increases the expression of p38, PPAR-γ in mammary tumours and shows maximum tumour reduction. Furthermore, cisplatin induced changes in histone acetylation, phosphorylation and methylation of histone H3 in mammary tumours was ameliorated by pre-treatment of rosiglitazone. Suggesting, PPAR-γ directly or indirectly alters aberrant gene expression in mammary tumours by changing histone modifications. Conclusion To best of our knowledge this is the first report which shows that pre-treatment of rosiglitazone synergizes the anticancer activity of cisplatin and minimizes cisplatin induced nephrotoxicity in DMBA induced breast cancer.

  5. Analysis of microRNA expression in canine mammary cancer stem-like cells indicates epigenetic regulation of transforming growth factor-beta signaling.

    Science.gov (United States)

    Rybicka, A; Mucha, J; Majchrzak, K; Taciak, B; Hellmen, E; Motyl, T; Krol, M

    2015-02-01

    Cancer stem cells (CSCs) display both unique self-renewal ability as well as the ability to differentiate into many kinds of cancer cells. They are supposed to be responsible for cancer initiation, recurrence and drug resistance. Despite the fact that a variety of methods are currently employed in order to target CSCs, little is known about the regulation of their phenotype and biology by miRNAs. The aim of our study was to assess miRNA expression in canine mammary cancer stem-like cells (expressing stem cell antigen 1, Sca-1; CD44 and EpCAM) sorted from canine mammary tumour cell lines (CMT-U27, CMT-309 and P114). In order to prove their stem-like phenotype, we conducted a colony formation assay that confirmed their ability to form colonies from a single cell. Profiles of miRNA expression were investigated using Agilent custom-designed microarrays. The results were further validated by real-time rt-PCR analysis of expression of randomly selected miRNAs. Target genes were indicated and analysed using Kioto Encyclopedia of Genes and Genomes (KEGG) and BioCarta databases. The results revealed 24 down-regulated and nine up-regulated miRNAs in cancer stem-like cells compared to differentiated tumour cells. According to KEGG and BioCarta databases, target genes (n=240) of significantly down-regulated miRNAs were involved in transforming growth factor-beta signaling, mitogen-activated protein kinases (MAPK) signaling pathway, anaplastic lymphoma receptor tyrosine kinase (ALK) and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1A) pathways. The analysis of single-gene overlapping with different pathways showed that the most important genes were: TGFBR1, TGFBR2, SOS1, CHUK, PDGFRA, SMAD2, MEF2A, MEF2C and MEF2D. All of them are involved in tumor necrosis factor-beta signaling and may indicate its important role in cancer stem cell biology. Increased expression of TGFBR2, SMAD2, MEF2A and MEF2D in canine mammary cancer stem-like cells was further

  6. High-Fat, High-Calorie Diet Enhances Mammary Carcinogenesis and Local Inflammation in MMTV-PyMT Mouse Model of Breast Cancer

    OpenAIRE

    Sarah Cowen; McLaughlin, Sarah L.; Gerald Hobbs; James Coad; Martin, Karen H.; Mark Olfert, I.; Linda Vona-Davis

    2015-01-01

    Epidemiological studies provide strong evidence that obesity and the associated adipose tissue inflammation are risk factors for breast cancer; however, the molecular mechanisms are poorly understood. We evaluated the effect of a high-fat/high-calorie diet on mammary carcinogenesis in the immunocompetent MMTV-PyMT murine model. Four-week old female mice (20/group) were randomized to receive either a high-fat (HF; 60% kcal as fat) or a low-fat (LF; 16% kcal) diet for eight weeks. Body weights ...

  7. Alterations of EGFR, p53 and PTEN that mimic changes found in basal-like breast cancer promote transformation of human mammary epithelial cells.

    Science.gov (United States)

    Pires, Maira M; Hopkins, Benjamin D; Saal, Lao H; Parsons, Ramon E

    2013-03-01

    Breast cancer can be classified into different molecular subtypes with varying clinical and pathological characteristics. The basal-like breast cancer subtype represents one of the most aggressive and lethal types of breast cancer, and due to poor mechanistic understanding, it lacks targeted therapy. Many basal-like breast cancer patient samples display alterations of established drivers of cancer development, including elevated expression of EGFR, p53 inactivating mutations and loss of expression of the tumor suppressor PTEN; however, their contribution to human basal-like breast cancer pathogenesis remains ill-defined. Using non-transformed human mammary epithelial cells, we set out to determine whether altering EGFR, p53 and PTEN in different combinations could contribute to basal-like breast cancer progression through transformation of cells. Altering PTEN in combination with either p53 or EGFR in contrast to any of the single alterations caused increased growth of transformed colonies in soft agar. Concomitantly modifying all three genes led to the highest rate of cellular proliferation and the greatest degree of anchorage-independent colony formation. Results from our effort to engineer a model of BBC expressing alterations of EGFR, p53 and PTEN suggest that these changes are cooperative and likely play a causal role in basal-like breast cancer pathogenesis. Consideration should be given to targeting EGFR and restoring p53 and PTEN signaling simultaneously as a strategy for treatment of this subtype of breast cancer.

  8. The gene expression profiles of canine mammary cancer cells grown with carcinoma-associated fibroblasts (CAFs as a co-culture in vitro

    Directory of Open Access Journals (Sweden)

    Król Magdalena

    2012-03-01

    Full Text Available Abstract Background It is supposed that fibroblasts present in tumour microenvironment increase cancer invasiveness and its ability to metastasize but the mechanisms have not been clearly defined yet. Thus, the current study was designed to assess changes in gene expression in five various cancer cell lines grown as a co-culture with the carcinoma-associated fibroblasts (CAFs in vitro. Results A carcinoma-associated fibroblast cell line was isolated from a canine mammary cancer. Then, a co-culture of cancer cells with the CAFs was established and maintained for 72 hrs. Having sorted the cells, a global gene expression in cancer cells using DNA microarrays was examined. The analysis revealed an up-regulation of 100 genes and a down-regulation of 106 genes in the cancer cells grown as a co-culture with the CAFs in comparison to control conditions. The PANTHER binomial statistics tool was applied to determine statistically over-manifested pathways (p Conclusion The results of the current study showed that the co-culturing of cancer cells and the CAFs caused significant changes to the cancer gene expression. The presence of the CAFs in a microenvironment of cancer cells promotes adhesion, angiogenesis and EMT.

  9. Hormonal prevention of breast cancer: Mimicking the protective effect of pregnancy

    OpenAIRE

    1999-01-01

    Full term pregnancy early in life is the most effective natural protection against breast cancer in women. Rats treated with chemical carcinogen are similarly protected by a previous pregnancy from mammary carcinogenesis. Proliferation and differentiation of the mammary gland does not explain this phenomenon, as shown by the relative ineffectiveness of perphenazine, a potent mitogenic and differentiating agent. Here, we show that short term treatment of nulliparous rats with pregnancy levels ...

  10. Age-dependent change in biological characteristics of stem cells in radiation-induced mammary carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Shimada, Yoshiya; Nishimura, Mayumi; Kakinuma, Shizuko; Imaoka, Tatsuhiko [National Institute of Radiological Sciences, Anagawa, Chiba (Japan); Yasukawa-Barnes, Jane; Gould, Michael N.; Clifton, Kelly H. [Univ. of Wisconsin, Department of Human Oncology, Madison, WI (United States)

    2003-07-01

    If you ask what types of cells are the targets for carcinogenesis, a popular answer would be that cancer arises from stem cells. Stem cells are cells that are capable of both self-renewal and generation of differentiated progenies. If the hypothesis of 'cancer as stem cell disease' is correct, the risk of carcinogenesis should be a function of the number of stem cells and their responsiveness of carcinogen-induced damage. In the present study, we addressed the feasibility of this hypothesis using the rat mammary carcinogenesis model. One of the important conclusions emerging from studies on atomic bomb survivors concerns age-related changes in the susceptibility to breast cancer. The relative risk of breast cancer is very high among women exposed to ionizing radiation before or during puberty, and it decreases thereafter. Little information is available, however, on age-related changes in the radiobiological nature of mammary stem cells. We examined age-associated changes in the number of mammary stem-like cells (clonogens) and their susceptibility to radiation in terms of cell death and carcinogenic initiation frequency. The results were as follows. (1) During the prepubertal period, the total number of mammary clonogens per rat increased exponentially with a population doubling time of {approx}4 days. After puberty, the doubling time lengthened to {approx}30 days. The total number of clonogens in abdominal and inguinal mammary glands was {approx}200 in 2-week-old rats, while it was {approx}5600 in 8-week-old rats. (2) The survival curves of clonogenic cells after irradiation indicated that radiation sensitivity of the cells before and during puberty was much higher than after puberty. (3) The initiation frequency of the clonogens from prepubertal rats after 5 Gy irradiation was four times higher than that of the clonogens from post-pubertal rats. These results suggest that changes in the number of stem cells and their radiobiological characteristics

  11. Detection of in situ mammary cancer in a transgenic mouse model: in vitro and in vivo MRI studies demonstrate histopathologic correlation

    Energy Technology Data Exchange (ETDEWEB)

    Jansen, S A; Fan, X; Zamora, M; Foxley, S; River, J; Newstead, G M; Karczmar, G S [Department of Radiology, University of Chicago, 5841 S Maryland Avenue, MC 2026, Chicago, IL 60637 (United States); Conzen, S D [Department of Medicine and Ben May Department for Cancer Research, University of Chicago, 5841 S Maryland Ave, MC 2115, Chicago, IL 60637 (United States); Krausz, T [Department of Pathology, University of Chicago, 5841 S Maryland Avenue, MC 6101, Chicago, IL 60637 (United States)], E-mail: gskarczm@uchicago.edu

    2008-10-07

    Improving the prevention and detection of preinvasive ductal carcinoma in situ (DCIS) is expected to lower both morbidity and mortality from breast cancer. Transgenic mouse models can be used as a 'test bed' to develop new imaging methods and to evaluate the efficacy of candidate preventive therapies. We hypothesized that despite its microscopic size, early murine mammary cancer, including DCIS, might be accurately detected by MRI. C3(1) SV40 TAg female mice (n = 23) between 10 and 18 weeks of age were selected for study. Eleven mice were subjected to in vitro imaging using a T{sub 2}-weighted spin echo sequence and 12 mice were selected for in vivo imaging using a T{sub 1}-weighted gradient echo, a T{sub 2}-weighted spin echo and high spectral and spatial resolution imaging sequences. The imaged glands were carefully dissected, formalin fixed and paraffin embedded, and then H and E stained sections were obtained. The ratio of image-detected versus histologically detected cancers was obtained by reviewing the MR images and H and E sections independently and using histology as the gold standard. MR images were able to detect 12/12 intramammary lymph nodes, 1/1 relatively large ({approx}5 mm) tumor, 17/18 small ({approx}1 mm) tumors and 13/16 ducts distended with DCIS greater than 300 {mu}m. Significantly, there were no false positives-i.e., image detection always corresponded to a histologically detectable cancer in this model. These results indicate that MR imaging can reliably detect both preinvasive in situ and early invasive mammary cancers in mice with high sensitivity. This technology is an important step toward the more effective use of non-invasive imaging in pre-clinical studies of breast cancer prevention, detection and treatment.

