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Sample records for cancer hormone receptor

  1. Sex Hormone Receptor Repertoire in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Gerald M. Higa

    2013-01-01

    Full Text Available Classification of breast cancer as endocrine sensitive, hormone dependent, or estrogen receptor (ER positive refers singularly to ERα. One of the oldest recognized tumor targets, disruption of ERα-mediated signaling, is believed to be the mechanistic mode of action for all hormonal interventions used in treating this disease. Whereas ERα is widely accepted as the single most important predictive factor (for response to endocrine therapy, the presence of the receptor in tumor cells is also of prognostic value. Even though the clinical relevance of the two other sex hormone receptors, namely, ERβ and the androgen receptor remains unclear, two discordant phenomena observed in hormone-dependent breast cancers could be causally related to ERβ-mediated effects and androgenic actions. Nonetheless, our understanding of regulatory molecules and resistance mechanisms remains incomplete, further compromising our ability to develop novel therapeutic strategies that could improve disease outcomes. This review focuses on the receptor-mediated actions of the sex hormones in breast cancer.

  2. Palbociclib in Combination With Tamoxifen as First Line Therapy for Metastatic Hormone Receptor Positive Breast Cancer

    Science.gov (United States)

    2016-10-04

    Hormone Receptor Positive Malignant Neoplasm of Breast; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; Estrogen Receptor Positive Breast Cancer; Progesterone Receptor Positive Tumor; Metastatic Breast Cancer

  3. Sex Steroid Hormone Receptor Expression Affects Ovarian Cancer Survival

    DEFF Research Database (Denmark)

    Jönsson, Jenny-Maria; Skovbjerg Arildsen, Nicolai; Malander, Susanne;

    2015-01-01

    BACKGROUND AND AIMS: Although most ovarian cancers express estrogen (ER), progesterone (PR), and androgen (AR) receptors, they are currently not applied in clinical decision making. We explored the prognostic impact of sex steroid hormone receptor protein and mRNA expression on survival...

  4. Estrogen and Progesterone hormone receptor expression in oral cavity cancer

    Science.gov (United States)

    Biegner, Thorsten; Teriete, Peter; Hoefert, Sebastian; Krimmel, Michael; Munz, Adelheid; Reinert, Siegmar

    2016-01-01

    Background Recent studies have shown an increase in the incidence of oral squamous cell carcinoma (OSCC) in younger patients. The hypothesis that tumors could be hormonally induced during pregnancy or in young female patients without the well-known risk factors alcohol or tobacco abuse seems to be plausible. Material and Methods Estrogen Receptor alpha (ERα) and Progesterone Receptor (PR) expression were analyzed in normal oral mucosa (n=5), oral precursor lesions (simple hyperplasia, n=11; squamous intraepithelial neoplasia, SIN I-III, n=35), and OSCC specimen. OSCCs were stratified in a young female (n=7) study cohort and older patients (n=46). In the young female study cohort three patients (n=3/7) developed OSCC during or shortly after pregnancy. Breast cancer tissues were used as positive control for ERα and PR expression. Results ERα expression was found in four oral precursor lesions (squamous intraepithelial neoplasia, SIN I-III, n=4/35, 11%) and in five OSCC specimen (n=5/46, 11%). The five ERα positive OSCC samples were older male patients. All patients within the young female study cohort were negatively stained for both ERα and PR. Conclusions ER expression could be regarded as a seldom risk factor for OSCC. PR expression seems to be not relevant for the development of OSCC. Key words:Oral squamous cell carcinoma, estrogen receptor, progesterone receptor, hormone receptor. PMID:27475696

  5. The androgen receptor in hormone-refractory prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Hai-Lei Mao; Zhi-Qi Zhu; Charlie Degui Chen

    2009-01-01

    Advanced prostate cancer is responsive to hormone therapy that interferes with androgen receptor (AR) signalling.However,the effect is short-lived,as nearly all tumours progress to a hormone-refractory (HR) state,a lethal stage of the disease.Intuitively,the AR should not be involved because hormone therapy that blocks or reduces AR activity is not effective in treating HR turnouts.However,there is still a consensus that AR plays an essential role in HR prostate cancer (HRPC) because AR signalling is still functional in HR tumours.AR signalling can be activated in HR turnouts through several mechanisms.First,activation of intracellular signal transduction pathways can sensitize the AR to castrate levels of androgens.Also,mutations in the AR can change AR ligand specificity,thereby allowing it to be activated by non-steroids or anti-androgens.Finally,overexpression of the wild-type AR sensitizes itself to low concentrations of androgens.Therefore,drugs targeting AR signalling could still be effective in treating HRPC.

  6. Hormone-receptor expression and ovarian cancer survival

    DEFF Research Database (Denmark)

    Sieh, Weiva; Köbel, Martin; Longacre, Teri A;

    2013-01-01

    Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated ...

  7. Expression profile and prognostic role of sex hormone receptors in gastric cancer

    International Nuclear Information System (INIS)

    Increasing interest has been devoted to the expression and possible role of sex hormone receptors in gastric cancer, but most of these findings are controversial. In the present study, the expression profile of sex hormone receptors in gastric cancer and their clinicopathological and prognostic value were determined in a large Chinese cohort. The mRNA and protein expression of estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), progesterone receptor (PR), and androgen receptor (AR) in primary gastric tumors and corresponding adjacent normal tissues from 60 and 866 Chinese gastric cancer patients was detected by real-time quantitative PCR and immunohistochemistry method, respectively. The expression profile of the four receptors was compared and their associations with clinicopathological characteristics were assessed by using Chi-square test. The prognostic value of the four receptors in gastric cancer was evaluated by using univariate and multivariate Cox regression analysis. The presence of ERα, ERβ, PR, and AR in both gastric tumors and normal tissues was confirmed but their expression levels were extremely low except for the predominance of ERβ. The four receptors were expressed independently and showed a decreased expression pattern in gastric tumors compared to adjacent normal tissues. The positive expression of the four receptors all correlated with high tumor grade and intestinal type, and ERα and AR were also associated with early TNM stage and thereby a favorable outcome. However, ERα and AR were not independent prognostic factors for gastric cancer when multivariate survival analysis was performed. Our findings indicate that the sex hormone receptors may be partly involved in gastric carcinogenesis but their clinicopathological and prognostic significance in gastric cancer appears to be limited

  8. Involvement of Ghrelin-Growth Hormone Secretagogue Receptor System in Pathoclinical Profiles of Digestive System Cancer

    Institute of Scientific and Technical Information of China (English)

    Zhigang WANG; Weigang WANG; Wencai QIU; Youben FAN; Jun ZHAO; Yu WANG; Qi ZHENG

    2007-01-01

    Ghrelin receptor has been shown to be expressed along the human gastrointestinal tract.Recent studies showed that ghrelin and a synthetic ghrelin receptor agonist improved weight gain and lean body mass retention in a rat model of cancer cachexia by acting on ghrelin receptor, that is, growth hormone secretagogue receptor (GHS-R). This study aims to explore the expression and the distribution of ghrelin receptor in human gastrointestinal tract cancers and to investigate the possible involvement of the ghrelin-GHS-R system in human digestive cancers. Surgical human digestive cancer specimens were obtained from various portions of the gastrointestinal tract from different patients. The expression of ghrelin receptor in these tissues was detected by tissue microarray technique. Our results showed that ghrelin receptor was expressed in cancers throughout the gastrointestinal tract, mainly in the cytoplasm of mucosal layer cells.Its expression level possibly correlated with organ type, histological grade, tumor-nodes-metastases stage,and nutrition status (weight loss) of the patients. For the first time, we identified the distribution of ghrelin receptor in digestive system cancers. Our results implied that the ghrelin-GHS-R system might be involved in the pathoclinical profiles of digestive cancers.

  9. Family history and breast cancer hormone receptor status in a Spanish cohort.

    Directory of Open Access Journals (Sweden)

    Xuejuan Jiang

    Full Text Available BACKGROUND: Breast cancer is a heterogenous disease that impacts racial/ethnic groups differently. Differences in genetic composition, lifestyles, reproductive factors, or environmental exposures may contribute to the differential presentation of breast cancer among Hispanic women. MATERIALS AND METHODS: A population-based study was conducted in the city of Santiago de Compostela, Spain. A total of 645 women diagnosed with operable invasive breast cancer between 1992 and 2005 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics of the tumors were collected. Hormone receptor negative tumors were compared with hormone receptor postive tumors on their clinico-pathological characteristics as well as risk factor profiles. RESULTS: Among the 645 breast cancer patients, 78% were estrogen receptor-positive (ER+ or progesterone receptor-positive (PR+, and 22% were ER-&PR-. Women with a family history of breast cancer were more likely to have ER-&PR- tumors than women without a family history (Odds ratio, 1.43; 95% confidence interval, 0.91-2.26. This association was limited to cancers diagnosed before age 50 (Odds ratio, 2.79; 95% confidence interval, 1.34-5.81. CONCLUSIONS: An increased proportion of ER-&PR- breast cancer was observed among younger Spanish women with a family history of the disease.

  10. Ability of luteinizing hormone releasing hormone-Pseudomonas aeruginosa exotoxin 40 binding to LHRH receptor on human liver cancer cells

    Institute of Scientific and Technical Information of China (English)

    Shou-Liang Gong; Gang Zhao; Hong-Guang Zhao; Wen-Tian Lü; Guang-Wei Liu; Ping Zhu

    2004-01-01

    AIM: To explore the ability of recombinant toxin luteinizing hormone releasing hormone-Pseudomonas aeruginosa exotoxin 40 (LHRH-PE40) anH binding to LHRH receptor(LHRHR) on the membrane surfa ogf hman liver cancer HEPG cells.METHODS: LHRH was beled by using 125I with enzymatic reaction. The affinity and receptor volume of LHRH-PE40and LHRH binding to LHRHR on the membrane surface of human liver cancer cells were measured with radioligand receptor assay.RESULTS:The specific activity of LHRH labeled with 125I was 2.7×104 kBq/μL, and its radiochemical purity reached to 99.2-99.7%. The binding of 125I to LHRH was maximal for 240 min in the warm cultivation, and this binding was stabilized. The inhibiting rates of 125I-LHRH and LHRH on the proliferation of human liver cancer HEPG cells were not significantly different. On the basis of the saturation curve of 125I-LHRH binding to the membrane LHRHR of HEPG cells, 125I-LHRH of 1×105 cpm was selected for radioligand receptor assay. The affinity constants (Kd) of LHRH-PE40and LHRH bively,and their receptor volumes were 0.37±0.15 μmol/g and0.42±0.13 μmol/g, respectively. The binding of LHRH-PE40to the membrane proteinof normal liver cells was not observed.CONCLUSION: The recombinant toxin LHRH-PE40 binding to the membrane surface of LHRHR of human liver cancer HEPG cells was very strong, while the specific binding of it to normal liver cells was not observed. The results provide an important experimental basis for the clinical application of LHRH-PE.

  11. Height, age at menarche and risk of hormone receptor-positive and -negative breast cancer: A cohort study

    NARCIS (Netherlands)

    Ritte, R.; Lukanova, A.; Tjonneland, A.; Olsen, A.; Overvad, K.; Mesrine, S.; Fagherazzi, G.; Dossus, L.; Teucher, B.; Duijnhoven, van F.J.B.

    2013-01-01

    Associations of breast cancer overall with indicators of exposures during puberty are reasonably well characterized; however, uncertainty remains regarding the associations of height, leg length, sitting height and menarcheal age with hormone receptor-defined malignancies. Within the European Prospe

  12. Pumpkin seed extract: Cell growth inhibition of hyperplastic and cancer cells, independent of steroid hormone receptors.

    Science.gov (United States)

    Medjakovic, Svjetlana; Hobiger, Stefanie; Ardjomand-Woelkart, Karin; Bucar, Franz; Jungbauer, Alois

    2016-04-01

    Pumpkin seeds have been known in folk medicine as remedy for kidney, bladder and prostate disorders since centuries. Nevertheless, pumpkin research provides insufficient data to back up traditional beliefs of ethnomedical practice. The bioactivity of a hydro-ethanolic extract of pumpkin seeds from the Styrian pumpkin, Cucurbita pepo L. subsp. pepo var. styriaca, was investigated. As pumpkin seed extracts are standardized to cucurbitin, this compound was also tested. Transactivational activity was evaluated for human androgen receptor, estrogen receptor and progesterone receptor with in vitro yeast assays. Cell viability tests with prostate cancer cells, breast cancer cells, colorectal adenocarcinoma cells and a hyperplastic cell line from benign prostate hyperplasia tissue were performed. As model for non-hyperplastic cells, effects on cell viability were tested with a human dermal fibroblast cell line (HDF-5). No transactivational activity was found for human androgen receptor, estrogen receptor and progesterone receptor, for both, extract and cucurbitin. A cell growth inhibition of ~40-50% was observed for all cell lines, with the exception of HDF-5, which showed with ~20% much lower cell growth inhibition. Given the receptor status of some cell lines, a steroid-hormone receptor independent growth inhibiting effect can be assumed. The cell growth inhibition for fast growing cells together with the cell growth inhibition of prostate-, breast- and colon cancer cells corroborates the ethnomedical use of pumpkin seeds for a treatment of benign prostate hyperplasia. Moreover, due to the lack of androgenic activity, pumpkin seed applications can be regarded as safe for the prostate.

  13. [Advanced luminal breast cancer (hormone receptor-positive, HER2 negative): New therapeutic options in 2015].

    Science.gov (United States)

    Vanacker, Hélène; Bally, Olivia; Kassem, Loay; Tredan, Olivier; Heudel, Pierre; Bachelot, Thomas

    2015-06-01

    Despite improvements in early detection, surgery and systemic therapy, metastatic breast cancer remains a major cause of death. Luminal type breast cancers expressing hormone estrogen receptor (ER) or progesterone (PR) and without HER2 overexpression are generally sensitive to endocrine therapy, but raise the issue of the occurrence of resistance to treatment, particularly at metastatic stage. A better understanding of hormone resistance may guide the development of new therapeutics. New strategies aim at enhancing and prolonging of endocrine sensitivity, by optimizing existing schemes, or by combining an endocrine therapy with a targeted therapies specific to hormone resistance pathways: ER signaling, PI3K/AKT/mTOR and Cyclin Dependent Kinase (CDK). Key corners of 2014 include confirmation of benefit of high dose fulvestrant, and commercialization of everolimus as the first mTOR inhibitor in this indication. Other strategies are being tested dealing with new endocrine therapies or new molecular targets such as PI3K inhibitors, insulin-like growth factor receptor (IGF-R) and histone deacetylase (HDAC) inhibitors. Coming years may be fruitful and might radically change our way to treat these patients. PMID:26118876

  14. Pumpkin seed extract: Cell growth inhibition of hyperplastic and cancer cells, independent of steroid hormone receptors.

    Science.gov (United States)

    Medjakovic, Svjetlana; Hobiger, Stefanie; Ardjomand-Woelkart, Karin; Bucar, Franz; Jungbauer, Alois

    2016-04-01

    Pumpkin seeds have been known in folk medicine as remedy for kidney, bladder and prostate disorders since centuries. Nevertheless, pumpkin research provides insufficient data to back up traditional beliefs of ethnomedical practice. The bioactivity of a hydro-ethanolic extract of pumpkin seeds from the Styrian pumpkin, Cucurbita pepo L. subsp. pepo var. styriaca, was investigated. As pumpkin seed extracts are standardized to cucurbitin, this compound was also tested. Transactivational activity was evaluated for human androgen receptor, estrogen receptor and progesterone receptor with in vitro yeast assays. Cell viability tests with prostate cancer cells, breast cancer cells, colorectal adenocarcinoma cells and a hyperplastic cell line from benign prostate hyperplasia tissue were performed. As model for non-hyperplastic cells, effects on cell viability were tested with a human dermal fibroblast cell line (HDF-5). No transactivational activity was found for human androgen receptor, estrogen receptor and progesterone receptor, for both, extract and cucurbitin. A cell growth inhibition of ~40-50% was observed for all cell lines, with the exception of HDF-5, which showed with ~20% much lower cell growth inhibition. Given the receptor status of some cell lines, a steroid-hormone receptor independent growth inhibiting effect can be assumed. The cell growth inhibition for fast growing cells together with the cell growth inhibition of prostate-, breast- and colon cancer cells corroborates the ethnomedical use of pumpkin seeds for a treatment of benign prostate hyperplasia. Moreover, due to the lack of androgenic activity, pumpkin seed applications can be regarded as safe for the prostate. PMID:26976217

  15. Phosphorylation of the androgen receptor by PIM1 in hormone refractory prostate cancer.

    Science.gov (United States)

    Ha, S; Iqbal, N J; Mita, P; Ruoff, R; Gerald, W L; Lepor, H; Taneja, S S; Lee, P; Melamed, J; Garabedian, M J; Logan, S K

    2013-08-22

    Integration of cellular signaling pathways with androgen receptor (AR) signaling can be achieved through phosphorylation of AR by cellular kinases. However, the kinases responsible for phosphorylating the AR at numerous sites and the functional consequences of AR phosphorylation are only partially understood. Bioinformatic analysis revealed AR serine 213 (S213) as a putative substrate for PIM1, a kinase overexpressed in prostate cancer. Therefore, phosphorylation of AR serine 213 by PIM1 was examined using a phosphorylation site-specific antibody. Wild-type PIM1, but not catalytically inactive PIM1, specifically phosphorylated AR but not an AR serine-to-alanine mutant (S213A). In vitro kinase assays confirmed that PIM1 can phosphorylate AR S213 in a ligand-independent manner and cell type-specific phosphorylation was observed in prostate cancer cell lines. Upon PIM1 overexpression, AR phosphorylation was observed in the absence of hormone and was further increased in the presence of hormone in LNCaP, LNCaP-abl and VCaP cells. Moreover, phosphorylation of AR was reduced in the presence of PIM kinase inhibitors. An examination of AR-mediated transcription showed that reporter gene activity was reduced in the presence of PIM1 and wild-type AR, but not S213A mutant AR. Androgen-mediated transcription of endogenous PSA, Nkx3.1 and IGFBP5 was also decreased in the presence of PIM1, whereas IL6, cyclin A1 and caveolin 2 were increased. Immunohistochemical analysis of prostate cancer tissue microarrays showed significant P-AR S213 expression that was associated with hormone refractory prostate cancers, likely identifying cells with catalytically active PIM1. In addition, prostate cancers expressing a high level of P-AR S213 were twice as likely to be from biochemically recurrent cancers. Thus, AR phosphorylation by PIM1 at S213 impacts gene transcription and is highly prevalent in aggressive prostate cancer.