  12. Detection of in situ mammary cancer in a transgenic mouse model: in vitro and in vivo MRI studies demonstrate histopathologic correlation

    Science.gov (United States)

    Jansen, S. A.; Conzen, S. D.; Fan, X.; Krausz, T.; Zamora, M.; Foxley, S.; River, J.; Newstead, G. M.; Karczmar, G. S.

    2008-10-01

    Improving the prevention and detection of preinvasive ductal carcinoma in situ (DCIS) is expected to lower both morbidity and mortality from breast cancer. Transgenic mouse models can be used as a 'test bed' to develop new imaging methods and to evaluate the efficacy of candidate preventive therapies. We hypothesized that despite its microscopic size, early murine mammary cancer, including DCIS, might be accurately detected by MRI. C3(1) SV40 TAg female mice (n = 23) between 10 and 18 weeks of age were selected for study. Eleven mice were subjected to in vitro imaging using a T2-weighted spin echo sequence and 12 mice were selected for in vivo imaging using a T1-weighted gradient echo, a T2-weighted spin echo and high spectral and spatial resolution imaging sequences. The imaged glands were carefully dissected, formalin fixed and paraffin embedded, and then H&E stained sections were obtained. The ratio of image-detected versus histologically detected cancers was obtained by reviewing the MR images and H&E sections independently and using histology as the gold standard. MR images were able to detect 12/12 intramammary lymph nodes, 1/1 relatively large (~5 mm) tumor, 17/18 small (~1 mm) tumors and 13/16 ducts distended with DCIS greater than 300 µm. Significantly, there were no false positives—i.e., image detection always corresponded to a histologically detectable cancer in this model. These results indicate that MR imaging can reliably detect both preinvasive in situ and early invasive mammary cancers in mice with high sensitivity. This technology is an important step toward the more effective use of non-invasive imaging in pre-clinical studies of breast cancer prevention, detection and treatment.

  13. Mammary phenotypic expression induced in epidermal cells by embryonic mammary mesenchyme.

    Science.gov (United States)

    Cunha, G R; Young, P; Christov, K; Guzman, R; Nandi, S; Talamantes, F; Thordarson, G

    1995-01-01

    The goal of this research was to establish methods for inducing mammary epithelial differentiation from nonmammary epithelium. For this purpose, mid-ventral or dorsal epidermis (skin epithelium; SKE) from 13-day rat or mouse embryos was associated with 13-day embryonic mouse mammary mesenchyme (mammary gland mesenchyme; MGM) (mouse MGM+rat or mouse SKE). The resultant MGM+SKE recombinants as well as controls (homotypic mouse mammary recombinants, homotypic mouse skin recombinants and mouse mammary mesenchyme by itself) were grafted under the renal capsule of syngeneic or athymic female nude mouse hosts. Most female hosts were induced to undergo lactogenesis by grafting an adult pituitary which elicited a state of hyperprolactinemia. Tissue recombinants of mouse MGM+rat or mouse SKE grown for 1 month in vivo formed a hair-bearing keratinized skin from which mammary ductal structures extended into the mesenchyme. The ducts were composed of columnar luminal epithelial cells as well as basal, actin-positive myoepithelial cells. When grown in pituitary-grafted hosts, the ductal epithelial cells expressed casein and alpha-lactalbumin as judged by immunocytochemistry. The expression of caseins in MGM+SKE recombinants was confirmed by Western blot. The epithelial cells in mouse MGM+rat SKE recombinants expressing milk proteins were shown to be rat cells while the surrounding connective tissue was composed of mouse cells based upon staining with Hoechst dye 33258. Using mammary-specific markers, these studies confirmed the earlier morphological studies of Propper and unequivocally demonstrated for the first time that embryonic mammary mesenchyme can induce morphological and functional mammary differentiation from nonmammary epithelium.

  14. Effects of maternal exposure to cow´s milk high or low in isoflavones on carcinogen-induced mammary tumorigenesis among rat offspring

    DEFF Research Database (Denmark)

    Nielsen, Tina Skau; Purup, Stig; Warri, A

    2011-01-01

    . No differences in maternal serum estradiol (P = 0.19) and IGF-1 levels (P = 0.15) at GD 19 or birth weight among the milk and water groups were seen, but estradiol, and IGF-1 levels and birth weight were numerically higher in the LIM than in the HIM group. Puberty onset occurred earlier in the LIM offspring than......We investigated whether maternal exposure during pregnancy to cow's milk containing endogenous estrogens and insulin like growth factor 1 (IGF-1) and either high or low levels of isoflavones from dietary legumes (HIM and LIM, respectively) affected carcinogen-induced mammary carcinogenesis...... to LIM in utero, did not exhibit increased breast cancer risk, despite having higher estradiol and IGF-1 environment and consequently earlier puberty onset. These results indicate that the phytochemical content in the cow's milk, consumed by a pregnant dam, determines how milk affects the offspring....

  15. ERBB2 in cat mammary neoplasias disclosed a positive correlation between RNA and protein low expression levels: a model for erbB-2 negative human breast cancer.

    Directory of Open Access Journals (Sweden)

    Sara Santos

    Full Text Available Human ERBB2 is a proto-oncogene that codes for the erbB-2 epithelial growth factor receptor. In human breast cancer (HBC, erbB-2 protein overexpression has been repeatedly correlated with poor prognosis. In more recent works, underexpression of this gene has been described in HBC. Moreover, it is also recognised that oncogenes that are commonly amplified or deleted encompass point mutations, and some of these are associated with HBC. In cat mammary lesions (CMLs, the overexpression of ERBB2 (27%-59.6% has also been described, mostly at the protein level and although cat mammary neoplasias are considered to be a natural model of HBC, molecular information is still scarce. In the present work, a cat ERBB2 fragment, comprising exons 10 to 15 (ERBB2_10-15 was achieved for the first time. Allelic variants and genomic haplotype analyses were also performed, and differences between normal and CML populations were observed. Three amino acid changes, corresponding to 3 non-synonymous genomic sequence variants that were only detected in CMLs, were proposed to damage the 3D structure of the protein. We analysed the cat ERBB2 gene at the DNA (copy number determination, mRNA (expression levels assessment and protein levels (in extra- and intra protein domains in CML samples and correlated the last two evaluations with clinicopathological features. We found a positive correlation between the expression levels of the ERBB2 RNA and erbB-2 protein, corresponding to the intracellular region. Additionally, we detected a positive correlation between higher mRNA expression and better clinical outcome. Our results suggest that the ERBB2 gene is post-transcriptionally regulated and that proteins with truncations and single point mutations are present in cat mammary neoplastic lesions. We would like to emphasise that the recurrent occurrence of low erbB-2 expression levels in cat mammary tumours, suggests the cat mammary neoplasias as a valuable model for erbB-2

  16. Reduced metastasis of transgenic mammary cancer in urokinase-deficient mice

    DEFF Research Database (Denmark)

    Almholt, Kasper; Lund, L.R.; Rygaard, Jørgen

    2005-01-01

    A prominent phenotype of plasmin deficiency in mice is reduced metastasis in the MMTV-PymT transgenic breast cancer model. Proteolytically active plasmin is generated from inactive plasminogen by one of 2 activators, uPA or tPA. We now find that uPA deficiency alone significantly reduces metastasis...... >7-fold in the MMTV-PymT model. We studied a cohort of 55 MMTV-PymT transgenic mice, either uPA-deficient or wild-type controls. Tumor incidence, latency, growth rate and final primary tumor burden were not significantly affected by uPA deficiency. In contrast, average lung metastasis volume...

  17. Roles of Breast Cancer Susceptibility Genes BRCA’s in Mammary Epithelial Cell Differentiation

    Science.gov (United States)

    2006-03-01

    associated factor 3 - 3.0 IFNAR1 AA133989 interferon (alpha, beta and omega) receptor 1 -3.1 PDXK AW449022 pyridoxal ( pyridoxine , vitamin B6...IFNAR1 AA133989 Interferon (, , and ) receptor 1 3.1 PDXK AW449022 Pyridoxal ( pyridoxine , vitamin B6) kinase 4.0 HTATIP2 BC002439 HIV-1 Tat...evaluate the risk of breast cancer. N Engl J Med 336, 1409-1415. 26 Cullmann, G., Fien, K., Kobayashi, R., and Stillman, B. (1995). Characterization

  18. Differentiation and cancer in the mammary gland: shedding light on an old dichotomy

    DEFF Research Database (Denmark)

    Petersen, Ole William; Rønnov-Jessen, L; Weaver, V M;

    1998-01-01

    In this brief review, the development of breast cancer is discussed from the vantage of phenotypic differentiation, similar to what has been considered over the years for leukemias and melanomas, both of which express easily visible differentiation markers (Hart and Easty, 1991; Clarke et al., 1995......; Lynch, 1995; Sachs, 1996; Sledge, 1996). The review is divided into a theoretical background for human breast differentiation and a discussion of recent experimental results in our laboratories with differentiation of breast epithelial cells. In the theoretical background, in situ markers...... of differentiation of normal breast and carcinomas are discussed with emphasis on their possible implications for tumor therapy. So far, most of the emphasis regarding differentiation therapy of tumors has been focused on the possible action of soluble factors, such as colony-stimulating factors in leukemias...