  16. Epigenetics of Estrogen Receptor Signaling: Role in Hormonal Cancer Progression and Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Mann, Monica; Cortez, Valerie [Department of Cellular and Structural Biology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229 (United States); Vadlamudi, Ratna K., E-mail: vadlamudi@uthscsa.edu [Department of Obstetrics and Gynecology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229 (United States)

    2011-03-29

    Estrogen receptor (ERα) signaling plays a key role in hormonal cancer progression. ERα is a ligand-dependent transcription factor that modulates gene transcription via recruitment to the target gene chromatin. Emerging evidence suggests that ERα signaling has the potential to contribute to epigenetic changes. Estrogen stimulation is shown to induce several histone modifications at the ERα target gene promoters including acetylation, phosphorylation and methylation via dynamic interactions with histone modifying enzymes. Deregulation of enzymes involved in the ERα -mediated epigenetic pathway could play a vital role in ERα driven neoplastic processes. Unlike genetic alterations, epigenetic changes are reversible, and hence offer novel therapeutic opportunities to reverse ERα driven epigenetic changes. In this review, we summarize current knowledge on mechanisms by which ERα signaling potentiates epigenetic changes in cancer cells via histone modifications.

  17. Epigenetics of Estrogen Receptor Signaling: Role in Hormonal Cancer Progression and Therapy

    International Nuclear Information System (INIS)

    Estrogen receptor (ERα) signaling plays a key role in hormonal cancer progression. ERα is a ligand-dependent transcription factor that modulates gene transcription via recruitment to the target gene chromatin. Emerging evidence suggests that ERα signaling has the potential to contribute to epigenetic changes. Estrogen stimulation is shown to induce several histone modifications at the ERα target gene promoters including acetylation, phosphorylation and methylation via dynamic interactions with histone modifying enzymes. Deregulation of enzymes involved in the ERα -mediated epigenetic pathway could play a vital role in ERα driven neoplastic processes. Unlike genetic alterations, epigenetic changes are reversible, and hence offer novel therapeutic opportunities to reverse ERα driven epigenetic changes. In this review, we summarize current knowledge on mechanisms by which ERα signaling potentiates epigenetic changes in cancer cells via histone modifications

  18. Reproductive factors and hormone receptor status among very young (<35 years) breast cancer patients.

    Science.gov (United States)

    Jia, Xiaoqing; Liu, Guangyu; Mo, Miao; Cheng, Jingyi; Shen, Zhenzhou; Shao, Zhimin

    2015-09-15

    The prognosis for breast cancer occurs in young women is usually poor. The impact of different reproductive factors on disease characteristics is still largely unknown. We analyzed 261 patients aged ≤35 years old who were treated at the Cancer Hospital of Fudan University, Shanghai, China. The relationships between certain reproductive factors (age at menarche, parity, number of children, breastfeeding, history of abortion, age at first full-term pregnancy and oral contraceptive (OC) use) and disease characteristics were evaluated. Compared with patients who experienced fewer full-term pregnancies (menarche was ≥15 years exhibited a greater chance of PR-positive tumors (64.8%) (P = 0.036) compared with those whose age of menarche was menarche are more possible to exhibit hormone receptor-positive tumors. Additionally, patients who have taken OCs are more likely to present with advanced disease.

  19. Expansion of microsatellite in the thyroid hormone receptor-alpha1 gene linked to increased receptor expression and less aggressive thyroid cancer

    DEFF Research Database (Denmark)

    Onda, Masamitsu; Li, Daisy; Suzuki, Shinichi;

    2002-01-01

    PURPOSE: The purpose of this study was to determine whether the length of the THRA1 microsatellite, which resides in a noncoding portion of the thyroid hormone receptor-alpha1 gene, affects receptor expression and is linked to clinicopathological parameters in thyroid cancer. EXPERIMENTAL DESIGN:...

  20. Steroid hormone receptors and prostate cancer: role of structural dynamics in therapeutic targeting

    Science.gov (United States)

    Kumar, Raj

    2016-01-01

    Steroid hormone receptors (SHRs) act in cell type- and gene-specific manner through interactions with coregulatory proteins to regulate numerous physiological and pathological processes at the level of gene regulation. Binding of steroid receptor modulator (SRM) ligand leads to allosteric changes in SHR to exert positive or negative effects on the expression of target genes. Due, in part, to the fact that current SRMs generally target ligand binding domain (LBD)/AF2 and neglect intrinsically disordered (ID) N-terminal domain (NTD)/AF1, clinically relevant SRMs lack selectivity and are also prone to the development of resistance over time. Therefore, to maximize the efficacy of SHR-based therapeutics, the possibility of developing unique modulators that act to control AF1 activity must be considered. Recent studies targeting androgen receptor's (AR's) ID AF1 domain for the castration-resistant prostate cancer has provided the possibility of therapeutically targeting ID NTD/AF1 surfaces by allosteric modulations to achieve desired effects. In this review article, we discuss how inter- and intra- molecular allosteric regulations controlled by AR's structural flexibility and dynamics particularly the ID NTD/AF1 is an emerging area of investigation, which could be exploited for drug development and therapeutic targeting of prostate cancer. PMID:27364545

  1. The effects of radiotherapy on the hormone receptor concentration and tumor growth in xenotransplanted human breast cancer

    International Nuclear Information System (INIS)

    The influence of radiotherapy on tumor growth and hormone receptor concentration (estrogen-, progesteronreceptor) in xenotransplanted human breast cancer is observed. Tumor growth significantly is delayed under therapy during the first 35 days after radiation. Renewed growth follows after that time. After the first days of treatment the ER and PR concentration decreases considerably and finally reaches 40% respectively 30% of the pretreatment level for a period of approximately 35 days after the end of radiotherapy. In general radiation therapy seems to affect the PR stronger than the ER. After this period ER and PR levels increase again with the regrowing tumor. The results point out that radiotherapy reduces the concentration of ER and PR in human breast cancer. Therefore the assay of steroid receptors in human breast cancer after radiation therapy is useful in predicting hormone dependency and prognosis only when receptor concentrations are positive. (orig.)

  2. Endocrine therapy initiation among Medicaid-insured breast cancer survivors with hormone receptor-positive tumors

    Science.gov (United States)

    Wheeler, Stephanie Brooke; Kohler, Racquel Elizabeth; Reeder-Hayes, Katherine Elizabeth; Goyal, Ravi K.; Lich, Kristen Hassmiller; Moore, Alexis; Smith, Timothy W.; Melvin, Cathy L.; Muss, Hyman Bernard

    2016-01-01

    Purpose Hormone receptor positive (HR+) cancers account for most breast cancer diagnoses and deaths. Among survivors with HR+ breast cancers, endocrine therapy (ET) reduces 5-year risk of recurrence by up to 40%. Observational studies in Medicare and privately-insured survivors suggest under-utilization of ET. We sought to characterize ET use in a low-income Medicaid-insured population in North Carolina. Methods Medicaid claims data were matched to state cancer registry records for survivors ages 18–64 diagnosed with stage 0-II HR+ breast cancer from 2003–2007, eligible for ET, and enrolled in Medicaid for at least 12 of 15 months post-diagnosis. We used multivariable logistic regression to model receipt of any ET medication during 15-months post-diagnosis controlling for age, race, tumor characteristics, receipt of other treatments, co-morbidity, residence, reason for Medicaid eligibility, involvement in the Breast and Cervical Cancer Control Program (BCCCP), and diagnosis year. Results Of 222 women meeting inclusion criteria, only 50% filled a prescription for ET. Involvement in BCCCP and earlier year of diagnoses were associated with significantly higher odds of initiating guideline-recommended ET (Adjusted Odds Ratio [AOR] for BCCCP: 3.76, 95%CI: 1.67–8.48; AOR for 2004 relative to 2007: 2.80, 95%CI: 1.03–7.62; AOR for 2005 relative to 2007: 2.11, 95%CI: 0.92–4.85). Conclusions Results suggest substantial under-utilization of ET in this population. Interventions are needed to improve timely receipt of ET and to better support survivors taking ET. Implications of cancer survivors Low-income survivors should be counseled on the importance of ET and offered support services to promote initiation and long-term adherence. PMID:24866922

  3. Vaginal estrogen products in hormone receptor-positive breast cancer patients on aromatase inhibitor therapy.

    Science.gov (United States)

    Sulaica, Elisabeth; Han, Tiffany; Wang, Weiqun; Bhat, Raksha; Trivedi, Meghana V; Niravath, Polly

    2016-06-01

    Atrophic vaginitis represents a major barrier to compliance with aromatase inhibitor (AI) therapy in breast cancer (BC) survivors. While local estrogen therapy is effective for postmenopausal vaginal dryness, the efficacy of such therapies has not been evaluated systematically in hormone receptor-positive (HR+) BC patients on AI therapy. Furthermore, the potential risk of breast cancer recurrence with vaginal estrogen therapy represents a long-term safety concern for the patients with HR + BC. Unfortunately, there is no standardized assay to measure very low concentrations of estradiol (E2) in these women being treated with AI therapy. This makes it difficult to evaluate even indirectly the potential risk of BC recurrence with vaginal estrogen therapy in HR + BC patients on AI therapy. In this review, we describe available assays to measure very low concentrations of E2, discuss the Food and Drug Administration-approved vaginal estrogen products on the market, and summarize published and ongoing clinical trials evaluating the safety and efficacy of vaginal estrogen in HR + BC patients on AI therapy. In the absence of any randomized controlled clinical trials, this review serves as a summary of available clinical data and ongoing studies to aid clinicians in selecting the best available option for their patients. PMID:27178335

  4. Vaginal estrogen products in hormone receptor-positive breast cancer patients on aromatase inhibitor therapy.

    Science.gov (United States)

    Sulaica, Elisabeth; Han, Tiffany; Wang, Weiqun; Bhat, Raksha; Trivedi, Meghana V; Niravath, Polly

    2016-06-01

    Atrophic vaginitis represents a major barrier to compliance with aromatase inhibitor (AI) therapy in breast cancer (BC) survivors. While local estrogen therapy is effective for postmenopausal vaginal dryness, the efficacy of such therapies has not been evaluated systematically in hormone receptor-positive (HR+) BC patients on AI therapy. Furthermore, the potential risk of breast cancer recurrence with vaginal estrogen therapy represents a long-term safety concern for the patients with HR + BC. Unfortunately, there is no standardized assay to measure very low concentrations of estradiol (E2) in these women being treated with AI therapy. This makes it difficult to evaluate even indirectly the potential risk of BC recurrence with vaginal estrogen therapy in HR + BC patients on AI therapy. In this review, we describe available assays to measure very low concentrations of E2, discuss the Food and Drug Administration-approved vaginal estrogen products on the market, and summarize published and ongoing clinical trials evaluating the safety and efficacy of vaginal estrogen in HR + BC patients on AI therapy. In the absence of any randomized controlled clinical trials, this review serves as a summary of available clinical data and ongoing studies to aid clinicians in selecting the best available option for their patients.

  5. Reproductive factors and risk of hormone receptor positive and negative breast cancer: a cohort study

    International Nuclear Information System (INIS)

    The association of reproductive factors with hormone receptor (HR)-negative breast tumors remains uncertain. Within the EPIC cohort, Cox proportional hazards models were used to describe the relationships of reproductive factors (menarcheal age, time between menarche and first pregnancy, parity, number of children, age at first and last pregnancies, time since last full-term childbirth, breastfeeding, age at menopause, ever having an abortion and use of oral contraceptives [OC]) with risk of ER-PR- (n = 998) and ER+PR+ (n = 3,567) breast tumors. A later first full-term childbirth was associated with increased risk of ER+PR+ tumors but not with risk of ER-PR- tumors (≥35 vs. ≤19 years HR: 1.47 [95% CI 1.15-1.88] ptrend < 0.001 for ER+PR+ tumors; ≥35 vs. ≤19 years HR: 0.93 [95% CI 0.53-1.65] ptrend = 0.96 for ER-PR- tumors; Phet = 0.03). The risk associations of menarcheal age, and time period between menarche and first full-term childbirth with ER-PR-tumors were in the similar direction with risk of ER+PR+ tumors (phet = 0.50), although weaker in magnitude and statistically only borderline significant. Other parity related factors such as ever a full-term birth, number of births, age- and time since last birth were associated only with ER+PR+ malignancies, however no statistical heterogeneity between breast cancer subtypes was observed. Breastfeeding and OC use were generally not associated with breast cancer subtype risk. Our study provides possible evidence that age at menarche, and time between menarche and first full-term childbirth may be associated with the etiology of both HR-negative and HR-positive malignancies, although the associations with HR-negative breast cancer were only borderline significant

  6. Pharmacologic management of bone-related complications and bone metastases in postmenopausal women with hormone receptor-positive breast cancer

    OpenAIRE

    Yardley DA

    2016-01-01

    Denise A Yardley1,2 1Sarah Cannon Research Institute, Nashville, TN, USA; 2Tennessee Oncology, Nashville, TN, USA Abstract: There is a high risk for bone loss and skeletal-related events, including bone metastases, in postmenopausal women with hormone receptor-positive breast cancer. Both the disease itself and its therapeutic treatments can negatively impact bone, resulting in decreases in bone mineral density and increases in bone loss. These negative effects on the bone can significantly ...

  7. Considerations for payers in managing hormone receptor-positive advanced breast cancer.

    Science.gov (United States)

    Chitre, Mona; Reimers, Kristen M

    2014-01-01

    Breast cancer (BC) is the second most common cause of death in women. In 2010, the direct cost associated with BC care in the US was $16.5 billion, the highest among all cancers. By the year 2020, at the current rates of incidence and survival, the cost is projected to increase to approximately $20 billion. Although endocrine therapies to manage hormone receptor-positive (HR+) BC are highly effective, endocrine resistance results in disease progression. Increased understanding of endocrine resistance and the mechanisms of disease progression has led to development and subsequent approval of novel targeted treatments, resulting in the expansion of the therapeutic armamentarium to combat HR+ BC. Clear guidelines based on the safety and efficacy of treatment options exist; however, the optimal sequence of therapy is unknown, and providers, payers, and other key players in the health care system are tasked with identifying cost-effective and evidence-based treatment strategies that will improve patient outcomes and, in time, help curb the staggering increase in cost associated with BC care. Safety and efficacy are key considerations, but there is also a need to consider the impact of a given therapy on patient quality of life, treatment adherence, and productivity. To minimize cost associated with overall management, cost-effectiveness, and financial burden that the therapy can impose on patients, caregivers and managed care plans are also important considerations. To help evaluate and identify the optimal choice of therapy for patients with HR+ advanced BC, the available data on endocrine therapies and novel agents are discussed, specifically with respect to the safety, efficacy, financial impact on patients and the managed care plan, impact on quality of life and productivity of patients, and improvement in patient medication adherence.

  8. Treatment challenges for community oncologists treating postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer

    Directory of Open Access Journals (Sweden)

    Gradishar WJ

    2016-07-01

    Full Text Available William J Gradishar Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Abstract: Community-based oncologists are faced with challenges and opportunities when delivering quality patient care, including high patient volumes and diminished resources; however, there may be the potential to deliver increased patient education and subsequently improve outcomes. This review discusses the treatment of postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in order to illustrate considerations in the provision of pertinent quality education in the treatment of these patients and the management of therapy-related adverse events. An overview of endocrine-resistant breast cancer and subsequent treatment challenges is also provided. Approved treatment options for endocrine-resistant breast cancer include hormonal therapies and mammalian target of rapamycin inhibitors. Compounds under clinical investigation are also discussed. Keywords: community oncologists, hormone receptor-positive advanced breast cancer, endocrine resistance

  9. Maintenance bevacizumab beyond first-line paclitaxel plus bevacizumab in patients with Her2-negative hormone receptor-positive metastatic breast cancer: efficacy in combination with hormonal therapy

    International Nuclear Information System (INIS)

    Data on efficacy of bevacizumab (B) beyond first-line taxane -including regimen (BT) as first-line treatment are lacking. Although preclinical results that anti-angiogenic agents combined with hormonal therapy (HT) could be active, no clinical data exist about combination of maintenance Bevacizumab (mBev) with HT. Thirty-five patients who experienced a response after first-line BT, were given mBev at the dose of 15 mg/kg every 3 weeks. Among 30 pts with hormonal receptor-positive metastatic breast cancer (MBC), 20 (66.6%) received HT with mBev (mHTBev). Objective of the study was the outcome and safety of mBev and in two groups of patients receiving HT or not. Complete response and partial response was achieved/maintained in 4 (11.4%) and 13 (37.1%) patients, respectively (overall response rate: 48.5%). Clinical benefit was obtained on 23 patients (65.7%). Median of mBev PFS and clinical benefit were 6.8 months (95% CI: 0.8-12.7) and 17.1 months (95% CI :12.2-21.9), respectively. Median PFS of patients who received mHTBev was longer than mBev without HT (13 months and 4.1 months, respectively, p = 0.05). The most common severe toxicities were proteinuria (11.4%) and hypertension (8.5%). No additional toxicity was observed with HTBev. Maintenance bevacizumab with or without anti-hormonal therapy in patients with hormone receptor positive breast cancer is tolerable and associated with long-term clinical outcome; these results encourage the strategy of prolonging bevacizumab until progression in combination with anti-hormonal agents

  10. Tolerability of Therapies Recommended for the Treatment of Hormone Receptor-Positive Locally Advanced or Metastatic Breast Cancer.

    Science.gov (United States)

    Ohno, Shinji

    2016-08-01

    For women with hormone receptor-positive advanced breast cancer, endocrine therapies, including the selective estrogen receptor modulator tamoxifen, the aromatase inhibitors anastrozole, letrozole, and exemestane, and the selective estrogen receptor degrader fulvestrant, are recommended in clinical guidelines. The addition of targeted agents such as everolimus or palbociclib to aromatase inhibitors are also recommended as treatment options. Chemotherapy remains an option, although clinical guidelines have recommended these agents be reserved for patients with immediately life-threatening disease or if resistance to endocrine therapy is known or suspected. The present review has consolidated the tolerability profiles of the agents approved for use in the treatment of hormone receptor-positive advanced or metastatic breast cancer based on phase III registration trial data. Endocrine therapies are generally well tolerated, although the addition of targeted therapies to aromatase inhibitors or fulvestrant appears to increase the proportion of patients experiencing adverse events, and palbociclib and chemotherapy appear to be more closely associated with serious adverse events, including neutropenia. PMID:27151773

  11. Considerations for payers in managing hormone receptor-positive advanced breast cancer

    Directory of Open Access Journals (Sweden)

    Chitre M

    2014-07-01

    Full Text Available Mona Chitre,1 Kristen M Reimers21Pharmacy Management, Excellus BlueCross BlueShield, Rochester, NY, USA; 2Clinical Drug Programs, Magellan Health/Icore, Orlando, FL, USAAbstract: Breast cancer (BC is the second most common cause of death in women. In 2010, the direct cost associated with BC care in the US was $16.5 billion, the highest among all cancers. By the year 2020, at the current rates of incidence and survival, the cost is projected to increase to approximately $20 billion. Although endocrine therapies to manage hormone receptor-positive (HR+ BC are highly effective, endocrine resistance results in disease progression. Increased understanding of endocrine resistance and the mechanisms of disease progression has led to development and subsequent approval of novel targeted treatments, resulting in the expansion of the therapeutic armamentarium to combat HR+ BC. Clear guidelines based on the safety and efficacy of treatment options exist; however, the optimal sequence of therapy is unknown, and providers, payers, and other key players in the health care system are tasked with identifying cost-effective and evidence-based treatment strategies that will improve patient outcomes and, in time, help curb the staggering increase in cost associated with BC care. Safety and efficacy are key considerations, but there is also a need to consider the impact of a given therapy on patient quality of life, treatment adherence, and productivity. To minimize cost associated with overall management, cost-effectiveness, and financial burden that the therapy can impose on patients, caregivers and managed care plans are also important considerations. To help evaluate and identify the optimal choice of therapy for patients with HR+ advanced BC, the available data on endocrine therapies and novel agents are discussed, specifically with respect to the safety, efficacy, financial impact on patients and the managed care plan, impact on quality of life and

  12. Hormone therapy for prostate cancer

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000908.htm Hormone therapy for prostate cancer To use the sharing ... helps slow the growth of prostate cancer. Male Hormones and Prostate Cancer Androgens are male sex hormones. ...

  13. Progesterone receptor loss identifies hormone receptor-positive and HER2-negative breast cancer subgroups at higher risk of relapse: a retrospective cohort study

    Directory of Open Access Journals (Sweden)

    Sun JY

    2016-03-01

    Full Text Available Jia-Yuan Sun,1,* San-Gang Wu,2,* Feng-Yan Li,1 Huan-Xin Lin,1 Zhen-Yu He1 1Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, People’s Republic of China; 2Department of Radiation Oncology, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China *These authors contributed equally to this work Background: To assess the prognostic value of progesterone receptor (PR expression in patients with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2-negative breast cancer subgroups.Methods: A retrospective review of breast cancer patients who underwent mastectomy or breast-conserving surgery between January 1998 and December 2007 was performed. The prognostic impact of PR status on disease-free survival (DFS was analyzed.Results: Of the 1,301 patients included in this study, the median follow-up time was 64 months, and the median age was 46 years. There were 18.4% of patients (n=219 with PR negative (PR– cancer. Women with PR– breast cancer were more likely to be postmenopausal (P<0.001 and have pN3 stage (P=0.031 and Stage III (P=0.049 cancer. Cox regression univariate and multivariate analysis showed that PR status was a significant prognostic factor for DFS. Patients with PR– status had poorer DFS (hazard ratio =1.626, 95% confidence interval =1.060–2.497, P=0.026. The 5-year DFS for patients with PR– and PR+ breast cancer was 79.4% and 86.2%, respectively, and the 8-year DFS for patients with PR– and PR+ breast cancer was 69.6% and 78.1%, respectively (P=0.012. A significant difference in DFS was observed between PR– and PR+ disease in patients with node-negative cancer, but was not for patients with lymph node metastasis (P=0.242. In premenopausal patients, DFS varied significantly by PR status (P=0.049. A marginally

  14. Rapid steroid hormone actions via membrane receptors.

    Science.gov (United States)

    Schwartz, Nofrat; Verma, Anjali; Bivens, Caroline B; Schwartz, Zvi; Boyan, Barbara D

    2016-09-01

    Steroid hormones regulate a wide variety of physiological and developmental functions. Traditional steroid hormone signaling acts through nuclear and cytosolic receptors, altering gene transcription and subsequently regulating cellular activity. This is particularly important in hormonally-responsive cancers, where therapies that target classical steroid hormone receptors have become clinical staples in the treatment and management of disease. Much progress has been made in the last decade in detecting novel receptors and elucidating their mechanisms, particularly their rapid signaling effects and subsequent impact on tumorigenesis. Many of these receptors are membrane-bound and lack DNA-binding sites, functionally separating them from their classical cytosolic receptor counterparts. Membrane-bound receptors have been implicated in a number of pathways that disrupt the cell cycle and impact tumorigenesis. Among these are pathways that involve phospholipase D, phospholipase C, and phosphoinositide-3 kinase. The crosstalk between these pathways has been shown to affect apoptosis and proliferation in cardiac cells, osteoblasts, and chondrocytes as well as cancer cells. This review focuses on rapid signaling by 17β-estradiol and 1α,25-dihydroxy vitamin D3 to examine the integrated actions of classical and rapid steroid signaling pathways both in contrast to each other and in concert with other rapid signaling pathways. This new approach lends insight into rapid signaling by steroid hormones and its potential for use in targeted drug therapies that maximize the benefits of traditional steroid hormone-directed therapies while mitigating their less desirable effects. PMID:27288742

  15. Potential antitumor effects of nitrogen-containing bisphosphonate in hormone receptor negative breast cancer patients with bone metastases

    International Nuclear Information System (INIS)

    This retrospective study evaluated, according to hormone receptor status, the antitumor effects of bisphosphonate especially on survival and disease progression in breast cancer patients with metastatic bone disease. Of 317 patients with initial bone metastasis and known breast cancer subtypes, 230 patients (72.6%) had hormone receptor (HR) positive tumors, and 87 patients (27.4%) had HR negative tumors. We assessed the primary outcome of overall survival (OS), after adjusting for other factors, comparing a group that received bisphosphonates (BPs) with a group that did not receive it. 87.8% of HR positive and 69.0% of HR negative patients received BPs with a median number of 17.7 cycles. Although BPs treatment made no survival benefit in HR positive group, HR negative patients showed a significant prolonged survival when they received BPs treatment (hazard ratio = 0.56 [95% CI 0.34 to 0.91], P = 0.019). In multivariate analysis, disease free interval > 2 years (P = 0.036), a sum of metastatic sites < 3 (P = 0.034), and BP treatments (P = 0.007) were significant factors for survival in HR negative patients. Bisphosphonate treatment can result in a survival benefit in metastatic breast cancer patients with HR negative tumors

  16. UDP-glucuronosyltransferase and sulfotransferase polymorphisms, sex hormone concentrations, and tumor receptor status in breast cancer patients

    International Nuclear Information System (INIS)

    UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes are involved in removing sex hormones from circulation. Polymorphic variation in five UGT and SULT genes – UGT1A1 ((TA)6/(TA)7), UGT2B4 (Asp458Glu), UGT2B7 (His268Tyr), UGT2B15 (Asp85Tyr), and SULT1A1 (Arg213His) – may be associated with circulating sex hormone concentrations, or the risk of an estrogen receptor-negative (ER-) or progesterone receptor-negative (PR-) tumor. Logistic regression analysis was used to estimate the odds ratios of an ER- or PR- tumor associated with polymorphisms in the genes listed above for 163 breast cancer patients from a population-based cohort study of women in western Washington. Adjusted geometric mean estradiol, estrone, and testosterone concentrations were calculated within each UGT and SULT genotype for a subpopulation of postmenopausal breast cancer patients not on hormone therapy 2–3 years after diagnosis (n = 89). The variant allele of UGT1A1 was associated with reduced risk of an ER- tumor (P for trend = 0.03), and variants of UGT2B15 and SULT1A1 were associated with non-statistically significant risk reductions. There was some indication that plasma estradiol and testosterone concentrations varied by UGT2B15 and SULT1A1 genotypes; women with the UGT2B15 Asp/Tyr and Tyr/Tyr genotypes had higher concentrations of estradiol than women with the Asp/Asp genotype (P = 0.004). Compared with women with the SULT1A1 Arg/Arg and Arg/His genotypes, women with the His/His genotype had elevated concentrations of testosterone (P = 0.003). The risk of ER- breast cancer tumors may vary by UGT or SULT genotype. Further, plasma estradiol and testosterone concentrations in breast cancer patients may differ depending on some UGT and SULT genotypes

  17. Risk of Breast Cancer in Relation to Combined Effects of Hormone Therapy, Body Mass Index, and Alcohol Use, by Hormone-receptor Status

    DEFF Research Database (Denmark)

    Hvidtfeldt, Ulla Arthur; Tjonneland, Anne; Keiding, Niels;

    2015-01-01

    BACKGROUND: Alcohol consumption, increased body mass index (BMI), and hormone therapy are risk factors for postmenopausal breast cancer, but their combined effects are not well understood. Because hormone therapy is effective for the relief of menopausal symptoms, the identification of "high...... therapy users across all BMI strata (P for interaction = 0.003). A markedly higher risk of breast cancer was also observed for alcohol combined with hormone therapy use compared with abstinent nonusers (P for interaction = 0.02). These effects were primarily restricted to ER-positive cases. Combined...... effects of hormone therapy/high BMI and hormone therapy/alcohol on serum estradiol and testosterone supported the hypothesis of a hormonal pathway linking these exposures to breast cancer. CONCLUSION: These analyses suggest an increased risk of breast cancer associated with hormone therapy use-a risk...

  18. Luteal versus follicular phase surgical oophorectomy plus tamoxifen in premenopausal women with metastatic hormone receptor positive breast cancer

    Science.gov (United States)

    Love, Richard R.; Hossain, Syed Mozammel; Hussain, Md. Margub; Mostafa, Mohammad Golam; Laudico, Adriano V.; Siguan, Stephen Sixto S.; Adebamowo, Clement; Sun, Jing-zhong; Fei, Fei; Shao, Zhi-Ming; Yunjiang, Liu; Akram Hussain, Syed Md.; Zhang, Baoning; Lin, Cheng; Panigaro, Sonar; Walta, Fardiana; Chuan, Jiang Hong; Mirasol-Lumague, Maria Rica; Yip, Cheng-Har; Navarro, Narciso S.; Huang, Chiun-sheng; Lu, Yen-shen; Ferdousy, Tahmina; Salim, Reza; Akhter, Chameli; Nahar, Shamsun; Uy, Gemma; Young, Gregory S.; Hade, Erinn M.; Jarjoura, David

    2016-01-01

    Purpose In premenopausal women with metastatic hormone receptor positive breast cancer, hormonal therapy is the first line therapy. GnRH + tamoxifen therapies have been found to be more effective. The pattern of recurrence risk over time after primary surgery suggests that peri-operative factors impact recurrence. Secondary analyses of an adjuvant trial suggested that the luteal phase timing of surgical oophorectomy in the menstrual cycle simultaneous with primary breast surgery favorably influenced long-term outcomes. Methods 249 premenopausal women with incurable or metastatic hormone receptor positive breast cancer entered a trial in which they were randomized to historical mid-luteal or mid-follicular phase surgical oophorectomy followed by oral tamoxifen treatment. Kaplan-Meier methods, the log-rank test, and multivariable Cox regression models were used to assess overall and progression free survival in the two randomized groups and by hormone confirmed menstrual cycle phase. Results Overall survival (OS) and progression-free survival were not demonstrated to be different in the two randomized groups. In a secondary analysis, OS appeared worse in luteal phase surgery patients with progesterone levels of <2ng/ml (anovulatory patients) (adjusted hazard ratio 1.46, 95% CI: 0.89–2.41, p=0.14) compared to patients in luteal phase with progesterone 2ng/ml or higher. Median overall survival was 2.0 years (95% CI: 1.7 – 2.3) and OS at 4 years was 26%. Conclusions The history-based timing of surgical oophorectomy in the menstrual cycle did not influence outcomes in this trial of metastatic patients. ClinicalTrials.gov number NCT 00293540 PMID:27107325

  19. Non-steroidal anti-inflammatory drug use, hormone receptor status, and breast cancer-specific mortality in the Carolina Breast Cancer Study.

    Science.gov (United States)

    Allott, E H; Tse, C-K; Olshan, A F; Carey, L A; Moorman, P G; Troester, M A

    2014-09-01

    Epidemiologic studies report a protective association between non-steroidal anti-inflammatory drug (NSAID) use and hormone receptor-positive breast cancer risk, a finding consistent with NSAID-mediated suppression of aromatase-driven estrogen biosynthesis. However, the association between NSAID use and breast cancer-specific mortality is uncertain and it is unknown whether this relationship differs by hormone receptor status. This study comprised 935 invasive breast cancer cases, of which 490 were estrogen receptor (ER)-positive, enrolled between 1996 and 2001 in the Carolina Breast Cancer Study. Self-reported NSAID use in the decade prior to diagnosis was categorized by duration and regularity of use. Differences in tumor size, stage, node, and receptor status by NSAID use were examined using Chi-square tests. Associations between NSAID use and breast cancer-specific mortality were examined using age- and race-adjusted Cox proportional hazards analysis. Tumor characteristics did not differ by NSAID use. Increased duration and regularity of NSAID use was associated with reduced breast cancer-specific mortality in women with ER-positive tumors (long-term regular use (≥8 days/month for ≥ 3 years) versus no use; hazard ratio (HR) 0.48; 95 % confidence interval (CI) 0.23-0.98), with a statistically significant trend with increasing duration and regularity (p-trend = 0.036). There was no association for ER-negative cases (HR 1.19; 95 %CI 0.50-2.81; p-trend = 0.891). Long-term, regular NSAID use in the decade prior to breast cancer diagnosis was associated with reduced breast cancer-specific mortality in ER-positive cases. If confirmed, these findings support the hypothesis that potential chemopreventive properties of NSAIDs are mediated, at least in part, through suppression of estrogen biosynthesis. PMID:25151293

  20. Endocrine therapy use among elderly hormone receptor-pos...

    Data.gov (United States)

    U.S. Department of Health & Human Services — Clinical guidelines recommend that women with hormone-receptor positive breast cancer receive endocrine therapy (selective estrogen receptor modulators or aromatase...

  1. Mutation analysis underlying the downregulation of the thyroid hormone receptor β1 gene in the Chinese breast cancer population

    Directory of Open Access Journals (Sweden)

    Ling YQ

    2015-10-01

    Full Text Available Yaqin Ling,1 Xiaoling Ling,2 Lu Fan,1 Yong Wang,3,* Qing Li1,* 1Department of Pathophysiology, College of Basic Medical, Lanzhou University, 2Medical Oncology, Lanzhou University First Hospital, 3Department of Gastroenterology, Lanzhou General Hospital of Lanzhou Military Command of PLA, Lanzhou, Gansu Province, People’s Republic of China *These authors contributed equally to this work Purpose: There are a growing number of reports suggesting that the aberrant expression and mutation of the thyroid hormone receptor β1 (TRβ1 gene is associated with the development of human neoplasms. However, its exact role in the pathogenesis of breast cancer remains elusive. In the present study, we analyzed the mRNA expression and mutations of the TRβ1 gene in the Chinese breast cancer population.Methods: The expression of TRβ1 mRNA was examined by real-time quantitative reverse transcription polymerase chain reaction, and mutations in the TRβ1 gene in the hotspot region that spans exons 7–10 were analyzed by polymerase chain reaction single-strand conformation polymorphism and automated DNA sequencing.Results: TRβ1 mRNA expression was significantly reduced in all 105 breast cancer specimens examined. A total of 20 samples showed truncating mutations within the exons 7–10 of the TRβ1 gene, where eight cases harbored a frame shift mutation (five cases of c.850insA in exon 7 and three cases c.1028delA in exon 8, whereas missense mutations were observed in 12 breast cancer cases. The 20 cases with mutation in the TRβ1 gene showed a reduction in TRβ1 mRNA expression compared with that observed in matched normal tissues. The mutation was also correlated with menopausal stage and estrogen receptor status.Conclusion: The findings of the present study suggest that the aberrant expression and mutations of the TRβ1 gene are associated with the development of breast cancer and that the ­mutations in the TRβ1 gene partly serve as the underlying

  2. Patients’ preferences and willingness-to-pay for postmenopausal hormone receptor-positive, HER2-negative advanced breast cancer treatments after failure of standard treatments

    OpenAIRE

    Ngorsuraches, Surachat; Thongkeaw, Klangjai

    2015-01-01

    Patients’ preferences increasingly play roles in cancer treatments. The objective of this study is to examine breast cancer patients’ preferences and willingness-to-pay (WTP) for postmenopausal hormone receptor-positive, HER2-negative advanced breast cancer treatments after failure of standard treatments. Four attributes, i.e. progression free survival (PFS), anemia, pneumonitis, and cost, and their levels of exemestane and exemestane plus everolimus from literature and patient interviews wer...