  19. Boldine Inhibits Mouse Mammary Carcinoma In Vivo and Human MCF-7 Breast Cancer Cells In Vitro.

    Science.gov (United States)

    Tomšík, Pavel; Mičuda, Stanislav; Muthná, Darina; Čermáková, Eva; Havelek, Radim; Rudolf, Emil; Hroch, Miloš; Kadová, Zuzana; Řezáčová, Martina; Ćmielová, Jana; Živný, Pavel

    2016-11-01

    Boldine is an aporphine alkaloid widely consumed in the folk medicine of some regions. Its anticancer potential has been shown but not yet elucidated. We compared the antitumor effect of orally and parenterally applied boldine in mice bearing solid Ehrlich tumor. We also explored the effects of boldine on breast adenocarcinoma MCF-7 cells in vitro. Repeated i. p. injections of 30, 60, or 90 mg boldine/kg, either alone or combined with doxorubicin, slowed tumor growth in vivo. The latter two doses also prolonged the post-therapeutic survival of the mice. When fed food supplemented with boldine at a dose of 90 mg/kg, the tumor-bearing mice survived significantly longer, but there was no effect on tumor size. Interestingly, continuous p. o. administration did not produce detectable levels of boldine in plasma or tissue samples, in contrast to high but short-lived concentrations after i. p. injections. There was neither antagonism nor synergism between boldine and doxorubicin, except a possible synergism of i. p. boldine 90 mg/kg combined with doxorubicin when compared with doxorubicin alone.Boldine was cytotoxic to MCF-7 cells and reduced their viability and proliferation in vitro. Exposure to boldine decreased bromodeoxyuridine incorporation and histone H3 phosphorylation but did not induce apoptosis. Boldine treatment resulted in p38, ERK, and JNK activation in the mitogen-activated protein kinase pathway in a dose-dependent manner. Since bioavailability in mice seems to be different from that reported in rats, pharmacokinetic studies in humans are needed to evaluate the role of boldine in the beneficial effects of Boldo infusions. Georg Thieme Verlag KG Stuttgart · New York.

  20. Survey on Correlation between Eating Habits and Female Mammary Cancer%饮食习惯与女性乳腺癌关系调查

    Institute of Scientific and Technical Information of China (English)

    赵越

    2016-01-01

    目的:探究饮食习惯与女性乳腺癌的关系调查。方法2014年3月—2015年7月共选取1859例参加体检的女性体检者进行研究,对所有患者进行体检,并对所有体检人员进行饮食习惯资料收集,采用Logistic回归分析探讨对患者髋关节功能恢复的影响因素。结果按照体检结果将所有体检人员分为A﹑B两组,A组人员全为乳腺癌患者,共589例(31.08%),B组为健康人群,共1270例(68.32%)。两组患者在饮酒﹑豆制品﹑高脂食品﹑咖啡﹑茶﹑维生素方面均存在明显差异,(P<0.05)。将两组患者有差异的饮食习惯资料带入Logistic回归方程中计算,发现饮酒﹑豆制品﹑高脂食品﹑咖啡﹑茶﹑维生素均为女性乳腺癌的相关影响因素。结论为预防女性乳腺癌,应当为女性普及可降低乳腺癌防病率的饮食习惯。%Objective To survey the correlation between eating habits and female mammary cancer. Methods 1859 cases of females receiving the physical examination from March 2014 to June 2015 were selected for research, and all received the physical examination, and the data of eating habits of them were collected, and the influence factors of hip joint functional recovery of patients were analyzed and studied by the Logistic regression and analysis. Results All the physical examination staff were divided into the group A with 589 cases of patients with mammary cancer, accounting for 31.08%, and the group B with healthy people with 1270 cases, accounting for 68.32% according to the results,, and there were obvious differences in the drinking, bean products, high-fat food, coffee, tea and vitamin between the two groups, P<0.05, and the eating habits with difference were brought into the Logistic regression equation, and the results showed that the drinking, bean products, high-fat food, coffee, tea and vitamin were the related influence factors of female mammary cancer. Conclusion In order to prevent the female mammary

  1. Mouse Mammary Tumor Virus Molecular Biology and Oncogenesis

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    Susan R. Ross

    2010-09-01

    Full Text Available Mouse mammary tumor virus (MMTV, which was discovered as a milk‑transmitted, infectious cancer-inducing agent in the 1930s, has been used since that time as an animal model for the study of human breast cancer. Like other complex retroviruses, MMTV encodes a number of accessory proteins that both facilitate infection and affect host immune response. In vivo, the virus predominantly infects lymphocytes and mammary epithelial cells. High level infection of mammary epithelial cells ensures efficient passage of virus to the next generation. It also results in mammary tumor induction, since the MMTV provirus integrates into the mammary epithelial cell genome during viral replication and activates cellular oncogene expression. Thus, mammary tumor induction is a by-product of the infection cycle. A number of important oncogenes have been discovered by carrying out MMTV integration site analysis, some of which may play a role in human breast cancer.

  2. Effect of Semecarpus anacardium Linn. nut extract on mammary and hepatic expression of xenobiotic enzymes in DMBA-induced mammary carcinoma.

    Science.gov (United States)

    Mathivadhani, P; Shanthi, P; Sachdanandam, P

    2007-05-01

    Breast cancer is the major cause of cancer death in women worldwide. Environmental risk factors particularly genotoxic chemicals such as polycyclic aromatic hydrocarbons (PAH) are likely to account for a much higher mortality. Xenobiotic metabolising enzymes in breast tissue are potentially important determinants in both the susceptibility to the mutagenic effects of chemical carcinogens and in the response of breast tumors to chemotherapy. The well known carcinogen 7,12-dimethylbenz(a)anthrazene of PAH family was given (25mg/ml) orally by gastric intubation to induce mammary carcinoma in Sprague-Dawley rats. Increased level of cytochromes (P(450), B(5)), EROD, PROD activities, Phase I biotransformation enzymes (NADPH-cytochrome (P(450)) reductase, NADPH-cytochrome (b(5)) reductase, epoxide hydrolase) and expression of CYP1A1, CYP1A2 and CYP1B1 in liver and breast tissue microsome were documented in DMBA treated group. Phase II enzyme activities (glutathione-S-transferase, gluthatione peroxidase, gluatathione reductase, UDP-glucuronyl transferease) were decreased markedly in cancerous rats. The nut extract of Semecarpus anacardium was administered orally (200mg/kg body wt/day) to the mammary carcinoma rats for 14 days. Drug treatment restored back the altered Phase I and II biotransformation enzymes thus achieving complete detoxification of the carcinogen. These findings suggest that S. anacardium can effectively modulate the catabolism of xenobiotics in rats. Copyright © 2007. Published by Elsevier B.V.

  3. Modulating Effect of Hypnea musciformis (Red Seaweed) on Lipid Peroxidation, Antioxidants and Biotransforming Enzymes in 7,12-Dimethylbenz (a) Anthracene Induced Mammary Carcinogenesis in Experimental Animals

    Science.gov (United States)

    Balamurugan, Mohan; Sivakumar, Kathiresan; Mariadoss, Arokia Vijaya Anand; Suresh, Kathiresan

    2017-01-01

    Background: Breast cancer is the second most widespread diagnosed cancer and second leading cause of cancer death in women. Objective: The present work was carried out to evaluate the chemo preventive potential of Hypnea musciformis (ethanol extract) seaweed on oxidative stress markers, bio transforming enzymes, incidence of tumors, and pathological observation in 7,12-dimethylbenzanthracene (DMBA) exposed experimental mammary carcinogenesis. Materials and Methods: Female Sprague–Dawley rats were randomly divided into four groups. Rats in the group 1 served as control. Rats in the group 2 and 3 received a single subcutaneous injection of DMBA (25 mg/kg body weight (b.w)) in the mammary gland to develop mammary carcinoma. In addition, group 3 rats were orally administrated with 200 mg/kg between of H. musciformis along with DMBA injection and group 4 rats received ethanolic extract of H. musciformis every day orally (200 mg/kg b.w) throughout the experimental period of 16 weeks. Results: Our results revealed that treatment with H. musciformis ethanolic extract to DMBA treated rats significantly reduced the incidence of tumor and tumor volume as compared to DMBA alone treated rats. Moreover, our results showed imbalance in the activities/levels of lipid peroxidation by products, antioxidant enzymes, and bio transforming phase I and II enzymes in the circulation, liver and mammary tissues of DMBA treated rats which were significantly modulated to near normal on treatment with ethanolic extract of H. musciformis. All these alterations were supported by histochemical findings. Conclusion: The results obtained from this study suggest that chemo preventive potential of H. musciformis ethanol extract is probably due to their free radicals quenching effect and modulating potential of bio transforming enzymes during DMBA exposed experimental mammary carcinogenesis. SUMMARY DMBA is a source of well-established site specific carcinogenHypnea musciformis act as a free radical

  4. Milk fat conjugated linoleic acid (CLA) inhibits growth of human mammary MCF-7 cancer cells.

    Science.gov (United States)

    O'Shea, M; Devery, R; Lawless, F; Murphy, J; Stanton, C

    The relationship between growth and the antioxidant enzyme defence system in human MCF-7 (breast) cancer cells treated with bovine milk fat enriched with conjugated linoleic acid (CLA) was studied. Milk enriched in CLA was obtained from cows on pasture supplemented with full fat rapeseeds and full fat soyabeans (1). Cell number decreased up to 90% (p milk fat yielding CLA concentrations between 16.9 and 22.6 ppm. Growth suppression and prooxidant effects of milk fat CLA were independent of the variable composition of the milk fat samples, suggesting that CLA was the active ingredient in milk fat responsible for the cytotoxic effect. Mixtures containing isomers of CLA (c9, t11-, t10, c12-, c11, t13- and minor amounts of other isomers) and linoleic acid (LA) at similar concentrations to the milk fat samples were as effective at inhibiting growth and stimulating peroxidation of MCF-7 cells as the milk fatty acids. Incubation of the cells with the c9, t11 CLA isomer (20 ppm) or the mixture of CLA isomers (20 ppm) for 8 days resulted in a 60% decrease (p milk fat than the c9, t11 synthetic CLA isomer. Superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) activities were induced in MCF-7 cells exposed to milk fat (containing 16.9-22.6 ppm CLA) over 8 days. The data indicate that milk fat triglyceride-bound CLA, consisting primarily of the c9, t11 isomer, was cytotoxic towards MCF-7 cells.