  3. Determination of HER2 phosphorylation at tyrosine 1221/1222 improves prediction of poor survival for breast cancer patients with hormone receptor-positive tumors

    DEFF Research Database (Denmark)

    Frogne, Thomas; Laenkholm, Anne-Vibeke; Lyng, Maria B;

    2009-01-01

    INTRODUCTION: High expression of total HER2 protein confers poor prognosis for breast cancer patients. HER2 is a member of the HER family consisting of four receptors, HER1 to HER4. HER receptor activity is regulated by a variety of mechanisms, and phosphorylation of the C-terminal part of the HER...... receptor expression in metastatic versus primary tumors showed a significant increase in expression of pHER1 and pHER3 in the metastases. CONCLUSIONS: In hormone receptor-positive breast cancer, determination of pHER2 yields additional prognostic information about poor prognosis compared with the current...... metastases, by evaluating the expression of phosphorylated HER1, HER2, HER3, Erk, Akt and the total level of HER4 and HER2. METHODS: Immunohistochemical analysis was performed on 268 primary breast tumors and 30 paired metastatic lesions from postmenopausal women with hormone receptor-positive breast tumors...

  4. Estrogen Receptor-Targeted Contrast Agents for Molecular Magnetic Resonance Imaging of Breast Cancer Hormonal Status.

    Science.gov (United States)

    Pais, Adi; Degani, Hadassa

    2016-01-01

    The estrogen receptor (ER) α is overexpressed in most breast cancers, and its level serves as a major prognostic factor. It is important to develop quantitative molecular imaging methods that specifically detect ER in vivo and assess its function throughout the entire primary breast cancer and in metastatic breast cancer lesions. This study presents the biochemical and molecular features, as well as the magnetic resonance imaging (MRI) effects of two novel ER-targeted contrast agents (CAs), based on pyridine-tetra-acetate-Gd(III) chelate conjugated to 17β-estradiol (EPTA-Gd) or to tamoxifen (TPTA-Gd). The experiments were conducted in solution, in human breast cancer cells, and in severe combined immunodeficient mice implanted with transfected ER-positive and ER-negative MDA-MB-231 human breast cancer xenografts. Binding studies with ER in solution and in human breast cancer cells indicated affinities in the micromolar range of both CAs. Biochemical and molecular studies in breast cancer cell cultures showed that both CAs exhibit estrogen-like agonistic activity, enhancing cell proliferation, as well as upregulating cMyc oncogene and downregulating ER expression levels. The MRI longitudinal relaxivity was significantly augmented by EPTA-Gd in ER-positive cells as compared to ER-negative cells. Dynamic contrast-enhanced studies with EPTA-Gd in vivo indicated specific augmentation of the MRI water signal in the ER-positive versus ER-negative xenografts, confirming EPTA-Gd-specific interaction with ER. In contrast, TPTA-Gd did not show increased enhancement in ER-positive tumors and did not appear to interact in vivo with the tumors' ER. However, TPTA-Gd was found to interact strongly with muscle tissue, enhancing muscle signal intensity in a mechanism independent of the presence of ER. The specificity of EPTA-Gd interaction with ER in vivo was further verified by acute and chronic competition with tamoxifen. The chronic tamoxifen treatment also revealed that this

  5. Estrogen receptor targeted contrast agents for molecular magnetic resonance imaging of breast cancer hormonal status

    Directory of Open Access Journals (Sweden)

    Adi ePais

    2016-04-01

    Full Text Available The estrogen receptor α (ER is over expressed in most breast cancers and its level serves as a major prognostic factor. It is important to develop quantitative molecular imaging methods that specifically detect ER in vivo and assess its function throughout the entire primary breast cancer, as well as in metastatic breast cancer lesions. This study presents the biochemical and molecular features, as well as the magnetic resonance imaging effects of two novel ER- targeted contrast agents (CAs based on pyridine-tetra-acetate-Gd(III chelate conjugated to 17β-estradiol (EPTA-Gd or to tamoxifen (TPTA-Gd. The experiments were conducted in solution, in human breast cancer cells and in severe combined immunodeficient mice implanted with transfected ER-positive and ER-negative MDA-MB-231 human breast cancer xenografts. Binding studies with ER in solution and in human breast cancer cells indicated affinities in the micromolar range of both CAs. Biochemical and molecular studies in breast cancer cell cultures showed that both CAs exhibit estrogen like agonistic activity, enhancing cell proliferation, as well as up-regulating cMyc oncogene and down-regulating ER expression levels. The MRI longitudinal relaxivity was significantly augmented by EPTA-Gd in ER-positive cells as compared to ER-negative cells. Dynamic contrast enhanced studies with EPTA-Gd in vivo indicated specific augmentation of the MRI water signal in the ER-positive versus ER-negative xenografts, confirming EPTA-Gd specific interaction with ER. In contrast, TPTA-Gd did not show increased enhancement in ER-positive tumors and did not appear to interact in vivo with the tumors’ ER. However, TPTA-Gd was found to interact strongly with muscle tissue, enhancing muscle signal intensity in a mechanism independent of the presence of ER. The specificity of EPTA-Gd interaction with ER in vivo was further verified by acute and chronic competition with tamoxifen. The chronic tamoxifen treatment also

  6. Human epidermal growth factor receptor type 2 protein expression in Chinese metastatic prostate cancer patients correlates with cancer specific survival and increases after exposure to hormonal therapy

    Institute of Scientific and Technical Information of China (English)

    Bo Dai; Yun-Yi Kong; Ding-Wei Ye; Chun-Guang Ma; Xiao-Yan Zhou; Xu-Dong Yao

    2008-01-01

    Aim: To investigate human epidermal growth factor receptor type 2 (HER2) protein expression and gene amplification in Chinese metastatic prostate cancer patients and their potential value as prognostic factors. Methods: Immuno-histochemistry (IHC) was performed to investigate HER2 protein expression in prostate biopsy specimens from 104 Chinese metastatic prostate cancer patients. After 3-11 months of hormonal therapy, 12 patients underwent transure- thral resection of the prostate (TURP). HER2 protein expression of TURP specimens was compared with that of the original biopsy specimens. Of these, 10 biopsy and 4 TURP specimens with HER2 IHC staining scores ≥ 2+ were investigated for HER2 gene amplification status by fluorescent in situ hybridization (FISH). Results: Of the 104 prostate biopsy specimens, HER2 protein expression was 0, 1+, 2+ and 3+ in 49 (47.1%), 45 (43.3%), 8 (7.7%) and 2 (1.9%) cases, respectively. There was a significant association between HER2 expression and Gleason score (P = 0.026). HER2 protein expression of prostate cancer tissues increased in 33.3% of patients after hormonal therapy. None of the 14 specimens with HER2 IHC scores > 2+ showed HER2 gene amplification. Patients with HER2 scores ≥ 2+ had a significantly higher chance of dying from prostate cancer than those with HER2 scores of 0 (P = 0.004) and 1+ (P = 0.034). Multivariate Cox regression analysis showed that HER2 protein expression intensity was an independent predictor of cancer-related death (P = 0.039). Conclusion: An HER2 IHC score ≥ 2+ should be defined as HER2 protein overexpression in prostate cancer. Overexpression of HER2 protein in cancer tissue might suggest an increased risk of dying from prostate cancer. HER2 protein expression increases in some individual patients after hormonal therapy.

  7. CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial

    DEFF Research Database (Denmark)

    Leyland-Jones, Brian; Gray, Kathryn P; Abramovitz, Mark;

    2015-01-01

    To determine whether CYP19A1 polymorphisms are associated with abnormal activity of aromatase and with musculoskeletal and bone side effects of aromatase inhibitors. DNA was isolated from tumor specimens of 4861 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG...

  8. Growth hormone receptor antagonism suppresses tumour regrowth after radiotherapy in an endometrial cancer xenograft model.

    Science.gov (United States)

    Evans, Angharad; Jamieson, Stephen M F; Liu, Dong-Xu; Wilson, William R; Perry, Jo K

    2016-08-28

    Human GH expression is associated with poor survival outcomes for endometrial cancer patients, enhanced oncogenicity of endometrial cancer cells and reduced sensitivity to ionising radiation in vitro, suggesting that GH is a potential target for anticancer therapy. However, whether GH receptor inhibition sensitises to radiotherapy in vivo has not been tested. In the current study, we evaluated whether the GH receptor antagonist, pegvisomant (Pfizer), sensitises to radiotherapy in vivo in an endometrial tumour xenograft model. Subcutaneous administration of pegvisomant (20 or 100 mg/kg/day, s.c.) reduced serum IGF1 levels by 23% and 68%, respectively, compared to vehicle treated controls. RL95-2 xenografts grown in immunodeficient NIH-III mice were treated with vehicle or pegvisomant (100 mg/kg/day), with or without fractionated gamma radiation (10 × 2.5 Gy over 5 days). When combined with radiation, pegvisomant significantly increased the median time tumours took to reach 3× the pre-radiation treatment volume (49 days versus 72 days; p = 0.001). Immunohistochemistry studies demonstrated that 100 mg/kg pegvisomant every second day was sufficient to abrogate MAP Kinase signalling throughout the tumour. In addition, treatment with pegvisomant increased hypoxic regions in irradiated tumours, as determined by immunohistochemical detection of pimonidazole adducts, and decreased the area of CD31 labelling in unirradiated tumours, suggesting an anti-vascular effect. Pegvisomant did not affect intratumoral staining for HIF1α, VEGF-A, CD11b, or phospho-EGFR. Our results suggest that blockade of the human GH receptor may improve the response of GH and/or IGF1-responsive endometrial tumours to radiation.

  9. Growth hormone receptor antagonism suppresses tumour regrowth after radiotherapy in an endometrial cancer xenograft model.

    Science.gov (United States)

    Evans, Angharad; Jamieson, Stephen M F; Liu, Dong-Xu; Wilson, William R; Perry, Jo K

    2016-08-28

    Human GH expression is associated with poor survival outcomes for endometrial cancer patients, enhanced oncogenicity of endometrial cancer cells and reduced sensitivity to ionising radiation in vitro, suggesting that GH is a potential target for anticancer therapy. However, whether GH receptor inhibition sensitises to radiotherapy in vivo has not been tested. In the current study, we evaluated whether the GH receptor antagonist, pegvisomant (Pfizer), sensitises to radiotherapy in vivo in an endometrial tumour xenograft model. Subcutaneous administration of pegvisomant (20 or 100 mg/kg/day, s.c.) reduced serum IGF1 levels by 23% and 68%, respectively, compared to vehicle treated controls. RL95-2 xenografts grown in immunodeficient NIH-III mice were treated with vehicle or pegvisomant (100 mg/kg/day), with or without fractionated gamma radiation (10 × 2.5 Gy over 5 days). When combined with radiation, pegvisomant significantly increased the median time tumours took to reach 3× the pre-radiation treatment volume (49 days versus 72 days; p = 0.001). Immunohistochemistry studies demonstrated that 100 mg/kg pegvisomant every second day was sufficient to abrogate MAP Kinase signalling throughout the tumour. In addition, treatment with pegvisomant increased hypoxic regions in irradiated tumours, as determined by immunohistochemical detection of pimonidazole adducts, and decreased the area of CD31 labelling in unirradiated tumours, suggesting an anti-vascular effect. Pegvisomant did not affect intratumoral staining for HIF1α, VEGF-A, CD11b, or phospho-EGFR. Our results suggest that blockade of the human GH receptor may improve the response of GH and/or IGF1-responsive endometrial tumours to radiation. PMID:27241667

  10. Neoadjuvant hormonal therapy is associated with comparable outcomes to neoadjuvant chemotherapy in post-menopausal women with estrogen receptor-positive breast cancer

    OpenAIRE

    Marcus, David M.; Switchenko, Jeffrey M.; Roshan ePrabhu; Ruth eO'Regan; Amelia eZelnak; Carolina eFasola; Donna eMister; Torres, Mylin A.

    2013-01-01

    Objectives: We compared outcomes in post-menopausal estrogen receptor-positive (ER+) breast cancer patients treated with neoadjuvant hormonal therapy (NAHT) or neoadjuvant chemotherapy (NACT).Methods: We retrospectively identified post-menopausal women who received either NAHT or NACT for non-metastatic, non-inflammatory, ER+, Her2neu negative breast cancer from 2004 to 2011. We compared long-term rates of locoregional relapse free survival (LRFS), distant metastasis free survival (DMFS), ...

  11. Neoadjuvant Hormonal Therapy is Associated with Comparable Outcomes to Neoadjuvant Chemotherapy in Post-Menopausal Women with Estrogen Receptor-Positive Breast Cancer

    OpenAIRE

    Marcus, David M.; Switchenko, Jeffrey M.; Prabhu, Roshan; O’Regan, Ruth; Zelnak, Amelia; Fasola, Carolina; Mister, Donna; Torres, Mylin A.

    2013-01-01

    Objectives: We compared outcomes in post-menopausal estrogen receptor-positive (ER+) breast cancer patients treated with neoadjuvant hormonal therapy (NAHT) or neoadjuvant chemotherapy (NACT). Methods: We retrospectively identified post-menopausal women who received either NAHT or NACT for non-metastatic, non-inflammatory, ER+, Her2neu negative breast cancer from 2004 to 2011. We compared long-term rates of locoregional relapse free survival (LRFS), distant metastasis free survival (DMFS),...

  12. Surgery Should Complement Endocrine Therapy for Elderly Postmenopausal Women with Hormone Receptor-Positive Early-Stage Breast Cancer

    Directory of Open Access Journals (Sweden)

    Olivier Nguyen

    2012-01-01

    Full Text Available Introduction. Endocrine therapy (ET is an integral part of breast cancer (BC treatment with surgical resection remaining the cornerstone of curative treatment. The objective of this study is to compare the survival of elderly postmenopausal women with hormone receptor-positive early-stage BC treated with ET alone, without radiation or chemotherapy, versus ET plus surgery. Materials and Methods. This is a retrospective study based on a prospective database. The medical records of postmenopausal BC patients referred to the surgical oncology service of two hospitals during an 8-year period were reviewed. All patients were to receive ET for a minimum of four months before undergoing any surgery. Results. Fifty-one patients were included and divided in two groups, ET alone and ET plus surgery. At last follow-up in exclusive ET patients (n=28, 39% had stable disease or complete response, 22% had progressive disease, of which 18% died of breast cancer, and 39% died of other causes. In surgical patients (n=23, 78% were disease-free, 9% died of recurrent breast cancer, and 13% died of other causes. Conclusions. These results suggest that surgical resection is beneficial in this group and should be considered, even for patients previously deemed ineligible for surgery.

  13. Proliferative response of human prostate cancer cell to hormone inhibited by androgen receptor antisense RNA

    Institute of Scientific and Technical Information of China (English)

    江军; 王洛夫; 方玉华; 靳风烁; 靳文生

    2004-01-01

    Background The failure of endocrine treatment for advanced prostate cancer might be related to aberrant activation of androgen receptor (AR). Prostate cancer cell line LNCaP contains AR that can be activated by androgen, estrogen and progesterone. This study was set to investigate the effects of antisense AR RNA on growth of LNCaP cultured in medium containing varied concentrations of R1881, 17β-estradiol, and progesterone, respectively. Methods LNCaP cells transfected with antisense AR RNA retroviral vector pL-AR-SN were designated as LNCaPas-AR. LNCaP cells containing empty vector pLXSN served as LNCaPNeo. LNCaP and LNCaPNeo were taken as controls. In vitro cell growth assay, proliferative cells of LNCaP and tranfected LNCaPs were counted by typan staining when they cultured with synthetic androgen R1881, 17β-estradiol, and progesterone, respectively. Results Growth of LNCaPas-AR was inhibited significantly (P<0.05) compared with that of LNCaP and LNCaPNeo at 1 nmol/L R1881, 10 nmol/L 17β-estradiol, and 1 nmol/L progesterone, respectively. No difference was seen between LNCaP and LNCaPNeo(P>0.05). Microscopic observation showed that LNCaP and LNCaPNeo cells grew well, but only few LNCaPas-AR cells were alive. Conclusions Our observations indicate that antisense AR RNA retroviral vector pL-AR-SN could change androgen-independent characteristics of LNCaP cells, which might shed some novel insights into the treatment of androgen-independent prostate cancer.

  14. Hormonal-receptor positive breast cancer: IL-6 augments invasion and lymph node metastasis via stimulating cathepsin B expression

    Directory of Open Access Journals (Sweden)

    Sherif A. Ibrahim

    2016-09-01

    Full Text Available Hormonal-receptor positive (HRP breast cancer patients with positive metastatic axillary lymph nodes are characterized by poor prognosis and increased mortality rate. The mechanisms by which cancer cells invade lymph nodes have not yet been fully explored. Several studies have shown that expression of IL-6 and the proteolytic enzyme cathepsin B (CTSB was associated with breast cancer poor prognosis. In the present study, the effect of different concentrations of recombinant human IL-6 on the invasiveness capacity of HRP breast cancer cell line MCF-7 was tested using an in vitro invasion chamber assay. The impact of IL-6 on expression and activity of CTSB was also investigated. IL-6 treatment promoted the invasiveness potential of MCF-7 cells in a dose-dependent manner. Furthermore, MCF-7 cells displayed elevated CTSB expression and activity associated with loss of E-cadherin and upregulation of vimentin protein levels upon IL-6 stimulation. To validate these results in vivo, the level of expression of IL-6 and CTSB in the carcinoma tissues of HRP-breast cancer patients with positive and negative axillary metastatic lymph nodes (pLNs and nLNs was assessed. Western blot and immunohistochemical staining data showed that expression of IL-6 and CTSB was higher in carcinoma tissues in HRP-breast cancer with pLNs than those with nLNs patients. ELISA results showed carcinoma tissues of HRP-breast cancer with pLNs exhibited significantly elevated IL-6 protein levels by approximately 2.8-fold compared with those with nLNs patients (P < 0.05. Interestingly, a significantly positive correlation between IL-6 and CTSB expression was detected in clinical samples of HRP-breast cancer patients with pLNs (r = 0.78, P < 0.01. Collectively, this study suggests that IL-6-induced CTSB may play a role in lymph node metastasis, and that may possess future therapeutic implications for HRP-breast cancer patients with pLNs. Further studies are necessary to fully

  15. Hormonal-receptor positive breast cancer: IL-6 augments invasion and lymph node metastasis via stimulating cathepsin B expression.

    Science.gov (United States)

    Ibrahim, Sherif A; El-Ghonaimy, Eslam A; Hassan, Hebatallah; Mahana, Noha; Mahmoud, Mahmoud Abdelbaky; El-Mamlouk, Tahani; El-Shinawi, Mohamed; Mohamed, Mona M

    2016-09-01

    Hormonal-receptor positive (HRP) breast cancer patients with positive metastatic axillary lymph nodes are characterized by poor prognosis and increased mortality rate. The mechanisms by which cancer cells invade lymph nodes have not yet been fully explored. Several studies have shown that expression of IL-6 and the proteolytic enzyme cathepsin B (CTSB) was associated with breast cancer poor prognosis. In the present study, the effect of different concentrations of recombinant human IL-6 on the invasiveness capacity of HRP breast cancer cell line MCF-7 was tested using an in vitro invasion chamber assay. The impact of IL-6 on expression and activity of CTSB was also investigated. IL-6 treatment promoted the invasiveness potential of MCF-7 cells in a dose-dependent manner. Furthermore, MCF-7 cells displayed elevated CTSB expression and activity associated with loss of E-cadherin and upregulation of vimentin protein levels upon IL-6 stimulation. To validate these results in vivo, the level of expression of IL-6 and CTSB in the carcinoma tissues of HRP-breast cancer patients with positive and negative axillary metastatic lymph nodes (pLNs and nLNs) was assessed. Western blot and immunohistochemical staining data showed that expression of IL-6 and CTSB was higher in carcinoma tissues in HRP-breast cancer with pLNs than those with nLNs patients. ELISA results showed carcinoma tissues of HRP-breast cancer with pLNs exhibited significantly elevated IL-6 protein levels by approximately 2.8-fold compared with those with nLNs patients (P positive correlation between IL-6 and CTSB expression was detected in clinical samples of HRP-breast cancer patients with pLNs (r = 0.78, P node metastasis, and that may possess future therapeutic implications for HRP-breast cancer patients with pLNs. Further studies are necessary to fully identify IL-6/CTSB axis in different molecular subtypes of breast cancer. PMID:27482469

  16. Epigenetic reactivation of estrogen receptor-α (ERα by genistein enhances hormonal therapy sensitivity in ERα-negative breast cancer

    Directory of Open Access Journals (Sweden)

    Li Yuanyuan

    2013-02-01

    Full Text Available Abstract Background Estrogen receptor-α (ERα-negative breast cancer is clinically aggressive and normally does not respond to conventional estrogen target-directed therapies. The soybean isoflavone, genistein (GE, has been shown to prevent and inhibit breast cancer and recent studies have suggested that GE can enhance the anticancer capacity of an estrogen antagonist, tamoxifen (TAM, especially in ERα-positive breast cancer cells. However, the role of GE in ERα-negative breast cancer remains unknown. Methods We have evaluated the in vitro and in vivo epigenetic effects of GE on ERα reactivation by using MTT assay, real-time reverse transcription-polymerase chain reaction (RT-PCR assay, western-blot assay, immunoprecipitation (ChIP assay, immunohistochemistry and epigenetic enzymatic activity analysis. Preclinical mouse models including xenograft and spontaneous breast cancer mouse models were used to test the efficacy of GE in vivo. Results We found that GE can reactivate ERα expression and this effect was synergistically enhanced when combined with a histone deacetylase (HDAC inhibitor, trichostatin A (TSA, in ERα-negative MDA-MB-231 breast cancer cells. GE treatment also re-sensitized ERα-dependent cellular responses to activator 17β-estradiol (E2 and antagonist TAM. Further studies revealed that GE can lead to remodeling of the chromatin structure in the ERα promoter thereby contributing to ERα reactivation. Consistently, dietary GE significantly prevented cancer development and reduced the growth of ERα-negative mouse breast tumors. Dietary GE further enhanced TAM-induced anti-cancer efficacy due at least in part to epigenetic ERα reactivation. Conclusions Our studies suggest that soybean genistein can epigenetically restore ERα expression, which in turn increases TAM-dependent anti-estrogen therapeutic sensitivity in vitro and in vivo. The results from our studies reveal a novel therapeutic combination approach using bioactive

  17. Hepatic growth hormone and glucocorticoid receptor signaling in body growth, steatosis and metabolic liver cancer development.

    Science.gov (United States)

    Mueller, Kristina M; Themanns, Madeleine; Friedbichler, Katrin; Kornfeld, Jan-Wilhelm; Esterbauer, Harald; Tuckermann, Jan P; Moriggl, Richard

    2012-09-25

    Growth hormone (GH) and glucocorticoids (GCs) are involved in the control of processes that are essential for the maintenance of vital body functions including energy supply and growth control. GH and GCs have been well characterized to regulate systemic energy homeostasis, particular during certain conditions of physical stress. However, dysfunctional signaling in both pathways is linked to various metabolic disorders associated with aberrant carbohydrate and lipid metabolism. In liver, GH-dependent activation of the transcription factor signal transducer and activator of transcription (STAT) 5 controls a variety of physiologic functions within hepatocytes. Similarly, GCs, through activation of the glucocorticoid receptor (GR), influence many important liver functions such as gluconeogenesis. Studies in hepatic Stat5 or GR knockout mice have revealed that they similarly control liver function on their target gene level and indeed, the GR functions often as a cofactor of STAT5 for GH-induced genes. Gene sets, which require physical STAT5-GR interaction, include those controlling body growth and maturation. More recently, it has become evident that impairment of GH-STAT5 signaling in different experimental models correlates with metabolic liver disease, ranging from hepatic steatosis to hepatocellular carcinoma (HCC). While GH-activated STAT5 has a protective role in chronic liver disease, experimental disruption of GC-GR signaling rather seems to ameliorate metabolic disorders under metabolic challenge. In this review, we focus on the current knowledge about hepatic GH-STAT5 and GC-GR signaling in body growth, metabolism, and protection from fatty liver disease and HCC development.

  18. Plant hormone receptors: new perceptions

    OpenAIRE

    Spartz, Angela K.; William M Gray

    2008-01-01

    Plant growth and development require the integration of a variety of environmental and endogenous signals that, together with the intrinsic genetic program, determine plant form. Central to this process are several growth regulators known as plant hormones or phytohormones. Despite decades of study, only recently have receptors for several of these hormones been identified, revealing novel mechanisms for perceiving chemical signals and providing plant biologists with a much clearer picture of...

  19. [18F]-fluorodeoxyglucose positron emission tomography can contribute to discriminate patients with poor prognosis in hormone receptor-positive breast cancer.

    Directory of Open Access Journals (Sweden)

    Sung Gwe Ahn

    Full Text Available Patients with hormone receptor-positive breast cancer typically show favorable survival. However, identifying individuals at high risk of recurrence among these patients is a crucial issue. We tested the hypothesis that [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET scans can help predict prognosis in patients with hormone receptor-positive breast cancer.Between April 2004 and December 2008, 305 patients with hormone receptor-positive breast cancer who underwent FGD-PET were enrolled. Patients with luminal B subtype were identified by positivity for human epidermal growth factor receptor-2 (HER2 or high Ki67 (≥14% according to criteria recently recommended by the St. Gallen panelists. The cut-off value of SUVmax was defined using the time-dependent receiver operator characteristic curve for recurrence-free survival (RFS.At a median follow up of 6.23 years, continuous SUVmax was a significant prognostic factor with a hazard ratio (HR of 1.21 (p = 0.021. The cut-off value of SUVmax was defined as 4. Patients with luminal B subtype (n = 82 or high SUVmax (n = 107 showed a reduced RFS (p = 0.031 and 0.002, respectively. In multivariate analysis for RFS, SUVmax carried independent prognostic significance (p = 0.012 whereas classification with immunohistochemical markers did not (p = 0.274. The Harell c-index was 0.729. High SUVmax was significantly associated with larger tumor size, positive nodes, HER2 positivity, high Ki67 (≥14%, high tumor grade, and luminal B subtype.Among patients with hormone receptor-positive breast cancer, FDG-PET can help discriminate patients at high risk of tumor relapse.

  20. Docetaxel, Carboplatin, Trastuzumab, and Pertuzumab With or Without Estrogen Deprivation in Treating Patients With Hormone Receptor-Positive, HER2-Positive Operable or Locally Advanced Breast Cancer

    Science.gov (United States)

    2016-09-08

    Estrogen Receptor Positive; HER2/Neu Positive; Progesterone Receptor Positive; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  1. The growth hormone receptor: mechanism of activation and clinical implications.

    Science.gov (United States)

    Brooks, Andrew J; Waters, Michael J

    2010-09-01

    Growth hormone is widely used clinically to promote growth and anabolism and for other purposes. Its actions are mediated via the growth hormone receptor, both directly by tyrosine kinase activation and indirectly by induction of insulin-like growth factor 1 (IGF-1). Insensitivity to growth hormone (Laron syndrome) can result from mutations in the growth hormone receptor and can be treated with IGF-1. This treatment is, however, not fully effective owing to the loss of the direct actions of growth hormone and altered availability of exogenous IGF-1. Excessive activation of the growth hormone receptor by circulating growth hormone results in gigantism and acromegaly, whereas cell transformation and cancer can occur in response to autocrine activation of the receptor. Advances in understanding the mechanism of receptor activation have led to a model in which the growth hormone receptor exists as a constitutive dimer. Binding of the hormone realigns the subunits by rotation and closer apposition, resulting in juxtaposition of the catalytic domains of the associated tyrosine-protein kinase JAK2 below the cell membrane. This change results in activation of JAK2 by transphosphorylation, then phosphorylation of receptor tyrosines in the cytoplasmic domain, which enables binding of adaptor proteins, as well as direct phosphorylation of target proteins. This model is discussed in the light of salient information from closely related class 1 cytokine receptors, such as the erythropoietin, prolactin and thrombopoietin receptors. PMID:20664532

  2. The association of soy food consumption with the risk of subtype of breast cancers defined by hormone receptor and HER2 status.

    Science.gov (United States)

    Baglia, Michelle L; Zheng, Wei; Li, Honglan; Yang, Gong; Gao, Jing; Gao, Yu-Tang; Shu, Xiao-Ou

    2016-08-15

    Soy food intake has previously been associated with reduced breast cancer risk. Epidemiological evidence for subgroups of breast cancer, particularly by menopausal and hormone receptor status, is less consistent. To evaluate the role of hormone receptor and menopausal status on the association between soy food intake and breast cancer risk, we measured usual soy food intake in adolescence and adulthood via food frequency questionnaire in 70,578 Chinese women, aged 40-70 years, recruited to the Shanghai Women's Health Study (1996-2000). After a median follow-up of 13.2 years (range: 0.01-15.0), 1,034 incident breast cancer cases were identified. Using Cox models, we found that adult soy intake was inversely associated with breast cancer risk [hazard ratio (HR) for fifth versus first quintile soy protein intake = 0.78; 95% confidence interval (CI):0.63-0.97]. The association was predominantly seen in premenopausal women (HR = 0.46; 95% CI:0.29-0.74). Analyses further stratified by hormone receptor status showed that adult soy intake was associated with significantly decreased risk of estrogen receptor (ER)+/progesterone receptor (PR)+ breast cancer in postmenopausal women (HR = 0.72; 95% CI:0.53-0.96) and decreased risk of ER-/PR- breast cancer in premenopausal women (HR = 0.46; 95% CI:0.22-0.97). The soy association did not vary by human epidermal growth factor-2 (HER2) status. Furthermore, we found that high soy intake during adulthood and adolescence was associated with reduced premenopausal breast cancer risk (HR = 0.53; 95% CI: 0.32-0.88; comparing third vs. first tertile) while high adulthood soy intake was associated with postmenopausal breast cancer only when adolescent intake was low (HR = 0.63; 95% CI: 0.43-0.91). Our study suggests that hormonal status, menopausal status and time window of exposure are important factors influencing the soy-breast cancer association. PMID:27038352

  3. Metformin increases survival in hormone receptor-positive, HER2-positive breast cancer patients with diabetes

    OpenAIRE

    Kim, Hee Jeong; Kwon, Hyunwook; Lee, Jong Won; Kim, Hwa Jung; Lee, Sae Byul; Park, Hee Sung; Sohn, Guiyun; Lee, Yura; Koh, Beom Seok; Yu, Jong Han; Son, Byung Ho; Ahn, Sei Hyun

    2015-01-01

    Introduction Metformin use has recently been observed to decrease both the rate and mortality of breast cancer. Our study was aim to determine whether metformin use is associated with survival in diabetic breast cancer patients by breast cancer subtype and systemic treatment. Methods Data from the Asan Medical Center Breast Cancer Database from 1997 to 2007 were analyzed. The study cohort comprised 6,967 nondiabetic patients, 202 diabetic patients treated with metformin, and 184 diabetic pati...

  4. Dietary flavonoid and lignan intake and breast cancer risk according to menopause and hormone receptor status in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study.

    Science.gov (United States)

    Zamora-Ros, Raul; Ferrari, Pietro; González, Carlos A; Tjønneland, Anne; Olsen, Anja; Bredsdorff, Lea; Overvad, Kim; Touillaud, Marina; Perquier, Florence; Fagherazzi, Guy; Lukanova, Annekatrin; Tikk, Kaja; Aleksandrova, Krasimira; Boeing, Heiner; Trichopoulou, Antonia; Trichopoulos, Dimitrios; Dilis, Vardis; Masala, Giovanna; Sieri, Sabina; Mattiello, Amalia; Tumino, Rosario; Ricceri, Fulvio; Bueno-de-Mesquita, H Bas; Peeters, Petra H M; Weiderpass, Elisabete; Skeie, Guri; Engeset, Dagrun; Menéndez, Virginia; Travier, Noémie; Molina-Montes, Esther; Amiano, Pilar; Chirlaque, Maria-Dolores; Barricarte, Aurelio; Wallström, Peter; Sonestedt, Emily; Sund, Malin; Landberg, Rikard; Khaw, Kay-Thee; Wareham, Nicholas J; Travis, Ruth C; Scalbert, Augustin; Ward, Heather A; Riboli, Elio; Romieu, Isabelle

    2013-05-01

    Evidence on the association between dietary flavonoids and lignans and breast cancer (BC) risk is inconclusive, with the possible exception of isoflavones in Asian countries. Therefore, we investigated prospectively dietary total and subclasses of flavonoid and lignan intake and BC risk according to menopause and hormonal receptor status in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The study included 334,850 women, mostly aged between 35 and 70 years from ten European countries. At baseline, country-specific validated dietary questionnaires were used. A flavonoid and lignan food composition database was developed from the US Department of Agriculture, the Phenol-Explorer and the UK Food Standards Agency databases. Cox regression models were used to analyse the association between dietary flavonoid/lignan intake and the risk of developing BC. During an average 11.5-year follow-up, 11,576 incident BC cases were identified. No association was observed between the intake of total flavonoids [hazard ratio comparing fifth to first quintile (HRQ5-Q1) 0.97, 95 % confidence interval (CI): 0.90-1.04; P trend = 0.591], isoflavones (HRQ5-Q1 1.00, 95 % CI: 0.91-1.10; P trend = 0.734), or total lignans (HRQ5-Q1 1.02, 95 % CI: 0.93-1.11; P trend = 0.469) and overall BC risk. The stratification of the results by menopausal status at recruitment or the differentiation of BC cases according to oestrogen and progesterone receptors did not affect the results. This study shows no associations between flavonoid and lignan intake and BC risk, overall or after taking into account menopausal status and BC hormone receptors. PMID:23572295

  5. Thyroid Hormone Receptor-β (TRβ) Mediates Runt-Related Transcription Factor 2 (Runx2) Expression in Thyroid Cancer Cells: A Novel Signaling Pathway in Thyroid Cancer.