  5. A Mouse Mammary Gland Involution mRNA Signature Identifies Biological Pathways Potentially Associated with Breast Cancer Metastasis

    NARCIS (Netherlands)

    T. Stein; N. Salomonis; D.S.A. Nuyten; M.J. van de Vijver; B.A. Gusterson

    2009-01-01

    Mouse mammary gland involution resembles a wound healing response with suppressed inflammation. Wound healing and inflammation are also associated with tumour development, and a 'wound-healing' gene expression signature can predict metastasis formation and survival. Recent studies have shown that an

  6. Inhibitory effects of intrathecal p38β antisense oligonucleotide on bone cancer pain in rats.

    Science.gov (United States)

    Dong, Hang; Xiang, Hong-Bing; Ye, Da-Wei; Tian, Xue-Bi

    2014-01-01

    To evaluate the effects of intrathecal administration p38β antisense oligonucleotide on the development of bone cancer pain rats. Forty female SD rats weighing 180~220 g were randomly divided into 4 groups (n = 10 each): Group A (control group): intra-tibial injection of 3 μl Hank's solution; group B (model group): intra-tibial injection of 3 μl MADB-106 mammary gland carcinoma cells of rats (4.8 × 10(3)/μl); group C (p38β-SODN 20 μg); group D (p38β-ASODN 20 μg). The model procedures in group C and D were same to those in the group B. From the 14th day after operation, p38β-SODN 20 μg and p38β-ASODN 20 μg were respectively intrathecally administrated in group C and D once daily for 6 days whereas normal saline was for group A and B. Mechanical withdrawal threshold and radiant heat threshold of rat hind paws were measured before operation and every other day until 22 d of post-operation. The lumbar 4-6 spinal cord was removed on the 22(nd) day. The expression of spinal p38β protein was determined by Western blot. No significant differences in mechanical withdrawal threshold and radiant heat threshold were found at all time points in control group. During the first 6 days after operation there were obvious differences in radiant heat stimulus between control group between the other groups (P 0.05). The expression of p38β protein in lumbar spinal cord was significantly higher between p38β-SODN group and Model group than that in control group (P 0.05). Hyperalgesia induced by bone cancer can be inhibited by intrathecal administration of p38β antisense oligonucleotide, which is achieved by reducing expression of p38β protein.

  7. c-Jun N-terminal kinase 2 prevents luminal cell commitment in normal mammary glands and tumors by inhibiting p53/Notch1 and breast cancer gene 1 expression.

    Science.gov (United States)

    Cantrell, Michael A; Ebelt, Nancy D; Pfefferle, Adam D; Perou, Charles M; Van Den Berg, Carla Lynn

    2015-05-20

    Breast cancer is a heterogeneous disease with several subtypes carrying unique prognoses. Patients with differentiated luminal tumors experience better outcomes, while effective treatments are unavailable for poorly differentiated tumors, including the basal-like subtype. Mechanisms governing mammary tumor subtype generation could prove critical to developing better treatments. C-Jun N-terminal kinase 2 (JNK2) is important in mammary tumorigenesis and tumor progression. Using a variety of mouse models, human breast cancer cell lines and tumor expression data, studies herein support that JNK2 inhibits cell differentiation in normal and cancer-derived mammary cells. JNK2 prevents precocious pubertal mammary development and inhibits Notch-dependent expansion of luminal cell populations. Likewise, JNK2 suppresses luminal populations in a p53-competent Polyoma Middle T-antigen tumor model where jnk2 knockout causes p53-dependent upregulation of Notch1 transcription. In a p53 knockout model, JNK2 restricts luminal populations independently of Notch1, by suppressing Brca1 expression and promoting epithelial to mesenchymal transition. JNK2 also inhibits estrogen receptor (ER) expression and confers resistance to fulvestrant, an ER inhibitor, while stimulating tumor progression. These data suggest that therapies inhibiting JNK2 in breast cancer may promote tumor differentiation, improve endocrine therapy response, and inhibit metastasis.

  8. Freund's vaccine adjuvant promotes Her2/Neu breast cancer

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    Woditschka Stephan

    2009-01-01

    Full Text Available Abstract Background Inflammation has been linked to the etiology of many organ-specific cancers. Indirect evidence suggests a possible role for inflammation in breast cancer. We investigated whether the systemic inflammation induced by Freund's adjuvant (FA promotes mammary carcinogenesis in a rat model in which cancer is induced by the neu oncogene. Methods The effects of FA on hyperplastic mammary lesions and mammary carcinomas were determined in a neu-induced rat model. The inflammatory response to FA treatment was gauged by measuring acute phase serum haptoglobin. In addition, changes in cell proliferation and apoptosis following FA treatment were assessed. Results Rats receiving FA developed twice the number of mammary carcinomas as controls. Systemic inflammation following FA treatment is chronic, as shown by a doubling of the levels of the serum biomarker, haptoglobin, 15 days following initial treatment. We also show that this systemic inflammation is associated with the increased growth of hyperplastic mammary lesions. This increased growth results from a higher rate of cellular proliferation in the absence of changes in apoptosis. Conclusion Our data suggests that systemic inflammation induced by Freund's adjuvant (FA promotes mammary carcinogenesis. It will be important to determine whether adjuvants currently used in human vaccines also promote breast cancer.

  9. Sclerotium rolfsii lectin induces stronger inhibition of proliferation in human breast cancer cells than normal human mammary epithelial cells by induction of cell apoptosis.

    Science.gov (United States)

    Savanur, Mohammed Azharuddin; Eligar, Sachin M; Pujari, Radha; Chen, Chen; Mahajan, Pravin; Borges, Anita; Shastry, Padma; Ingle, Arvind; Kalraiya, Rajiv D; Swamy, Bale M; Rhodes, Jonathan M; Yu, Lu-Gang; Inamdar, Shashikala R

    2014-01-01

    Sclerotium rolfsii lectin (SRL) isolated from the phytopathogenic fungus Sclerotium rolfsii has exquisite binding specificity towards O-linked, Thomsen-Freidenreich (Galβ1-3GalNAcα1-Ser/Thr, TF) associated glycans. This study investigated the influence of SRL on proliferation of human breast cancer cells (MCF-7 and ZR-75), non-tumorigenic breast epithelial cells (MCF-10A) and normal mammary epithelial cells (HMECs). SRL caused marked, dose-dependent, inhibition of proliferation of MCF-7 and ZR-75 cells but only weak inhibition of proliferation of non-tumorigenic MCF-10A and HMEC cells. The inhibitory effect of SRL on cancer cell proliferation was shown to be a consequence of SRL cell surface binding and subsequent induction of cellular apoptosis, an effect that was largely prevented by the presence of inhibitors against caspases -3, -8, or -9. Lectin histochemistry using biotin-labelled SRL showed little binding of SRL to normal human breast tissue but intense binding to cancerous tissues. In conclusion, SRL inhibits the growth of human breast cancer cells via induction of cell apoptosis but has substantially less effect on normal epithelial cells. As a lectin that binds specifically to a cancer-associated glycan, has potential to be developed as an anti-cancer agent.

  10. Sclerotium rolfsii Lectin Induces Stronger Inhibition of Proliferation in Human Breast Cancer Cells than Normal Human Mammary Epithelial Cells by Induction of Cell Apoptosis

    Science.gov (United States)

    Savanur, Mohammed Azharuddin; Eligar, Sachin M.; Pujari, Radha; Chen, Chen; Mahajan, Pravin; Borges, Anita; Shastry, Padma; Ingle, Arvind.; Kalraiya, Rajiv D.; Swamy, Bale M.; Rhodes, Jonathan M.; Yu, Lu-Gang; Inamdar, Shashikala R.

    2014-01-01

    Sclerotium rolfsii lectin (SRL) isolated from the phytopathogenic fungus Sclerotium rolfsii has exquisite binding specificity towards O-linked, Thomsen-Freidenreich (Galβ1-3GalNAcα1-Ser/Thr, TF) associated glycans. This study investigated the influence of SRL on proliferation of human breast cancer cells (MCF-7 and ZR-75), non-tumorigenic breast epithelial cells (MCF-10A) and normal mammary epithelial cells (HMECs). SRL caused marked, dose-dependent, inhibition of proliferation of MCF-7 and ZR-75 cells but only weak inhibition of proliferation of non-tumorigenic MCF-10A and HMEC cells. The inhibitory effect of SRL on cancer cell proliferation was shown to be a consequence of SRL cell surface binding and subsequent induction of cellular apoptosis, an effect that was largely prevented by the presence of inhibitors against caspases -3, -8, or -9. Lectin histochemistry using biotin-labelled SRL showed little binding of SRL to normal human breast tissue but intense binding to cancerous tissues. In conclusion, SRL inhibits the growth of human breast cancer cells via induction of cell apoptosis but has substantially less effect on normal epithelial cells. As a lectin that binds specifically to a cancer-associated glycan, has potential to be developed as an anti-cancer agent. PMID:25364905

  11. Induction of experimental mammary carcinogenesis in rats with 7,12-dimethylbenz(aanthracene Indução da carcinogênese mamária experimental em ratas com 7,12-dimetilbenz(aantraceno

    Directory of Open Access Journals (Sweden)

    Alfredo Carlos S. D. Barros

    2004-01-01

    Full Text Available PURPOSE: To test an experimental model of chemical mammary carcinogenesis induction in rats. METHODS: Twenty young virgin Sprague-Dawley female rats, aged 47 days, received 20 mg of 7,12-dimethylbenz(aanthracene (DMBA intragastrically by gavage. Afterwards, at 8 and 13 weeks, their mammary glands were examined. At the end of the experiment, the animals were sacrificed, and the mammary tumors were measured and weighed. Tumor fragments were analyzed using light microscopy. RESULTS: Eight weeks after DMBA injection, 16 rats presented at least 1 breast tumor (80%. After 13 weeks, all of them (100% developed breast carcinomas that were confirmed by histopathological analysis. CONCLUSION: This experimental animal model of chemical mammary induced carcinogenesis is feasible and can be used in further experiments on the role of tumorigenic biomodulator substances.OBJETIVO: Testar um modelo experimental de indução química de carcinogênese mamária em ratas. MATERIAL E MÉTODOS: Com 47 dias de vida, 20 ratas Sprague-Dawley, jovens e virgens, receberam por gavagem intragástrica 20 mg de 7,12-dimetilbenz(aantraceno (DMBA. Oito e 13 semanas depois da injeção de droga as mamas das ratas foram examinadas. Ao final os animais foram sacrificados e fragmentos dos tumores foram estudados ao microscópio. RESULTADO: Oito semanas depois da injeção de DMBA 16 ratas apresentavam tumor nas mamas (80%. Com 13 semanas todas desenvolveram carcinomas de mama (100%, que foram confirmados por análise histopatológica. CONCLUSÃO: Este modelo experimental de indução química de carcinogênese mamária é factível e pode ser empregado em futuras pesquisas para avaliar o papel de substâncias biomoduladoras da tumorigênese.

  12. Radiogenic neoplasia in thyroid and mammary clonogens

    Energy Technology Data Exchange (ETDEWEB)

    Clifton, K.H.

    1991-05-31

    We have developed rat thyroid and mammary clonogen transplantation systems for the study of radiogenic cancer induction at the target cell level in vivo. The epithelial cell populations of both glands contain small subpopulations of cells which are capable of giving rise to monoclonal glandular structures when transplanted and stimulated with appropriate hormones. During the end of the last grant year and the first half of the current grant year, we have completed analyses and summarized for publication: investigations on the relationship between grafted thyroid cell number and the rapidity and degree of reestablishment of the thyroid-hypothalamicpituitary axis in thyroidectomized rats maintained on a normal diet or an iodine deficient diet; studies of the persistence of, and the differentiation potential and functional characteristics of, the TSH- (thyrotropin-) responsive sub-population of clonogens during goitrogenesis, the plateau-phase of goiter growth, and goiter involution; studies of changes in the size of the clonogen sub-population during goitrogenesis, goiter involution and the response to goitrogen rechallenge; and the results of the large carcinogenesis experiment on the nature of the grafted thyroid cell number-dependent suppression of promotion/progression to neoplasia in grafts of radiation-initiated thyroid cells. We are testing new techniques for the culture, cytofluorescent analysis and characterization mammary epithelial cells and of clonogens in a parallel project, and plan to apply similar technology to the thyroid epithelial cells and clonogen population. Data from these studies will be used in the design of future carcinogenesis experiments on neoplastic initiation by high and low LET radiations and on cells interactions during the neoplastic process.

  13. Robust spinal neuroinflammation mediates mechanical allodynia in Walker 256 induced bone cancer rats

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    Mao-Ying Qi-Liang

    2012-05-01

    Full Text Available Abstract It has been reported that remarkable and sustained activation of astrocytes and/or microglia occurs in cancer induced pain (CIP, which is different from neuropathic and inflammatory pain. The present study was designed to investigate the role of spinal Toll-like receptor 4 (TLR4 induced glial neuroinflammation in cancer induced pain using a modified rat model of bone cancer. The rat model of CIP consisted of unilateral intra-tibial injection with Walker 256 mammary gland carcinoma. Nine days after Walker 256 inoculation, a robust activation of both astrocytes and microglia in bilateral spinal dorsal horn was observed together with significant bilateral mechanical allodynia. This neuroinflammation was characterized by enhanced immunostaining of both glial fibrillary acidic protein (GFAP, astrocyte marker and OX-42 (microglia marker, and an elevated level of IL-1β, IL-6 and TNF-α mRNA. I.t. administration of fluorocitrate (an inhibitor of glial metabolism, 1 nmol or minocycline (an inhibitor of microglia, 100 μg has significant anti-allodynic effects on day 12 after Walker 256 inoculation. Naloxone (a nonstereoselective TLR4 signaling blocker, 60 μg, i.t. also significantly alleviated mechanical allodynia and simultaneously blocked the increased inflammatory cytokine mRNA. The results suggested that spinal TLR4 might play an important role in the sustained glial activation that critically contributed to the robust and sustained spinal neuroinflammation in CIP. This result could potentially help clinicians and researchers to better understand the mechanism of complicated cancer pain.

  14. Radiotherapy of internal mammary lymph nodes in breast cancer. Principle considerations on the basis of dosimetric data

    Energy Technology Data Exchange (ETDEWEB)

    Sautter-Bihl, M.L.; Hueltenschmidt, B.; Melcher, U. [Staedtisches Klinikum Karlsruhe (Germany). Dept. of Radiotherapy; Ulmer, H.U. [Dept. of Gynecology, Staedtisches Klinikum Karlsruhe (Germany)

    2002-01-01

    Background: Radiotherapy of internal mammary lymph nodes (IMN) in breast cancer is discussed controversially due to its potential toxicity and debatable efficacy. Aim of the present study was to assess the cardiac and lung dose in 3-D planned radiotherapy and to discuss these results with regard to arguments pro and contra IMN irradiation. Patients and Methods: 32 patients underwent 3-D planning (Helax TMS) for irradiation of breast and IMN in three different techniques either using separate IMN fields (A, B) or a wide tangent (C). For each technique the respective doses to the heart (including the base of the aorta and the ostium of the coronary arteries) and lung were analyzed in dose volume histograms. Results: The mean dose to the heart (left side irradiation) was 6.4 Gy (A), 8.1 Gy (B) and 3.8 Gy (C). The mean dose to the lung was 11.7 Gy (A), 15.4 Gy (B) and 10.2 Gy (C). The 10-Gy isodose comprised 19.5% (A), 32.9% (B) and 5.6% (C) of the heart (left breast). The respective values for the 20-Gy isodose were 7.8, 11.5 and 4.4%. The irradiated volumes of the lung were 37.7% (A), 52.7% (B) and 20% (C) in the 10-Gy isodose. The 20-Gy isodose comprised 16.7% (A), 28.3% (B) and 17.8% (C). Conclusion: Whether radiotherapy of the IMN may improve treatment results in breast cancer is currently unresolved. However, the present data indicate that relevant cardiovascular side effects are unlikely to occur. Thus, the indication should be considered on the basis of individual risk factors. (orig.) [German] Hintergrund: Die Strahlentherapie der Mammaria-interna-Lymphknoten (IMN) wird kontrovers diskutiert, da ihre potenzielle Toxizitaet gefuerchtet und ihre Wirksamkeit angezweifelt werden. Ziel der vorliegenden Studie war, die Herz- und Lungendosis bei 3-D-geplanter Strahlentherapie zu ermitteln und anhand dieser Resultate die Argumente fuer und wider eine IMN-Bestrahlung zu diskutieren. Patienten und Methoden: Bei 32 Patientinnen erfolgte die 3-D-Planung (Helax TMS) zur

  15. α-Mangostin extracted from the pericarp of the mangosteen (Garcinia mangostana Linn reduces tumor growth and lymph node metastasis in an immunocompetent xenograft model of metastatic mammary cancer carrying a p53 mutation

    Directory of Open Access Journals (Sweden)

    Okuno Yasushi

    2011-06-01

    Full Text Available Abstract Background The mangosteen fruit has a long history of medicinal use in Chinese and Ayurvedic medicine. Recently, the compound α-mangostin, which is isolated from the pericarp of the fruit, was shown to induce cell death in various types of cancer cells in in vitro studies. This led us to investigate the antitumor growth and antimetastatic activities of α-mangostin in an immunocompetent xenograft model of mouse metastatic mammary cancer having a p53 mutation that induces a metastatic spectrum similar to that seen in human breast cancers. Methods Mammary tumors, induced by inoculation of BALB/c mice syngeneic with metastatic BJMC3879luc2 cells, were subsequently treated with α-mangostin at 0, 10 and 20 mg/kg/day using mini-osmotic pumps and histopathologically examined. To investigate the mechanisms of antitumor ability by α-mangostin, in vitro studies were also conducted. Results Not only were in vivo survival rates significantly higher in the 20 mg/kg/day α-mangostin group versus controls, but both tumor volume and the multiplicity of lymph node metastases were significantly suppressed. Apoptotic levels were significantly increased in the mammary tumors of mice receiving 20 mg/kg/day and were associated with increased expression of active caspase-3 and -9. Other significant effects noted at this dose level were decreased microvessel density and lower numbers of dilated lymphatic vessels containing intraluminal tumor cells in mammary carcinoma tissues. In vitro, α-mangostin induced mitochondria-mediated apoptosis and G1-phase arrest and S-phase suppression in the cell cycle. Since activation by Akt phosphorylation plays a central role in a variety of oncogenic processes, including cell proliferation, anti-apoptotic cell death, angiogenesis and metastasis, we also investigated alterations in Akt phosphorylation induced by α-mangostin treatment both in vitro and in vivo. Quantitative analysis and immunohistochemistry showed that

  16. In vivo tumour and metastasis reduction and in vitro effects on invasion assays of the ruthenium RM175 and osmium AFAP51 organometallics in the mammary cancer model.