    Science.gov (United States)

    Carr, Frances E; Tai, Phillip W L; Barnum, Michael S; Gillis, Noelle E; Evans, Katherine G; Taber, Thomas H; White, Jeffrey H; Tomczak, Jennifer A; Jaworski, Diane M; Zaidi, Sayyed K; Lian, Jane B; Stein, Janet L; Stein, Gary S

    2016-08-01

    Dysregulation of the thyroid hormone receptor (TR)β is common in human cancers. Restoration of functional TRβ delays tumor progression in models of thyroid and breast cancers implicating TRβ as a tumor suppressor. Conversely, aberrant expression of the runt-related transcription factor 2 (Runx2) is established in the progression and metastasis of thyroid, breast, and other cancers. Silencing of Runx2 diminishes tumor invasive characteristics. With TRβ as a tumor suppressor and Runx2 as a tumor promoter, a compelling question is whether there is a functional relationship between these regulatory factors in thyroid tumorigenesis. Here, we demonstrated that these proteins are reciprocally expressed in normal and malignant thyroid cells; TRβ is high in normal cells, and Runx2 is high in malignant cells. T3 induced a time- and concentration-dependent decrease in Runx2 expression. Silencing of TRβ by small interfering RNA knockdown resulted in a corresponding increase in Runx2 and Runx2-regulated genes, indicating that TRβ levels directly impact Runx2 expression and associated epithelial to mesenchymal transition molecules. TRβ specifically bound to 3 putative thyroid hormone-response element motifs within the Runx2-P1 promoter ((-)105/(+)133) as detected by EMSA and chromatin immunoprecipitation. TRβ suppressed Runx2 transcriptional activities, thus confirming TRβ regulation of Runx2 at functional thyroid hormone-response elements. Significantly, these findings indicate that a ratio of the tumor-suppressor TRβ and tumor-promoting Runx2 may reflect tumor aggression and serve as biomarkers in biopsy tissues. The discovery of this TRβ-Runx2 signaling supports the emerging role of TRβ as a tumor suppressor and reveals a novel pathway for intervention. PMID:27253998

  6. Steroid Hormone Receptor Signals as Prognosticators for Urothelial Tumor

    Directory of Open Access Journals (Sweden)

    Hiroki Ide

    2015-01-01

    Full Text Available There is a substantial amount of preclinical or clinical evidence suggesting that steroid hormone receptor-mediated signals play a critical role in urothelial tumorigenesis and tumor progression. These receptors include androgen receptor, estrogen receptors, glucocorticoid receptor, progesterone receptor, vitamin D receptor, retinoid receptors, peroxisome proliferator-activated receptors, and others including orphan receptors. In particular, studies using urothelial cancer tissue specimens have demonstrated that elevated or reduced expression of these receptors as well as alterations of their upstream or downstream pathways correlates with patient outcomes. This review summarizes and discusses available data suggesting that steroid hormone receptors and related signals serve as biomarkers for urothelial carcinoma and are able to predict tumor recurrence or progression.

  7. Genetic features of thyroid hormone receptors

    Indian Academy of Sciences (India)

    Maha Rebaï; Imen Kallel; Ahmed Rebaï

    2012-12-01

    Thyroid hormone receptors (TR) are prototypes of nuclear transcription factors that regulate the expression of target genes. These receptors play an important role in many physiological processes. Moreover, a dysfunction of these proteins is often implicated in several human diseases and malignancies. Here we report genetic variations and alterations of the TRs that have been described in the literature as well as their potential role in the development of some human diseases including cancers. The functional effects of some mutations and polymorphisms in TRs on disease susceptibility, especially on cancer risk, are now established. Therefore, further investigations are needed in order to use these receptors as therapeutic targets or as biological markers to decide on appropriate forms of treatment.

  8. Strategies for Imaging Androgen Receptor Signaling Pathway in Prostate Cancer: Implications for Hormonal Manipulation and Radiation Treatment

    Directory of Open Access Journals (Sweden)

    Gravina Giovanni Luca

    2013-01-01

    Full Text Available Prostate cancer (Pca is a heterogeneous disease; its etiology appears to be related to genetic and epigenetic factors. Radiotherapy and hormone manipulation are effective treatments, but many tumors will progress despite these treatments. Molecular imaging provides novel opportunities for image-guided optimization and management of these treatment modalities. Here we reviewed the advances in targeted imaging of key biomarkers of androgen receptor signaling pathways. A computerized search was performed to identify all relevant studies in Medline up to 2013. There are well-known limitations and inaccuracies of current imaging approaches for monitoring biological changes governing tumor progression. The close integration of molecular biology and clinical imaging could ease the development of new molecular imaging agents providing novel tools to monitor a number of biological events that, until a few years ago, were studied by conventional molecular assays. Advances in translational research may represent the next step in improving the oncological outcome of men with Pca who remain at high risk for systemic failure. This aim may be obtained by combining the anatomical properties of conventional imaging modalities with biological information to better predict tumor response to conventional treatments.

  9. 11q13 is a Susceptibility Locus for Hormone Receptor Positive Breast Cancer

    DEFF Research Database (Denmark)

    Lambrechts, Diether; Truong, Therese; Justenhoven, Christina;

    2012-01-01

    A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10 and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we ge...

  10. Attribution to Heterogeneous Risk Factors for Breast Cancer Subtypes Based on Hormone Receptor and Human Epidermal Growth Factor 2 Receptor Expression in Korea.

    Science.gov (United States)

    Park, Boyoung; Choi, Ji-Yeob; Sung, Ho Kyung; Ahn, Choonghyun; Hwang, Yunji; Jang, Jieun; Lee, Juyeon; Kim, Heewon; Shin, Hai-Rim; Park, Sohee; Han, Wonshik; Noh, Dong-Young; Yoo, Keun-Young; Kang, Daehee; Park, Sue K

    2016-04-01

    We conducted a heterogeneous risk assessment of breast cancer based on the hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) calculating the risks and population-based attributable fractions (PAFs) for modifiable and nonmodifiable factors.Using matched case-control study design from the Seoul Breast Cancer Study and the national prevalence of exposure, the risks and PAFs for modifiable and nonmodifiable factors were estimated for total breast cancers and subtypes.The attribution to modifiable factors was different for each subtype (luminal A, PAF = 61.4% [95% confidence interval, CI = 54.3%-69.8%]; luminal B, 21.4% [95% CI = 18.6-24.9%]; HER2-overexpression, 59.4% [95% CI = 47.8%-74.3%], and triple negative tumors [TNs], 27.1% [95% CI = 22.9%-32.4%)], and the attribution to the modifiable factors for the luminal A and HER2-overexpression subtypes was higher than that of the luminal B and TN subtypes (P heterogeneity  ≤  0.001). The contribution of modifiable reproductive factors to luminal A type in premenopausal women was higher than that of the other subtypes (18.2% for luminal A; 3.1%, 8.1%, and -3.1% for luminal B, HER2-overexpression, and TN subtypes, respectively; P heterogeneity  ≤  0.001). Physical activity had the highest impact preventing 32.6% of luminal A, 14.5% of luminal B, 38.0% of HER2-overexpression, and 26.9% of TN subtypes (P heterogeneity = 0.014). Total reproductive factors were also heterogeneously attributed to each breast cancer subtype (luminal A, 65.4%; luminal B, 24.1%; HER2-overexpression, 57.9%, and TN subtypes, -3.1%; P heterogeneity  ≤  0.001).Each pathological subtype of breast cancer by HRs and HER2 status may be associated with heterogeneous risk factors and their attributable risk, suggesting a different etiology. The luminal B and TN subtypes seemed to be less preventable despite intervention for alleged risk factors, even though physical activity had a high

  11. Hormone Therapy for Breast Cancer in Men

    Science.gov (United States)

    ... Topic Targeted therapy for breast cancer in men Hormone therapy for breast cancer in men Hormone therapy ... fatigue, and pain at the injection site. Luteinizing hormone-releasing hormone (LHRH) analogs and anti-androgens LHRH ...

  12. [Adiposity percentage relationship with hormone receptors immunoreactive score in breast cancer mexican women].

    Science.gov (United States)

    Balderas-Peña, Luz-Ma-Adriana; Sat-Muñoz, Daniel; Castro Cervantes, Juan Manuel; Ramírez-Orozco, Ricardo-Ernesto; Ángeles-Bueno, Wenceslao-Guillermo; Flores-Márquez, María-Rosa; Macías-López, Griselda-Guadalupe; Ruiz-Quezada, Sandra-Luz; Salcedo-Rocha, Ana-Leticia; García de Alba-García, Javier-Eduardo; Solano-Murillo, Pedro

    2013-01-01

    Introducción: El tejido adiposo es una importante fuente de estrógenos, los cuales se encuentran implicados en el desarrollo de cáncer de mama. Objetivo: Establecer la relación entre el porcentaje de adiposidad y el índice de inmunorreactividad de los receptores a estrógenos y a progesterona en mujeres mexicanas con cáncer de mama. Métodos: Estudio transversal analítico en pacientes con cáncer de mama confirmado con estudio histopatológico. Se estimó el % de adiposidad, y el índice de inmunorreactividad. Se realizó el análisis de correlación entre el porcentaje de adiposidad, el IMC, la presencia de DM2 e hipertensión arterial con la expresión de receptores a estrógeno y progesterona y regresión logística con cálculo de Odds Ratio. Resultados: Se estudiaron 43 pacientes con cáncer de mama y se observó asociación entre el porcentaje de adiposidad y el índice de inmunoreactividad para los RE y RP (rP 0,470; p 0,003 y rP 0,328; p 0,042 respectivamente). El factor de riesgo más importante en cáncer positivo a receptores estrogénicos fue la obesidad (OR 19,1, IC 95% 2,1 a 169,1, p 0,008) y obesidad previa en cáncer positivo a receptores a progesterona (OR 20,7, IC 95% 2,3 a 185,9, p 0,007). Conclusión: El porcentaje de adiposidad es un factor de riesgo importante para desarrollar cáncer de mama positivo a receptores hormonales.

  13. Data on alteration of hormone and growth factor receptor profiles over progressive passages of breast cancer cell lines representing different clinical subtypes.

    Science.gov (United States)

    Nair, Madhumathy G; Desai, Krisha; Prabhu, Jyothi S; Hari, P S; Remacle, Jose; Sridhar, T S

    2016-09-01

    Human breast cancers are a highly heterogeneous group of tumours consisting of several molecular subtypes with a variable profile of hormone, growth factor receptors and cytokeratins [1]. Here, the data shows immunofluorescence profiling of four different cell lines belonging to distinct clinical subtypes of breast cancer. Post revival, the cell lines were passaged in culture and immunophenotyping was done for ER, HER-2, AR and EGFR. Data for the markers from early passage (5th) through passages as late as 25 for the different cell lines is presented. PMID:27508248

  14. Racial disparities in individual breast cancer outcomes by hormone-receptor subtype, area-level socio-economic status and healthcare resources

    OpenAIRE

    Akinyemiju, Tomi; Moore, Justin Xavier; Ojesina, Akinyemi I.; Waterbor, John W.; Altekruse, Sean F.

    2016-01-01

    The aim of the study is to determine the influence of area-level socio-economic status and healthcare access in addition to tumor hormone-receptor subtype on individual breast cancer stage, treatment, and mortality among Non-Hispanic (NH)-Black, NH-White, and Hispanic US adults. Analysis was based on 456,217 breast cancer patients in the SEER database from 2000 to 2010. Multilevel and multivariable-adjusted logistic and Cox proportional hazards regression analysis was conducted to account for...

  15. Clinical utility of the combination of lapatinib and letrozole in the management of hormone receptor-positive and HER2-positive advanced breast cancer

    Directory of Open Access Journals (Sweden)

    Merriam PA

    2011-10-01

    Full Text Available Priscilla Merriam, William M Sikov Department of Medicine, Division of Hematology-Oncology, Warren Alpert Medical School of Brown University, Providence, RI, USA Abstract: Breast cancers that overexpress human epidermal growth factor receptor-2 (HER2-positive [HER2+] tend to be biologically aggressive and associated with a poor prognosis, even those that coexpress receptors for estrogen and/or progesterone (hormone receptor-positive [HR+]. Optimal therapy for patients with “double-positive” (HR+/HER2+ breast cancers is still being defined. In this subset of patients, the efficacy of targeted endocrine therapies appears to be diminished by cross-activation or “crosstalk” between estrogen receptor-mediated gene transcription and pathways activated by other growth factor receptors, including HER2. Lapatinib is a tyrosine kinase inhibitor which binds reversibly to the intracellular domains of the epidermal growth factor receptor and HER2, interfering with their ability to initiate signal transduction cascades that promote cancer cell proliferation, survival, and metastasis. In a recently published randomized, placebo-controlled Phase III study in postmenopausal HR+ metastatic breast cancer, the addition of lapatinib to the aromatase inhibitor letrozole significantly improved progression-free survival solely in women who were also HER2+. This article reviews the biology of “double-positive” breast cancers and the rationale underlying combining endocrine and HER2-targeted therapies, including the lapatinib/letrozole combination, for these tumors. Results from the Phase III trial are examined, as well as available data on other combinations of HR and HER2-targeted therapies. Ongoing trials and potential future applications of these combinations in both HR+/HER2+ and other subgroups of breast cancer patients are also discussed. Keywords: breast neoplasm, erbB2, estrogen receptor, letrozole, lapatinib

  16. Wild-type and specific mutant androgen receptor mediates transcription via 17β-estradiol in sex hormone-sensitive cancer cells.

    Science.gov (United States)

    Susa, Takao; Ikaga, Reina; Kajitani, Takashi; Iizuka, Masayoshi; Okinaga, Hiroko; Tamamori-Adachi, Mimi; Okazaki, Tomoki

    2015-07-01

    We previously encountered regulatory processes wherein dihydrotestosterone (DHT) exerted its inhibitory effect on parathyroid hormone-related protein (PTHrP) gene repression through the estrogen receptor (ER)α, but not the androgen receptor (AR), in breast cancer MCF-7 cells. Here, we investigated whether such aberrant ligand-nuclear receptor (NR) interaction is present in prostate cancer LNCaP cells. First, we confirmed that LNCaP cells expressed large amounts of AR at negligible levels of ERα/β or progesterone receptor. Both suppression of PTHrP and activation of prostate-specific antigen genes were observed after independent administration of 17β-estradiol (E2), DHT, or R5020. Consistent with the notion that the LNCaP AR lost its ligand specificity due to a mutation (Thr-Ala877), experiments with siRNA targeting the respective NR revealed that the AR monopolized the role of the mediator of shared hormone-dependent regulation, which was invariably associated with nuclear translocation of this mutant AR. Microarray analysis of gene regulation by DHT, E2, or R5020 disclosed that more than half of the genes downstream of the AR (Thr-Ala877) overlapped in the LNCaP cells. Of particular interest, we realized that the AR (wild-type [wt]) and AR (Thr-Ala877) were equally responsible for the E2-AR interactions. Fluorescence microscopy experiments demonstrated that both EGFP-AR (wt) and EGFP-AR (Thr-Ala877) were exclusively localized within the nucleus after E2 or DHT treatment. Furthermore, reporter assays revealed that some other cancer cells exhibited aberrant E2-AR (wt) signaling similar to that in the LNCaP cells. We herein postulate the presence of entangled interactions between wt AR and E2 in certain hormone-sensitive cancer cells.

  17. Prognosis of breast cancer with low-positive hormonal receptors using epidermal growth factor receptor and cytokeratin 5/6 as indi-cators

    Institute of Scientific and Technical Information of China (English)

    Li Jianyi; Xue Jinqi; Zhang Wenhai; Zhang Yang; Jia Shi; Qian Songying

    2016-01-01

    Objective Less than a decade ago, ER-positive and PgR-positive diagnostic criteria decrease from 10%to 1%. Up to 20%of current immunohistochemical determinations of ER and PgR worldwide may be inaccu-rate. It is necessary to study patients whose tumors are between luminal A (LABC) and triple-negative (TNBC) breast cancer. Methods Survival analysis grouping by the level of positive hormone receptor, CK5/6 and EGFR, and en-docrine therapy was carried out in 206 patients whose tumors were junction zone between LABC and TNBC. Re-sults There were no significant differences between the low-positive (1%-9%) HR group and positive HR (10%-19%) group in overall survival (OS) and disease-free survival (DFS). There was an apparent difference between the nor-mal-like group and basal-like group in OS and DFS, and between the patients with and without endocrine therapy. There were significant differences between death and tumor progression for EGFR and CK5/6, chemotherapy, and endocrine therapy. Conclusions We conclude that EGFR and CK5/6 are better prognostic indicators than the lev-el of positive HR in patients whose tumors are junction zone at the junction zone between LABC and TNBC. En-docrine therapy can be highly beneficial to these patients regardless of the positive HR level.

  18. A population-based study of Kurdish breast cancer in northern Iraq: Hormone receptor and HER2 status. A comparison with Arabic women and United States SEER data

    Directory of Open Access Journals (Sweden)

    Runnak Majid A

    2012-06-01

    Full Text Available Abstract Background Hormone receptor (HR and HER2 expression predict the therapeutic response and prognosis of breast cancer. In the Middle-East, breast cancer is diagnosed at a young age, and Arabic women are reported to have a low frequency of HR positive tumors. This study investigates HR and HER2 expression among Kurdish and Arabic women. Methods During 2008–2010, the Sulaimaniyah Directorate of Health records identified 514 Sulaimaniyah Kurdish women, 227 Kurdish women of other Governates, and 83 Arabic women with a first diagnosis of breast cancer. The breast cancers of 432 women had immunohistochemistry (IHC performed for estrogen and progesterone receptors (ER and PR and HER2. Age specific and age standardized incidence rates were calculated for Sulaimaniyah Kurds. Results were compared with Egypt and with United States (US SEER data. Results The median patient age was 46 years and 60.4% were  Conclusions Compared to the US, low age standardized and age specific breast cancer incidence rates were found in Kurdish women; nevertheless, the proportional expression of HR and HER2 for both Kurds and Arabs was comparable to that of US white women. The great majority of the breast cancer was ER+/HER2- and should respond to anti-estrogen therapy.

  19. Identification of a long non-coding RNA gene, growth hormone secretagogue receptor opposite strand, which stimulates cell migration in non-small cell lung cancer cell lines.