    Science.gov (United States)

    Bergamo, A; Masi, A; Peacock, A F A; Habtemariam, A; Sadler, P J; Sava, G

    2010-01-01

    We have compared the organometallic arene complexes [(eta(6)-biphenyl)M(ethylenediamine)Cl](+) RM175 (M=Ru(II)) and its isostructural osmium(II) analogue AFAP51 (M=Os(II)) for their ability to induce cell detachment resistance from fibronectin, collagen IV and poly-l-lysine, and cell re-adhesion after treatment, their effects on cell migration and cell viability, on matrix metalloproteinases production, and on primary tumour growth of MCa mammary carcinoma, the effect of human serum albumin on their cytotoxicity. There are differences between ruthenium and osmium. The Os complex is up to 6x more potent than RM175 towards highly-invasive breast MDA-MB-231, human breast MCF-7 and human epithelial HBL-100 cancer cells, but whereas RM175 was active against MCa mammary carcinoma in vivo and caused metastasis reduction, AFAP51 was not. Intriguingly the presence of human serum albumin in the growth medium enhanced the cytotoxicity of both compounds. RM175 increased the resistance of MDA-MB-231 cells to detachment from substrates and both compounds inhibited the production of MMP-2. These data confirm the key role of ruthenium itself in anti-metastatic activity. It will be interesting to explore the activity of osmium arene complexes in other tumour models and the possibility of changing the non-arene ligands to tune the anticancer activity of osmium in vivo.

  17. Effect of Semecarpus anacardium Linn. nut milk extract on glutathione and its associated enzymes in experimentally induced mammary carcinoma.

    Science.gov (United States)

    Mathivadhani, P; Shanthi, P; Sachdanandam, P

    2006-01-01

    Reduced glutathione (GSH) is a ubiquitous thiol-containing tripeptide that plays a key role in the etiology of many diseases and, in particular, cancer. GSH, the foremost internal protective system, participates directly in the destruction of free radical compounds and detoxification of carcinogens. The effect of Semecarpus anacardium nut milk extract was studied for gaining insight into the disease relationship to GSH and its metabolizing enzymes. Mammary carcinoma was induced by giving 7,12-dimethylbenz[a]anthracene (DMBA) (25 mg/mL of olive oil) perorally by gastric intubation, and nut milk extract of S. anacardium was administered orally (200 mg/kg of body weight/day) for 14 days to mammary carcinoma-bearing rats. The levels of GSH and its metabolizing enzyme activities were determined in liver and kidney homogenates. Significant decreases in GSH, glutathione peroxidase, glutathione S-transferase, glutathione reductase, and gamma-glutamylcysteine synthetase and a concomitant increase in oxidized glutathione, gamma-glutamyl transpeptidase, and glucose 6-phosphate dehydrogenase were observed in DMBA-induced mammary carcinoma in rats, while drug treatment reversed the conditions to near normal levels. There was a marked increase in GSH level and gamma-glutamylcysteine synthetase activity in drug control rats. These findings suggest that S. anacardium can exert its protective effect in maintaining the glutathione redox status by restoring the associated enzymes against oxidative stress in experimental mammary carcinoma.

  18. Multiple Susceptibility Loci for Radiation-Induced Mammary Tumorigenesis in F2[Dahl S x R]-Intercross Rats

    OpenAIRE

    Herrera, Victoria L.; Ponce, Lorenz R.; Nelson Ruiz-Opazo

    2013-01-01

    Although two major breast cancer susceptibility genes, BRCA1 and BRCA2, have been identified accounting for 20% of breast cancer genetic risk, identification of other susceptibility genes accounting for 80% risk remains a challenge due to the complex, multi-factorial nature of breast cancer. Complexity derives from multiple genetic determinants, permutations of gene-environment interactions, along with presumptive low-penetrance of breast cancer predisposing genes, and genetic heterogeneity o...

  19. A MYC-Driven Change in Mitochondrial Dynamics Limits YAP/TAZ Function in Mammary Epithelial Cells and Breast Cancer.

    Science.gov (United States)

    von Eyss, Björn; Jaenicke, Laura A; Kortlever, Roderik M; Royla, Nadine; Wiese, Katrin E; Letschert, Sebastian; McDuffus, Leigh-Anne; Sauer, Markus; Rosenwald, Andreas; Evan, Gerard I; Kempa, Stefan; Eilers, Martin

    2015-12-14

    In several developmental lineages, an increase in MYC expression drives the transition from quiescent stem cells to transit-amplifying cells. We show that MYC activates a stereotypic transcriptional program of genes involved in cell growth in mammary epithelial cells. This change in gene expression indirectly inhibits the YAP/TAZ co-activators, which maintain the clonogenic potential of these cells. We identify a phospholipase of the mitochondrial outer membrane, PLD6, as the mediator of MYC activity. MYC-dependent growth strains cellular energy resources and stimulates AMP-activated kinase (AMPK). PLD6 alters mitochondrial fusion and fission dynamics downstream of MYC. This change activates AMPK, which in turn inhibits YAP/TAZ. Mouse models and human pathological data show that MYC enhances AMPK and suppresses YAP/TAZ activity in mammary tumors.

  20. Sigma-1 Receptor Antagonist BD1047 Reduces Mechanical Allodynia in a Rat Model of Bone Cancer Pain through the Inhibition of Spinal NR1 Phosphorylation and Microglia Activation.

    Science.gov (United States)

    Zhu, Shanshan; Wang, Chenchen; Han, Yuan; Song, Chao; Hu, Xueming; Liu, Yannan

    2015-01-01

    Previous studies have demonstrated that sigma-1 receptor plays important roles in the induction phase of rodent neuropathic pain; however, whether it is involved in bone cancer pain (BCP) and the underlying mechanisms remain elusive. The aim of this study was to examine the potential role of the spinal sigma-1 receptor in the development of bone cancer pain. Walker 256 mammary gland carcinoma cells were implanted into the intramedullary space of the right tibia of Sprague-Dawley rats to induce ongoing bone cancer-related pain behaviors; our findings indicated that, on days 7, 10, 14, and 21 after operation, the expression of sigma-1 receptor in the spinal cord was higher in BCP rats compared to the sham rats. Furthermore, intrathecal injection of 120 nmol of sigma-1 receptor antagonist BD1047 on days 5, 6, and 7 after operation attenuated mechanical allodynia as well as the associated induction of c-Fos and activation of microglial cells, NR1, and the subsequent Ca(2+)-dependent signals of BCP rats. These results suggest that sigma-1 receptor is involved in the development of bone cancer pain and that targeting sigma-1 receptor may be a new strategy for the treatment of bone cancer pain.

  1. Celecoxib in the histological grade of chemically induced mammary tumor in rats%塞莱昔布对化学诱导大鼠乳腺肿瘤病理分级影响的研究

    Institute of Scientific and Technical Information of China (English)

    钱跃清; 姚雨石; 于忠和; 杨光之; 战淑君

    2011-01-01

    OBJECTIVE: To evaluate the impact of celecoxib, a selective cyclooxygenase-2 inhibitor, on the histological grades of chemically induced mammary tumor and normal mammary tissue in rats, METHODS: Single dose of 7, 12 dimethlbenz anthracene, DMBA) was administered I. G. Into female SD rats to induce mammary tumors, during which various dose levels of celecoxib was dosed. The incidence, number and size of tumor were recorded, and mammary tumors and normal mammary tissues were analyzed via pathological observation. RESULTS: Compared with control group, 100 mg/kg and 150 mg/kg celecoxib treatment groups had significantly decreased incidence and number of tumor, while comparable tumor size. More importantly, celecoxib could significantly reduced histopathological grades of both mammary tumors (100 mg/kg, P = 0. 021; 150 mg/kg, P = 0. 036) and DMBA caused lesions in mammary lobule and alveolus (100 mg/kg, P = 0.004). CONCLUSIONS: Prophylactic administer of celecoxib can reduce pathological grade of chemically induced rat mammary tumor, as well as protecting normal mammary tissues. Its clinical application is worthy of further investigation.%目的:评价预防性应用选择性环氧化酶-2(COX-2)抑制剂塞莱昔布对化学诱导大鼠乳腺肿瘤及正常乳腺组织病理分级的影响.方法:雌性SD大鼠予二甲基苯并蒽(DMBA)1次性灌胃诱发乳腺肿瘤过程中,给予不同剂量塞莱昔布,观察肿瘤发生率、数量和体积,并与正常对照组进行病理学分析.结果:与对照组相比,塞莱昔布100和150 mg/kg两剂量组大鼠乳腺肿瘤发生率和肿瘤数量均显著低于模型对照组,但各组间肿瘤平均体积差异无统计学意义,P>0.05.塞莱昔布显著降低大鼠乳腺肿瘤的组织病理分级(100mg/kg,P=0.021;150 mg/kg,P=0.036),显著降低DMBA导致的乳腺小叶和腺泡的病变程度(100mg/kg,P=0.004).结论:预防性应用塞莱昔布具有降低乳腺肿瘤的病理分级,保护正常乳腺组织的作

  2. Parathyroid hormone-related protein specifies the mammary mesenchyme and regulates embryonic mammary development.

    Science.gov (United States)

    Hiremath, Minoti; Wysolmerski, John

    2013-06-01

    Parathyroid Hormone related Protein (PTHrP) is a critical regulator of mammary gland morphogenesis in the mouse embryo. Loss of PTHrP, or its receptor, PTHR1, results in arrested mammary buds at day 15 of embryonic development (E15). In contrast, overexpression of PTHrP converts the ventral epidermis into hairless nipple skin. PTHrP signaling appears to be critical for mammary mesenchyme specification, which in turn maintains mammary epithelial identity, directs bud outgrowth, disrupts the male mammary rudiment and specifies the formation of the nipple. In the embryonic mammary bud, PTHrP exerts its effects on morphogenesis, in part, through epithelial-stromal crosstalk mediated by Wnt and BMP signaling. Recently, PTHLH has been identified as a strong candidate for a novel breast cancer susceptibility locus, although PTHrP's role in breast cancer has not been clearly defined. The effects of PTHrP on the growth of the embryonic mammary rudiment and its invasion into the dermis may, in turn, have connections to the role of PTHrP in breast cancer.

  3. Cox-2 levels in canine mammary tumors, including inflammatory mammary carcinoma: clinicopathological features and prognostic significance.

    Science.gov (United States)

    Queiroga, Felisbina Luisa; Perez-Alenza, Maria Dolores; Silvan, Gema; Peña, Laura; Lopes, Carlos; Illera, Juan Carlos

    2005-01-01

    Cyclo-oxygenase (Cox-2) plays an important role in mammary carcinogenesis, nevertheless, its role in canine mammary tumors, and particularly in inflammatory mammary carcinoma (IMC), is unknown. Tumor Cox-2 levels were analyzed by enzyme immunoassay, in post-surgical tumor homogenates of 129 mammary tumors (62 dysplasias and benign tumors, 57 malignant non-IMC and 10 IMC) from 57 female dogs. The highest Cox-2 values were detected in the IMC group. In non-IMC malignant tumors, high values of Cox-2 were related to skin ulceration (p IMC cases could indicate a special role of Cox-2 in the inflammatory phenotype and open the possibility of additional new therapeutic approaches in this special type of mammary cancer in humans and dogs.

  4. A complex between 6-iodolactone and the peroxisome proliferator-activated receptor type gamma may mediate the antineoplastic effect of iodine in mammary cancer.

    Science.gov (United States)

    Nuñez-Anita, R E; Arroyo-Helguera, O; Cajero-Juárez, M; López-Bojorquez, L; Aceves, C

    2009-06-01

    Recently we and other groups have shown that molecular iodine (I(2)) exhibits potent antiproliferative and apoptotic effects in mammary cancer models. In the human breast cancer cell line MCF-7, I(2) treatment generates iodine-containing lipids similar to 6-iodo-5-hydroxy-eicosatrienoic acid and the 6-iodolactone (6-IL) derivative of arachidonic acid (AA), and it significantly decreases cellular proliferation and induces caspase-dependent apoptosis. Several studies have shown that AA is a natural ligand of the peroxisome proliferator-activated receptors (PPARs), which are nuclear transcription factors thought to participate in regulating cancer cell proliferation. Our results show that in MCF-7 cells: (1) 6-IL binds specifically and with high affinity to PPAR proteins (EMSA assays), (2) 6-IL activates both transfected (by transactivation assays) and endogenous (by lipid accumulation) peroxisome proliferator response elements, and (3) 6-IL supplementation increases PPAR gamma and decreases PPAR alpha expression. These results implicate PPARs in a molecular mechanism by which I(2), through formation of 6-IL, inhibits the growth of human breast cancer cells.

  5. Toxicity and antitumor activity of the vitamin D analogs PRI-1906 and PRI-1907 in combined treatment with cyclophosphamide in a mouse mammary cancer model.

    Science.gov (United States)

    Wietrzyk, Joanna; Nevozhay, Dmitry; Milczarek, Magdalena; Filip, Beata; Kutner, Andrzej

    2008-10-01

    Active and less toxic vitamin D analogs could be useful for clinical applications. In the present study, we evaluated the toxicity and antitumor effect of two new synthetic analogs of vitamin D, namely PRI-1906 [(24E)-24a-Homo-(1S)-1,25-dihydroxyergocalciferol] and its side-chain unsaturated homo analog PRI-1907. The toxicity and calcemic activity, as well as antitumor effect of calcitriol analogs was investigated in vivo. The studies were performed in a mouse mammary 16/C cancer model. Since calcitriol and its analogs inhibited 16/C tumor growth only slightly, we applied them in the combined therapy with cyclophosphamide (CY). Moreover, cell cycle analysis and VDR and p27 expression were investigated. The LD50 values after five daily subcutaneous (s.c.) injections were 7.8, 10.0 and 2.4 microg/kg per day for calcitriol, PRI-1906 and PRI-1907, respectively. The serum calcium level increased to 40, 23 and 63% over the control for these compounds. We also compare the antitumor activity of the PRI-1906 with the calcitriol and previously studied PRI-2191 (1,24-dihydroxyvitamin D3, tacalcitol). Statistically significant inhibition of tumor growth by calcitriol up to the eighth day was observed in all schedules applied. PRI-1906 inhibited the tumor growth at doses 1 and 5 microg/kg per day, and PRI-2191 only at the dose 5 microg/kg per day. Addition of vitamin D analogs increased the antitumor effect of CY. PRI-1906 exhibited toxicity higher than PRI-2191 but lower than calcitriol and antitumor activity similar to both PRI-2191 and calcitriol. This new analog seems to be a good candidate for the combined treatment of mammary cancer.

  6. Dietary tocopherols inhibit cell proliferation, regulate expression of ERα, PPARγ, and Nrf2, and decrease serum inflammatory markers during the development of mammary hyperplasia.

    Science.gov (United States)

    Smolarek, Amanda K; So, Jae Young; Thomas, Paul E; Lee, Hong Jin; Paul, Shiby; Dombrowski, Anne; Wang, Chung-Xiou; Saw, Constance Lay-Lay; Khor, Tin Oo; Kong, Ah-Ng Tony; Reuhl, Kenneth; Lee, Mao-Jung; Yang, Chung S; Suh, Nanjoo

    2013-07-01

    Previous clinical and epidemiological studies of vitamin E have used primarily α-tocopherol for the prevention of cancer. However, γ-tocopherol has demonstrated greater anti-inflammatory and anti-tumor activity than α-tocopherol in several animal models of cancer. This study assessed the potential chemopreventive activities of a tocopherol mixture containing 58% γ-tocopherol (γ-TmT) in an established rodent model of mammary carcinogenesis. Female ACI rats were utilized due to their sensitivity to 17β-estradiol (E2 ) to induce mammary hyperplasia and neoplasia. The rats were implanted subcutaneously with sustained release E2 pellets and given dietary 0.3% or 0.5% γ-TmT for 2 or 10 wk. Serum E2 levels were significantly reduced by the treatment with 0.5% γ-TmT. Serum levels of inflammatory markers, prostaglandin E2 and 8-isoprostane, were suppressed by γ-TmT treatment. Histology of mammary glands showed evidence of epithelial hyperplasia in E2 -treated rats. Immunohistochemical analysis of the mammary glands revealed a decrease in proliferating cell nuclear antigen (PCNA), cyclooxygenase-2 (COX-2), and estrogen receptor α (ERα), while there was an increase in cleaved-caspase 3, peroxisome proliferator-activated receptor γ (PPARγ), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in γ-TmT-treated rats. In addition, treatment with γ-TmT resulted in a decrease in the expression of ERα mRNA, whereas mRNA levels of ERβ and PPARγ were increased. In conclusion, γ-TmT was shown to suppress inflammatory markers, inhibit E2 -induced cell proliferation, and upregulate PPARγ and Nrf2 expression in mammary hyperplasia, suggesting that γ-TmT may be a promising agent for human breast cancer prevention.

  7. Estrogen receptor beta growth-inhibitory effects are repressed through activation of MAPK and PI3K signalling in mammary epithelial and breast cancer cells.

    Science.gov (United States)

    Cotrim, C Z; Fabris, V; Doria, M L; Lindberg, K; Gustafsson, J-Å; Amado, F; Lanari, C; Helguero, L A

    2013-05-09

    Two thirds of breast cancers express estrogen receptors (ER). ER alpha (ERα) mediates breast cancer cell proliferation, and expression of ERα is the standard choice to indicate adjuvant endocrine therapy. ERbeta (ERβ) inhibits growth in vitro; its effects in vivo have been incompletely investigated and its role in breast cancer and potential as alternative target in endocrine therapy needs further study. In this work, mammary epithelial (EpH4 and HC11) and breast cancer (MC4-L2) cells with endogenous ERα and ERβ expression and T47-D human breast cancer cells with recombinant ERβ (T47-DERβ) were used to explore effects exerted in vitro and in vivo by the ERβ agonists 2,3-bis (4-hydroxy-phenyl)-propionitrile (DPN) and 7-bromo-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol (WAY). In vivo, ERβ agonists induced mammary gland hyperplasia and MC4-L2 tumour growth to a similar extent as the ERα agonist 4,4',4''-(4-propyl-(1H)-pyrazole-1,3,5-triyl) trisphenol (PPT) or 17β-estradiol (E2) and correlated with higher number of mitotic and lower number of apoptotic features. In vitro, in MC4-L2, EpH4 or HC11 cells incubated under basal conditions, ERβ agonists induced apoptosis measured as upregulation of p53 and apoptosis-inducible factor protein levels and increased caspase 3 activity, whereas PPT and E2 stimulated proliferation. However, when extracellular signal-regulated kinase 1 and 2 (ERK ½) were activated by co-incubation with basement membrane extract or epidermal growth factor, induction of apoptosis by ERβ agonists was repressed and DPN induced proliferation in a similar way as E2 or PPT. In a context of active ERK ½, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/RAC-alpha serine/threonine-protein kinase (AKT) signalling was necessary to allow proliferation stimulated by ER agonists. Inhibition of MEK ½ with UO126 completely restored ERβ growth-inhibitory effects, whereas inhibition of PI3K by LY294002 inhibited ERβ-induced proliferation. These

  8. Human mammary fibroblasts stimulate invasion of breast cancer cells in a three-dimensional culture and increase stroma development in mouse xenografts

    Directory of Open Access Journals (Sweden)

    Olsen Charlotta J

    2010-08-01

    Full Text Available Abstract Introduction Tumour phenotype is regulated in a complex fashion as a result of interactions between malignant cells and the tumour stroma. Fibroblasts are the most abundant and perhaps most active part of the tumour stroma. A better understanding of the changes that occur in fibroblasts in response to the presence of malignant cells may lead to the development of new strategies for cancer treatment. We explored the effects of fibroblasts on the growth and invasion of mammary carcinoma tumour cells in vitro and in vivo. Methods In order to analyse secreted factors that affect invasive abilities of breast cancer cells we co-cultured human mammary fibroblasts (HMF3s and cancer cells (MCF7S1 in three-dimensional (3D growth conditions devoid of heterogeneous cell-cell contact. To study the possible influence of fibroblasts on MCF7S1 cancer cell growth in vivo we co-injected HMF3s and MCF7S1 cells in Balb/c nu/nu mice. Results In 3D co-culture both HMF3s and MCF7S1 cells demonstrated enhanced invasion into a Matrigel matrix. This was correlated with enhanced expression of the metastasis promoting S100A4 protein in fibroblasts, stimulation of the matrix metalloproteinase (MMP-2 activity, and enhanced secretion of a range of different cytokines. Orthotopic injection of oestrogen-dependent MCF7S1 cancer cells together with fibroblasts showed stimulation of tumour growth in mice without an external oestrogen supply. The resulting tumours were characterized by increased development of extracellular matrix, as well as an increase of murine S100A4 concentration and activity of MMP-2 in the tumour interstitial fluid. Conclusion Stimulation of the invasive phenotype of tumour cells in 3D co-cultures with fibroblasts could be correlated with increased production of S100A4 and MMP-2. We propose that enhanced development of mouse host-derived tumour stroma in a MCF7S1 co-injection xenograft model leads to oestrogen independency and is triggered by the

  9. Gel-based proteomics of liver cancer progression in rat

    DEFF Research Database (Denmark)

    Albrethsen, Jakob; Miller, Leah M; Novikoff, Phyllis M

    2011-01-01

    carcinoma (HCC) and we identify novel candidate proteomic aberrations for further analysis in human HCC. In particular, increased levels of HSP70, HSP90, AKR1B1, AKR7A3, GCLM, ANXA5, VDBP, RGN and SULT1E1 were associated specifically with rat hepatomas, or with liver cancer progression in rat. In addition...