    Science.gov (United States)

    Whiteside, Eliza J; Seim, Inge; Pauli, Jana P; O'Keeffe, Angela J; Thomas, Patrick B; Carter, Shea L; Walpole, Carina M; Fung, Jenny N T; Josh, Peter; Herington, Adrian C; Chopin, Lisa K

    2013-08-01

    The molecular mechanisms involved in non‑small cell lung cancer tumourigenesis are largely unknown; however, recent studies have suggested that long non-coding RNAs (lncRNAs) are likely to play a role. In this study, we used public databases to identify an mRNA-like, candidate long non-coding RNA, GHSROS (GHSR opposite strand), transcribed from the antisense strand of the ghrelin receptor gene, growth hormone secretagogue receptor (GHSR). Quantitative real-time RT-PCR revealed higher expression of GHSROS in lung cancer tissue compared to adjacent, non-tumour lung tissue. In common with many long non-coding RNAs, GHSROS is 5' capped and 3' polyadenylated (mRNA-like), lacks an extensive open reading frame and harbours a transposable element. Engineered overexpression of GHSROS stimulated cell migration in the A549 and NCI-H1299 non-small cell lung cancer cell lines, but suppressed cell migration in the Beas-2B normal lung-derived bronchoepithelial cell line. This suggests that GHSROS function may be dependent on the oncogenic context. The identification of GHSROS, which is expressed in lung cancer and stimulates cell migration in lung cancer cell lines, contributes to the growing number of non-coding RNAs that play a role in the regulation of tumourigenesis and metastatic cancer progression.

  20. Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up

    DEFF Research Database (Denmark)

    Regan, Meredith M; Neven, Patrick; Giobbie-Hurder, Anita;

    2011-01-01

    Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast-cancer recurrence and death. Therefore, trials assessing endocrine therapies for this patient population need extended follow-up. We present an update of efficacy outcomes in the Breast...

  1. Structural Basis for Antibody Discrimination between Two Hormones That Recognize the Parathyroid Hormone Receptor

    Energy Technology Data Exchange (ETDEWEB)

    McKinstry, William J.; Polekhina, Galina; Diefenbach-Jagger, Hannelore; Ho, Patricia W.M.; Sato, Koh; Onuma, Etsuro; Gillespie, Matthew T.; Martin, T. John; Parker, Michael W.; (SVIMR-A); (Chugai); (Melbourne)

    2009-08-18

    Parathyroid hormone-related protein (PTHrP) plays a vital role in the embryonic development of the skeleton and other tissues. When it is produced in excess by cancers it can cause hypercalcemia, and its local production by breast cancer cells has been implicated in the pathogenesis of bone metastasis formation in that disease. Antibodies have been developed that neutralize the action of PTHrP through its receptor, parathyroid hormone receptor 1, without influencing parathyroid hormone action through the same receptor. Such neutralizing antibodies against PTHrP are therapeutically effective in animal models of the humoral hypercalcemia of malignancy and of bone metastasis formation. We have determined the crystal structure of the complex between PTHrP (residues 1-108) and a neutralizing monoclonal anti-PTHrP antibody that reveals the only point of contact is an {alpha}-helical structure extending from residues 14-29. Another striking feature is that the same residues that interact with the antibody also interact with parathyroid hormone receptor 1, showing that the antibody and the receptor binding site on the hormone closely overlap. The structure explains how the antibody discriminates between the two hormones and provides information that could be used in the development of novel agonists and antagonists of their common receptor.

  2. Adjuvant Surgical Oophorectomy Plus Tamoxifen in Premenopausal Women With Operable Hormone Receptor-Positive Breast Cancer: A Global Treatment Option.

    Science.gov (United States)

    Love, Richard R

    2016-08-01

    One third of annual new cases of breast cancer globally are now hormone receptor-positive tumors in premenopausal women from low- and middle-income countries. For this subgroup of women with breast cancer, high-income country guidelines suggest impractical and unaffordable adjuvant treatments. The balance of clinical trial evidence now suggests that surgical oophorectomy plus tamoxifen is a safe and practical treatment for these women in low- and middle-income countries. Additionally, new randomized trial data suggest that women in the second half of an anovulatory cycle benefit minimally from surgical oophorectomy done at this time, which implies that regularly cycling women will benefit more than has been shown from this procedure. Allred scoring of levels of hormone receptors is a practical and inexpensive approach to the assessment of magnitudes of response to oophorectomy plus tamoxifen. These circumstances suggest that more detailed consideration of this option should characterize clinical practice guidelines in high-income countries because of their global impact. PMID:27117241

  3. The Endocannabinoid System and Sex Steroid Hormone-Dependent Cancers

    OpenAIRE

    Thangesweran Ayakannu; Taylor, Anthony H; Marczylo, Timothy H.; Willets, Jonathon M.; Konje, Justin C.

    2013-01-01

    The “endocannabinoid system (ECS)” comprises the endocannabinoids, the enzymes that regulate their synthesis and degradation, the prototypical cannabinoid receptors (CB1 and CB2), some noncannabinoid receptors, and an, as yet, uncharacterised transport system. Recent evidence suggests that both cannabinoid receptors are present in sex steroid hormone-dependent cancer tissues and potentially play an important role in those malignancies. Sex steroid hormones regulate the endocannabinoid system ...

  4. Thyroid Hormone Deiodinases and Cancer

    Directory of Open Access Journals (Sweden)

    Antonio eBianco

    2012-06-01

    Full Text Available Deiodinases constitute a group of thioredoxin-containing selenoenzymes that play an important function in thyroid hormone homeostasis and control of thyroid hormone action. There are three known deiodinases: D1 and D2 activate the pro-hormone thyroxine (T4 to T3, the most active form of thyroid hormone, while D3 inactivates thyroid hormone and terminates T3 action. A number of studies indicate that deiodinase expression is altered in several types of cancers, suggesting that (i they may represent a useful cancer marker and/or (ii could play a role in modulating cell proliferation - in different settings thyroid hormone modulates cell proliferation. For example, although D2 is minimally expressed in human and rodent skeletal muscle, its expression level in rhabdomyosarcoma (RMS-13 cells is 3-4 fold higher. In basal cell carcinoma (BCC cells, sonic hedgehog (Shh-induced cell proliferation is accompanied by induction of D3 and inactivation of D2. Interestingly a 5-fold reduction in the growth of BCC in nude mice was observed if D3 expression was knocked down. A decrease in D1 activity has been described in renal clear cell carcinoma, primary liver cancer, lung cancer, and some pituitary tumors, while in breast cancer cells and tissue there is an increase in D1 activity. Furthermore D1 mRNA and activity were found to be decreased in papillary thyroid cancer while D1 and D2 activities were significantly higher in follicular thyroid cancer tissue, in follicular adenoma and in anaplastic thyroid cancer. It is conceivable that understanding how deiodinase dysregulation in tumor cells affect thyroid hormone signaling and possibly interfere with tumor progression could lead to new antineoplastic approaches.

  5. The role of epidermal growth factor-like module containing mucin-like hormone receptor 2 in human cancers

    Directory of Open Access Journals (Sweden)

    Michael Safaee

    2014-04-01

    Full Text Available G-protein coupled receptors (GPCRs are among the most diverse and ubiquitous proteins in all of biology. The epidermal growth factorseven span transmembrane (EGF-TM7 subfamily of adhesion GPCRs is a small subset whose members are mainly expressed on the surface of leukocytes. The EGF domains on the N-terminus add significant size to these receptors and they are considered to be among the largest members of the TM7 family. Although not all of their ligands or downstream targets have been identified, there is evidence implicating the EGF-TM7 family diverse processes such as cell adhesion, migration, inflammation, and autoimmune disease. Recent studies have identified expression of EGF-TM7 family members on human neoplasms including those of the thyroid, stomach, colon, and brain. Their presence on these tissues is not surprising given the ubiquity of GPCRs, but because their functional significance and pathways are not completely understood, they are of tremendous clinical and scientific interest. Current evidence suggests that expression of certain EGF-TM7 receptors is correlated with tumor grade, confers a more invasive phenotype, and increases the likelihood of metastatic disease. In this review, we will discuss the structure, function, and regulation of these receptors. We also describe the expression of these receptors in human cancers and explore their potential mechanistic significance.

  6. Hormone therapy and ovarian cancer

    DEFF Research Database (Denmark)

    Mørch, Lina Steinrud; Løkkegaard, Ellen; Andreasen, Anne Helms;

    2009-01-01

    CONTEXT: Studies have suggested an increased risk of ovarian cancer among women taking postmenopausal hormone therapy. Data are sparse on the differential effects of formulations, regimens, and routes of administration. OBJECTIVE: To assess risk of ovarian cancer in perimenopausal and postmenopau......CONTEXT: Studies have suggested an increased risk of ovarian cancer among women taking postmenopausal hormone therapy. Data are sparse on the differential effects of formulations, regimens, and routes of administration. OBJECTIVE: To assess risk of ovarian cancer in perimenopausal...... and postmenopausal women receiving different hormone therapies. DESIGN AND SETTING: Nationwide prospective cohort study including all Danish women aged 50 through 79 years from 1995 through 2005 through individual linkage to Danish national registers. Redeemed prescription data from the National Register...... bands included hormone exposures as time-dependent covariates. PARTICIPANTS: A total of 909,946 women without hormone-sensitive cancer or bilateral oophorectomy. MAIN OUTCOME MEASURE: Ovarian cancer. RESULTS: In an average of 8.0 years of follow-up (7.3 million women-years), 3068 incident ovarian...

  7. Impact of Breast Cancer Subtype Defined by Immunohistochemistry Hormone Receptor and HER2 Status on the Incidence of Immediate Postmastectomy Reconstruction.

    Science.gov (United States)

    Wu, Wei; Cheng, Shi; Deng, Heran; Wu, Jiannan; Mao, Kai; Cao, Minghui

    2016-01-01

    Immediate postmastectomy reconstruction has become an increasingly popular choice for breast cancer patients recently. However, whether molecular subtype of cancer impacts the incidence of breast reconstruction is unclear. We aimed to investigate the association between breast cancer subtype defined by immunohistochemistry hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status and recent rates of immediate postmastectomy reconstruction in the United States.The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database was used to evaluate stage I-III breast cancer patients with different subtypes who underwent either mastectomy alone or mastectomy plus reconstruction between 2010 and 2012. Univariate and multivariate analyses were conducted to identify factors influencing the incidence of immediate reconstruction.Of 47,123 women included, 33.1% (10,712/32,376) of HR+/HER2-, 33.1% (1912/5768) of HR+/HER2+, 29.6% (850/2875) of HR-/HER2+, and 27.7% (1689/6104) of triple negative breast cancer patients received immediate breast reconstruction (chi-square test, P breast cancer patients received significantly less breast reconstruction. After adjusting for demographic, socioeconomic, geographic, or clinicopathologic factors, HER2-overexpressing (OR 0.896, 95% CI 0.817-0.984) and triple negative (OR 0.806, 95% CI 0.751-0.866) breast cancer patients remained less likely to undergo immediate postmastectomy reconstruction compared with HR+/HER2- or HR+/HER2+ patients. No significant difference was found in the type of reconstruction among different subtypes. Subgroup analysis showed that the difference of breast reconstruction rates among distinct subtypes varied with different grade and stage groups, and the association between breast cancer subtype and the reconstruction rate was not significant in low grade and early stage patients.This population-based study determined that breast cancer subtype was an independent

  8. Correlation of human epidermal growth factor receptor 2 (HER-2/neu) receptor status with hormone receptors Oestrogen Receptor, Progesterone Receptor status and other prognostic markers in breast cancer: an experience at tertiary care hospital in Karachi

    International Nuclear Information System (INIS)

    Objective: To determine the frequency of human epidermal growth factor receptor 2 (HER-2/neu) positivity and to correlate its status in breast cancer patients with other prognostic markers. Methods: The comparative cross-sectional study was conducted at the Department of Histopathology, Liaquat National Hospital, Karachi, from January 1 to October 31, 2010. It included all specimens of mastectomy and lumpectomy with axillary tissue. Incisional, trucut and wedge biopsies as well as all non-epithelial tumours were excluded. All samples were processed as per standard guidelines and were evaluated by immunohistochemistry. SPSS 10 was used for statistical analysis. Results: The age of the 100 cases in the study ranged from 20 to 82 years with a mean of 51+-17.6 years. Two (2%) of the patients were males. HER-2/neu over-expression increased with increasing tumour size, grade, lymph node metastasis and with oestrogen receptor and progesterone receptor negativity. No significant correlation of HER-2/neu was seen with the age of patient and with the tumour type. Conclusions: The expression of HER-2/neu was associated with decrease in oestrogen receptor and progresterone receptor positivity, and increase in tumour size, high tumour grade and lymph node metastasis. (author)

  9. Neoadjuvant hormonal therapy is associated with comparable outcomes to neoadjuvant chemotherapy in post-menopausal women with estrogen receptor-positive breast cancer

    Directory of Open Access Journals (Sweden)

    David M. Marcus

    2013-12-01

    Full Text Available Objectives: We compared outcomes in post-menopausal estrogen receptor-positive (ER+ breast cancer patients treated with neoadjuvant hormonal therapy (NAHT or neoadjuvant chemotherapy (NACT.Methods: We retrospectively identified post-menopausal women who received either NAHT or NACT for non-metastatic, non-inflammatory, ER+, Her2neu negative breast cancer from 2004 to 2011. We compared long-term rates of locoregional relapse free survival (LRFS, distant metastasis free survival (DMFS, and overall survival (OS using the Kaplan-Meier method. The Cox proportional hazards model was used to identify patient and disease factors significantly associated with these endpoints. Results: We identified 99 patients in our study, including 27 who received NAHT and 72 who received NACT. There were no differences in 4-year LRFS, DMFS, or OS between groups. On Cox proportional hazards modeling, the type of systemic therapy (NAHT vs. NACT was not associated with OS. However, patients with progesterone receptor (PR positive disease had a 92% lower risk of death compared to patients with PR negative disease.Conclusions: Our data suggest that outcomes are not adversely affected by NAHT in post-menopausal women with ER+ breast cancer. Therefore, NAHT is a viable and potentially less toxic option than NACT in appropriately selected patients. Furthermore, although PR negative disease appears to be associated with poor prognosis, intensification of systemic treatment with chemotherapy may not be associated with improvement of disease-related outcomes in this patient population.

  10. Thyroid hormone receptor β1 suppresses proliferation and migration by inhibiting PI3K/Akt signaling in human colorectal cancer cells.

    Science.gov (United States)

    Zhu, Lei; Tian, Guangang; Yang, Qin; De, Gejing; Zhang, Zhigang; Wang, Yahui; Nie, Huizhen; Zhang, Yanli; Yang, Xiaomei; Li, Jun

    2016-09-01

    Thyroid hormone receptor β1 (TRβ1) is a ligand‑dependent transcription factor that belongs to the superfamily of nuclear receptors. TRβ1 has been found to act as a tumor suppressor in many solid tumors including breast cancer and hepatocellular carcinoma, but its role in the progression of human colorectal cancer (CRC) remains unclear. In this study, microarray data analysis revealed that TRβ1 mRNA was downregulated in CRC tumors compared with that in the normal counterparts in both The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Using a CRC tissue microarray (TMA), we confirmed that the expression of TRβ1 was decreased in human CRC tumor tissues in contrast to normal colorectal mucosal tissues. Notably, the TRβ1 expression was strongly correlated with tumor size (p=0.045). Furthermore, we found that CRC cell proliferation and migration were significantly inhibited by TRβ1 overexpression in vitro. Mechanistic studies indicated that activated phosphorylated Akt was clearly suppressed by TRβ1 in the CRC tissues and cells. In conclusion, this study provides evidence that TRβ1 plays a critical role in the progression of CRC via the PI3K/Akt pathway, and the TRβ1 gene may represent a novel target for CRC therapeutics. PMID:27431682

  11. Ethnic differences in initiation and timing of adjuvant endocrine therapy among older women with hormone receptor-positive breast cancer enrolled in Medicare Part D.

    Science.gov (United States)

    Farias, Albert J; Du, Xianglin L

    2016-02-01

    The aim of this study was to determine whether there are racial/ethnic differences in initiation and timing of adjuvant endocrine therapy (AET) after Medicare Part D drug coverage. We conducted a retrospective cohort study using data from the Surveillance, Epidemiology, and End Results-Medicare-linked data to assess ethnic, socio-demographic, and tumor characteristic variations in the initiation of AET among patients ≥65 with hormone receptor-positive breast cancer in 2007-2009 enrolled in Medicare Part D through 2010. Logistic regression models were performed to assess the association between race/ethnicity and the initiation of tamoxifen, aromatase inhibitors (AIs), and overall AET (tamoxifen or AIs) within the first 12 months of diagnosis. Of the 12,198 women with hormone receptor-positive breast cancer, 74.8 % received AET within 12 months of diagnosis, of which 17.3 % received tamoxifen and 82.8 % received AIs. After controlling for all variables, only Asian women were found to have a greater odds of initiation of overall AET compared to non-Hispanic white women (odds ratio (OR): 1.28, 95 % CI: 1.03-1.58). Hispanic Mexicans and non-Hispanic black patients had a significantly lower odds of tamoxifen initiation (0.70, 0.54-0.91; 0.25, 0.10-0.62). For AI initiation, Hispanic Mexicans and Asians had a higher odds compared to non-Hispanic white women (2.06, 1.34-3.10; 1.33, 1.11-1.61). A suboptimal proportion of women (25.2 %) did not initiate AET within 12 months of diagnosis and therefore did not receive the full benefits of treatment to reduce the risk of breast cancer recurrence and mortality. Racial/ethnic differences in the initiation of tamoxifen and AIs have important implications that require further investigation.

  12. Does growth hormone cause cancer?

    OpenAIRE

    Jenkins, P.J.; Mukherjee, A.; Shalet, S. M.

    2006-01-01

    KEYWORDS - CLASSIFICATION: adverse effects;Acromegaly;Adult;Animals;cancer epidemiology;complications;Child;Child Development;Colorectal Neoplasms;deficiency;epidemiology;etiology;Evaluation;Growth Hormone;Human Growth Hormone;Humans;Insulin-Like Growth Factor I;mechanisms of carcinogenesis;Neoplasm Recurrence,Local;Neoplasms;Neoplasms,Multiple Primary;physiology;physiopathology;Risk Factors;secretion;therapy. The ability of GH, via its mediator peptide IGF-1, to influence regulation of ce...