  10. Passive adoptive transfer of antitumor immunity induced by laser-dye-immunoadjuvant treatment in a rat metastatic breast cancer model

    Science.gov (United States)

    Chen, Wei R.; Liu, Hong; Singhal, Anil K.; Nordquist, Robert E.

    2000-06-01

    The ideal cancer treatment modalities should not only cause tumor regression and eradication but also induce a systemic anti-tumor immunity. This is essential for control of metastatic tumors and for long-term tumor resistance. Laser immunotherapy using a laser, a laser-absorbing dye and an immunoadjuvant has induced such a long-term immunity in treatment of a mammary metastatic tumor. The successfully treated rats established total resistance to multiple subsequent tumor challenges. For further mechanistic studies of the antitumor immunity induced by this novel treatment modality, passive adoptive transfer was performed using splenocytes as immune cells. The spleen cells harvested from successfully treated tumor-bearing rats provided 100% immunity in the naive recipients. The passively protected first cohort rats were immune to tumor challenge with an increased tumor dose; their splenocytes also prevented the establishment of tumor in the second cohort of naive recipient rats. This immunity transfer was accomplished without the usually required T-cell suppression in recipients.

  11. Mouse Mammary Tumor Virus-Like Nucleotide Sequences in Canine and Feline Mammary Tumors▿

    OpenAIRE

    Hsu, Wei-Li; Lin, Hsing-Yi; Chiou, Shyan-Song; Chang, Chao-Chin; Wang, Szu-Pong; Lin, Kuan-Hsun; Chulakasian, Songkhla; Wong, Min-Liang; Chang, Shih-Chieh

    2010-01-01

    Mouse mammary tumor virus (MMTV) has been speculated to be involved in human breast cancer. Companion animals, dogs, and cats with intimate human contacts may contribute to the transmission of MMTV between mouse and human. The aim of this study was to detect MMTV-like nucleotide sequences in canine and feline mammary tumors by nested PCR. Results showed that the presence of MMTV-like env and LTR sequences in canine malignant mammary tumors was 3.49% (3/86) and 18.60% (16/86), respectively. Fo...

  12. Proteomic profiling of mammary carcinomas identifies C7orf24, a gamma-glutamyl cyclotransferase, as a potential cancer biomarker

    DEFF Research Database (Denmark)

    Gromov, Pavel; Gromova, Irina; Friis, Esbern

    2010-01-01

    Breast cancer is the leading cause of cancer deaths in women today and is the most common cancer (excluding skin cancers) among women in the Western world. Although cancers detected by screening mammography are significantly smaller than nonscreening ones, noninvasive biomarkers for detection of ...

  13. Identification of stable and oestrus cycle-independent housekeeping genes in the rat mammary gland and other tissues

    DEFF Research Database (Denmark)

    Hvid, Henning; Ekstrøm, Claus T; Vienberg, Sara Gry

    2011-01-01

    of stably expressed genes across oestrus cycle phases. For normalization between samples from the entire panel of rat tissues, eight HKGs (Rps18, Eef1a1, B2m, Actb, Tbp, Hprt, Pgk1, and Sdha) were identified as the optimal combination. These HKGs are of general relevance for studies comparing gene...

  14. Bipotent mammary stem cells: now in amazing 3D

    NARCIS (Netherlands)

    van Amerongen, R.

    2014-01-01

    For many decades, developmental biologists and cancer researchers alike have been trying to understand the relationship between the basal and luminal cell compartments in the mouse mammary epithelium. Delineating the mammary stem and progenitor cell hierarchy will provide fundamental knowledge of ho

  15. Phospholipid makeup of the breast adipose tissue is impacted by obesity and mammary cancer in the mouse: Results of a pilot study.

    Science.gov (United States)

    Margolis, Michael; Perez, Osvaldo; Martinez, Mitchell; Santander, Ana M; Mendez, Armando J; Nadji, Mehrdad; Nayer, Ali; Bhattacharya, Sanjoy; Torroella-Kouri, Marta

    2015-01-01

    Obesity, an established risk factor for breast cancer (BC), is associated with systemic inflammation. The breast contains adipose tissue (bAT), yet whether it plays a role in BC progression in obese females is being intensively studied. There is scarce knowledge on the lipid composition of bAT in health and disease. The purpose of this pilot study was: 1) to determine whether obesity and BC are associated with inflammatory changes in bAT 2) to analyze for the first time the lipid profile of bAT in obese and lean mammary tumor-bearing and normal mice. Syngeneic E0771 mammary tumor cells were implanted into the mammary fat pad of lean and diet-induced obese C57BL/6 mice. BATs were analyzed four weeks after tumor cell inoculation by immunohistochemistry and mass spectrometry. Phospholipids were identified and subjected to ratiometric quantification using a TSQ Quantum Access Max triple quadrupole mass spectrometer utilizing precursor ion scan or neutral ion loss scan employing appropriate class specific lipid standards in a two step quantification process. Four main classes of phospholipids were analyzed: phosphatidylcholines phosphatidylserines, phosphatidylethanolamines and phosphatidylinositols. Our results showed that bAT in obese (normal and tumor-bearing) mice contained hypertrophic adipocytes compared with their corresponding samples in lean mice; higher numbers of macrophages and crown-like structures were observed in obese tumor bearers compared to obese normal mice. BAT from normal obese mice revealed higher concentrations of phosphatidylethanolamines. Furthermore, bAT from tumor-bearing mice expressed higher phosphatidylcholines than that from non-tumor bearing mice, suggesting the presence of the tumor is associated with phosphatidylcholines. Conversion of phosphatidylethanolamines to phosphatidylcholines will be investigated in E0771 cells. Additional studies are projected to investigate macrophage activation by these specific classes of phospholipids

  16. Does Skeletal Muscle Mass Influence Breast Cancer? Evaluating Mammary Tumorigenesis and Progression in Genetically Hyper-Muscular Mice

    Science.gov (United States)

    2007-07-01

    preserve muscle in the end-stages of cancer, cancer cachexia . Up to 25% of breast cancer deaths may be attributed to muscle wasting from the complex... cachexia . 15. SUBJECT TERMS Breast cancer, skeletal muscle, myostatin, MPA, DMBA, Activin receptor, cachexia . 16. SECURITY CLASSIFICATION OF: 17...progress, we turned to another question relating skeletal muscle and cancer—pathological muscle wasting in cancer cachexia . (6) (7) (8) Cancer cachexia

  17. Overexpression of Id1 in transgenic mice promotes mammary basal stem cell activity and breast tumorigenesis

    OpenAIRE

    Shin, Dong-Hui; Park, Ji-Hye; Lee, Jeong-Yeon; Won, Hee-Young; Jang, Ki-Seok; MIN, KYUENG-WHAN; Jang, Si-Hyong; Woo, Jong-Kyu; Oh, Seung Hyun; Kong, Gu

    2015-01-01

    Inhibitor of differentiation/DNA binding (Id)1 is a crucial regulator of mammary development and breast cancer progression. However, its effect on stemness and tumorigenesis in mammary epithelial cells remains undefined. Herein, we demonstrate that Id1 induces mammary tumorigenesis by increasing normal and malignant mammary stem cell (MaSC) activities in transgenic mice. MaSC-enriched basal cell expansion and increased self-renewal and in vivo regenerative capacity of MaSCs are observed in th...

  18. Computerized segmentation algorithm with personalized atlases of murine MRIs in a SV40 large T-antigen mouse mammary cancer model

    Science.gov (United States)

    Sibley, Adam R.; Markiewicz, Erica; Mustafi, Devkumar; Fan, Xiaobing; Conzen, Suzanne; Karczmar, Greg; Giger, Maryellen L.

    2016-03-01

    Quantities of MRI data, much larger than can be objectively and efficiently analyzed manually, are routinely generated in preclinical research. We aim to develop an automated image segmentation and registration pipeline to aid in analysis of image data from our high-throughput 9.4 Tesla small animal MRI imaging center. T2-weighted, fat-suppressed MRIs were acquired over 4 life-cycle time-points [up to 12 to 18 weeks] of twelve C3(1) SV40 Large T-antigen mice for a total of 46 T2-weighted MRI volumes; each with a matrix size of 192 x 256, 62 slices, in plane resolution 0.1 mm, and slice thickness 0.5 mm. These image sets were acquired with the goal of tracking and quantifying progression of mammary intraepithelial neoplasia (MIN) to invasive cancer in mice, believed to be similar to ductal carcinoma in situ (DCIS) in humans. Our segmentation algorithm takes 2D seed-points drawn by the user at the center of the 4 co-registered volumes associated with each mouse. The