  13. Postmenopausal Serum Sex Steroids and Risk of Hormone Receptor-Positive and -Negative Breast Cancer : a Nested Case-Control Study

    NARCIS (Netherlands)

    James, Rebecca E.; Lukanova, Annekatrin; Dossus, Laure; Becker, Susen; Rinaldi, Sabina; Tjonneland, Anne; Olsen, Anja; Overvad, Kim; Mesrine, Sylvie; Engel, Pierre; Clavel-Chapelon, Francoise; Chang-Claude, Jenny; Vrieling, Alina; Boeing, Heiner; Schuetze, Madlen; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Palli, Domenico; Krogh, Vittorio; Panico, Salvatore; Tumino, Rosario; Sacerdote, Carlotta; Rodriguez, Laudina; Buckland, Genevieve; Sanchez, Maria-Jose; Amiano, Pilar; Ardanaz, Eva; Bueno-de-Mesquita, Bas; Ros, Martine M.; van Gils, Carla H.; Peeters, Petra H.; Khaw, Kay-Tee; Wareham, Nick; Key, Timothy J.; Allen, Naomi E.; Romieu, Isabelle; Siddiq, Afshan; Cox, David; Riboli, Elio; Kaaks, Rudolf

    2011-01-01

    Prediagnostic endogenous sex steroid hormone levels have well established associations with overall risk of breast cancer. While evidence toward the existence of distinct subtypes of breast cancer accumulates, few studies have investigated the associations of sex steroid hormone levels with risk of

  14. Alterations of the genes involved in the PI3K and estrogen-receptor pathways influence outcome in human epidermal growth factor receptor 2-positive and hormone receptor-positive breast cancer patients treated with trastuzumab-containing neoadjuvant chemotherapy

    International Nuclear Information System (INIS)

    Chemotherapy with trastuzumab is widely used for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but a significant number of patients with the tumor fail to respond, or relapse. The mechanisms of recurrence and biomarkers that indicate the response to the chemotherapy and outcome are not fully investigated. Genomic alterations were analyzed using single-nucleotide polymorphism arrays in 46 HER2 immunohistochemistry (IHC) 3+ or 2+/fluorescent in situ hybridization (FISH)+ breast cancers that were treated with neoadjuvant chemotherapy with paclitaxel, cyclophosphamid, epirubicin, fluorouracil, and trastuzumab. Patients were classified into two groups based on presence or absence of alterations of 65 cancer-associated genes, and the two groups were further classified into four groups based on genomic HER2 copy numbers or hormone receptor status (HR+/−). Pathological complete response (pCR) and relapse-free survival (RFS) rates were compared between any two of the groups. The pCR rate was 54% in 37 patients, and the RFS rate at 3 years was 72% (95% CI, 0.55-0.89) in 42 patients. The analysis disclosed 8 tumors with nonamplified HER2 and 38 tumors with HER2 amplification, indicating the presence of discordance in tumors diagnosed using current HER2 testing. The 8 patients showed more difficulty in achieving pCR (P=0.019), more frequent relapse (P=0.018), and more frequent alterations of genes in the PI3K pathway (P=0.009) than the patients with HER2 amplification. The alterations of the PI3K and estrogen receptor (ER) pathway genes generally indicated worse RFS rates. The prognostic significance of the alterations was shown in patients with a HR+ tumor, but not in patients with a HR- tumor when divided. Alterations of the PI3K and ER pathway genes found in patients with a HR+ tumor with poor outcome suggested that crosstalk between the two pathways may be involved in resistance to the current chemotherapy with trastuzumab. We

  15. Racial disparities in individual breast cancer outcomes by hormone-receptor subtype, area-level socio-economic status and healthcare resources.

    Science.gov (United States)

    Akinyemiju, Tomi; Moore, Justin Xavier; Ojesina, Akinyemi I; Waterbor, John W; Altekruse, Sean F

    2016-06-01

    The aim of the study is to determine the influence of area-level socio-economic status and healthcare access in addition to tumor hormone-receptor subtype on individual breast cancer stage, treatment, and mortality among Non-Hispanic (NH)-Black, NH-White, and Hispanic US adults. Analysis was based on 456,217 breast cancer patients in the SEER database from 2000 to 2010. Multilevel and multivariable-adjusted logistic and Cox proportional hazards regression analysis was conducted to account for clustering by SEER registry of diagnosis. NH-Black women had greater area-level access to healthcare resources compared with women of other races. For instance, the average numbers of oncology hospitals per million population in counties with NH-Black, NH-White, and Hispanic women were 8.1, 7.7, and 5.0 respectively; average numbers of medical doctors per million in counties with NH-Black, NH-White, and Hispanic women were 100.7, 854.0, and 866.3 respectively; and average number of Ob/Gyn in counties with NH-Black, NH-White, and Hispanic women was 155.6, 127.4, and 127.3, respectively (all p values <0.001). Regardless, NH-Black women (HR 1.39, 95 % CI 1.36-1.43) and Hispanic women (HR 1.05, 95 % CI 1.03-1.08) had significantly higher breast cancer mortality compared with NH-White women even after adjusting for hormone-receptor subtype, area-level socio-economic status, and area-level healthcare access. In addition, lower county-level socio-economic status and healthcare access measures were significantly and independently associated with stage at presentation, surgery, and radiation treatment as well as mortality after adjusting for age, race/ethnicity, and HR subtype. Although breast cancer HR subtype is a strong, important, and consistent predictor of breast cancer outcomes, we still observed significant and independent influences of area-level SES and HCA on breast cancer outcomes that deserve further study and may be critical to eliminating breast cancer outcome

  16. Types of Cancer Treatment: Hormone Therapy

    Science.gov (United States)

    Describes how hormone therapy slows or stops the growth of breast and prostate cancers that use hormones to grow. Includes information about the types of hormone therapy and side effects that may happen.

  17. CYP19 Genetic Polymorphism Haplotype AASA Is Associated with a Poor Prognosis in Premenopausal Women with Lymph Node-Negative, Hormone Receptor-Positive Breast Cancer

    Directory of Open Access Journals (Sweden)

    Sung-Hsin Kuo

    2013-01-01

    Full Text Available Given the critical role of CYP19 in estrogen synthesis, we investigated the influence of CYP19 gene polymorphisms on the clinical outcome of lymph node- (LN- negative, hormone receptor- (HR- positive early breast cancers. Genotyping for the CYP19 polymorphisms rs4646 (A/C, rs1065779 (A/C, CYP19 (TTTAn (short allele/long (S/L allele using the 7 TTTA repeat polymorphism as the cut-off, and rs1870050 (A/C was performed on 296 patients with LN-negative, HR-positive breast cancers. All patients received adjuvant hormonal therapy. Associations were examined between these 4 genotypes and 6 common haplotypes of CYP19 and distant disease-free survival (DDFS, disease-free survival (DFS, and overall survival (OS. Patients were divided into the 6 subhaplotypes of CCLA (41.1%, AASA (17.1%, CASA (11.9%, CCLC (8.9%, CCSA (7.5%, AASC (8.9%, and others (4.6%. In premenopausal patients, haplotype AASA was significantly associated with a poor DDFS (adjusted hazard ratio (aHR, 3.3; P=0.001, DFS (aHR, 2.5; P=0.0008, and OS (aHR, 2.9; P=0.0004 after adjusting for age, tumor size, tumor grade, estrogen receptor status, progesterone receptor status, chemotherapy, pathology, adjuvant hormone therapy, menopausal status, and radiotherapy. Furthermore, haplotype AASA remained a negative prognostic factor for premenopausal patients receiving adjuvant chemotherapy in terms of DDFS (aHR, 4.5; P=0.0005, DFS (HR, 3.2; P=0.003, and OS (HR, 6.4; P=0.0009. However, in postmenopausal patients, haplotype AASA was not associated with a poor prognosis, whereas the AASC haplotype was significantly associated with a poor DFS (aHR, 3.1; P=0.03 and OS (aHR, 4.4; P=0.01. Our results indicate that, in patients with LN-negative, HR-positive breast cancers, genetic polymorphism haplotype AASA is associated with poor survival of premenopausal women but does not affect survival of postmenopausal women.

  18. Influence of estrogen receptor alpha and progesterone receptor polymorphisms on the effects of hormone therapy on mammographic density.

    NARCIS (Netherlands)

    Duijnhoven, F.J.B. van; Peeters, P.H.; Warren, R.M.; Bingham, S.; Uitterlinden, A.G.; Noord, P.A.H. van; Monninkhof, E.M.; Grobbee, D.E.; Gils, C.H. van

    2006-01-01

    Postmenopausal hormone therapy increases mammographic density, a strong breast cancer risk factor, but effects vary across women. We investigated whether the effect of hormone therapy use is modified by polymorphisms in the estrogen receptor (ESR1) and progesterone receptor (PGR) genes in the Dutch

  19. Hormone activation of baculovirus expressed progesterone receptors.

    Science.gov (United States)

    Elliston, J F; Beekman, J M; Tsai, S Y; O'Malley, B W; Tsai, M J

    1992-03-15

    Human and chicken progesterone receptors (A form) were overproduced in a baculovirus expression system. These recombinant progesterone receptors were full-length bound progesterone specifically and were recognized by monoclonal antibodies, AB52 and PR22, specific for human and chicken progesterone receptor, respectively. In gel retardation studies, binding of recombinant human and chicken progesterone receptors to their progesterone response element (PRE) was specific and was enhanced in the presence of progesterone. Binding of human progesterone receptor to the PRE was also enhanced in the presence of the antiprogestin, RU486, but very little effect was observed in the presence of estradiol, dexamethasone, testosterone, and vitamin D. In our cell-free transcription system, human progesterone receptor induced transcription in a receptor-dependent and hormone-activable manner. Receptor-stimulated transcription required the presence of the PRE in the test template and could be specifically inhibited by excess PRE oligonucleotides. Furthermore, chicken progesterone receptor also induced in vitro transcription in a hormone-activable manner. These results demonstrate that steroid receptors overexpressed in a baculovirus expression system are functional and exhibit steroid-responsive binding and transcription. These observations support our present understanding of the mechanism of steroid receptor-regulated gene expression and provide a technological format for studies of the role of hormone and antihormone in altering gene expression. PMID:1544902

  20. Tumour Fas ligand:Fas ratio greater than 1 is an independent marker of relative resistance to tamoxifen therapy in hormone receptor positive breast cancer

    International Nuclear Information System (INIS)

    The objective of the present study was to examine the prognostic and predictive significance of the apoptosis-related marker Fas ligand (FasL):Fas ratio in breast cancer. Tumour biopsies from 215 primary invasive breast cancer patients were examined for the expression of FasL and Fas mRNA transcripts by quantitative real-time RT-PCR. Their prognostic and predictive impact on patient survival was determined in univariate and multivariate survival analyses. Using a cutoff value of 1, a FasL:Fas ratio greater than 1 was found to have significant prognostic value for disease-free survival among the total population (median follow up 54 months). It was associated with a significantly decreased disease-free survival (P = 0.022) and with a tendency toward increased mortality (P = 0.14) in univariate analysis. Hormone receptor positive women exclusively treated with tamoxifen (n = 86) and with a FasL:Fas ratio greater than 1 had a significantly decreased disease-free survival (P = 0.008) and overall survival (P = 0.03) in univariate Kaplan–Meier analysis. Furthermore, tumour size and FasL:Fas ratio were of independent predictive significance in the multivariate model for disease-free and overall survival in that subgroup. Among postmenopausal patients (n = 148) both of those factors retained independent prognostic significance in the multivariate model for disease-free survival. In contrast, FasL:Fas ratio had no significant predictive value in patients exclusively treated with chemotherapy. The data presented indicate that FasL:Fas ratio may be useful not only as a prognostic factor but also as a predictive factor for projecting response to the antioestrogen tamoxifen. The results strongly support a correlation between FasL:Fas ratio greater than 1 and lack of efficacy of tamoxifen in hormone receptor positive patients

  1. Direct and in vitro observation of growth hormone receptor molecules in A549 human lung epithelial cells by nanodiamond labeling

    Science.gov (United States)

    Cheng, C.-Y.; Perevedentseva, E.; Tu, J.-S.; Chung, P.-H.; Cheng, C.-L.; Liu, K.-K.; Chao, J.-I.; Chen, P.-H.; Chang, C.-C.

    2007-04-01

    This letter presents direct observation of growth hormone receptor in one single cancer cell using nanodiamond-growth hormone complex as a specific probe. The interaction of surface growth hormone receptor of A549 human lung epithelial cells with growth hormone was observed using nanodiamond's unique spectroscopic signal via confocal Raman mapping. The growth hormone molecules were covalent conjugated to 100nm diameter carboxylated nanodiamonds, which can be recognized specifically by the growth hormone receptors of A549 cell. The Raman spectroscopic signal of diamond provides direct and in vitro observation of growth hormone receptors in physiology condition in a single cell level.

  2. Hormone Therapy for Breast Cancer

    Science.gov (United States)

    ... to stimulate the growth of breast cancer cells: Selective estrogen receptor modulators (SERMs) bind to estrogen receptors , preventing estrogen from binding. Examples of SERMs approved by the FDA are tamoxifen (Nolvadex®), ... called selective serotonin reuptake inhibitors, or SSRIs), inhibit an enzyme ...

  3. Amplification of ESR1 may predict resistance to adjuvant tamoxifen in postmenopausal patients with hormone receptor positive breast cancer

    DEFF Research Database (Denmark)

    Nielsen, Kirsten Vang; Ejlertsen, Bent; Müller, Sven;

    2011-01-01

    The estrogen receptor (ER) is the target of tamoxifen, but endocrine therapies do not benefit all patients with ER positive tumors. We therefore hypothesized that copy number changes in the ESR1 gene, encoding ER, confer resistance. Within a consecutive series of ER positive, postmenopausal...... was significantly associated with poor disease-free survival (P = 0.0054) and overall survival (P = 0.0004). This pilot study supports our hypothesis that ESR1 amplification is associated with a poorer outcome following adjuvant treatment with tamoxifen in ER positive early breast cancer. This study also revealed......1 copy number changes using FISH with a probe covering the ESR1 gene at 6q25 and a reference probe covering the centromere of chromosome 6. The assay was validated in a material of 120 normal breast samples. FISH analysis for ESR1 was successful in 91 patients (94%). Amplification (ratio ESR1/CEN-6...

  4. Flavokawain B, a kava chalcone, exhibits robust apoptotic mechanisms on androgen receptor-negative, hormone-refractory prostate cancer cell lines and reduces tumor growth in a preclinical model

    OpenAIRE

    Tang, Yaxiong; Li, Xuesen; Liu, Zhongbo; Simoneau, Anne R; Xie, Jun; Zi, Xiaolin

    2010-01-01

    Limited success has been achieved in extending the survival of patients with metastatic and hormone-refractory prostate cancer (HRPC). There is a strong need for novel agents in the treatment and prevention of HRPC. We have shown that flavokawain B (FKB), a kava chalcone, is about 4 to 12 fold more effective in reducing the cell viabilities of androgen receptor (AR)-negative, HRPC cell lines DU145 and PC-3 than AR–positive, hormone-sensitive prostate cancer cell lines LAPC4 and LNCaP, with mi...

  5. 激素受体阳性乳腺癌治疗进展%Treatment development in breast cancer with hormone receptor-positive

    Institute of Scientific and Technical Information of China (English)

    洪士开; 陆云飞; 曾健

    2011-01-01

    Chemotherapy and endocrine therapy are two kinds of important treatment modalities of breast cancer with hormone receptor-positive. Adjuvant chemotherapy whether can be proposed to the individual patient or not according to tumor burden factors, multi-gene prognostic signatures detection and molecular subtype classification for breast cancer. There are four different endocrine strategies, and each of them has its own advantage over others and cannot be replaced by others. Individualized therapy should be performed to Luminal A and Luminal B breast cancers.%化疗和内分泌治疗是雌激素受体和(或)孕激素受体阳性乳腺癌治疗的主要手段。肿瘤负荷因素、多基因标记物检测、肿瘤分子分型可用于指导乳腺癌患者是否需要化疗。不同内分泌治疗策略各有自身价值,不能相互取代。临床实践中应对Luminal A型和Luminal B型两种不同类型乳腺癌提供个体化治疗。

  6. NUREBASE: database of nuclear hormone receptors

    OpenAIRE

    Duarte, Jorge; Perrière, Guy; Laudet, Vincent; Robinson-Rechavi, Marc

    2002-01-01

    Nuclear hormone receptors are an abundant class of ligand activated transcriptional regulators, found in varying numbers in all animals. Based on our experience of managing the official nomenclature of nuclear receptors, we have developed NUREBASE, a database containing protein and DNA sequences, reviewed protein alignments and phylogenies, taxonomy and annotations for all nuclear receptors. The reviewed NUREBASE is completed by NUREBASE_DAILY, automatically updated every 24 h. Both databases...

  7. Reverse phase protein array based tumor profiling identifies a biomarker signature for risk classification of hormone receptor-positive breast cancer

    Directory of Open Access Journals (Sweden)

    Johanna Sonntag

    2014-03-01

    Full Text Available A robust subclassification of luminal breast cancer, the most common molecular subtype of human breast cancer, is crucial for therapy decisions. While a part of patients is at higher risk of recurrence and requires chemo-endocrine treatment, the other part is at lower risk and also poorly responds to chemotherapeutic regimens. To approximate the risk of cancer recurrence, clinical guidelines recommend determining histologic grading and abundance of a cell proliferation marker in tumor specimens. However, this approach assigns an intermediate risk to a substantial number of patients and in addition suffers from a high interobserver variability. Therefore, the aim of our study was to identify a quantitative protein biomarker signature to facilitate risk classification. Reverse phase protein arrays (RPPA were used to obtain quantitative expression data for 128 breast cancer relevant proteins in a set of hormone receptor-positive tumors (n = 109. Proteomic data for the subset of histologic G1 (n = 14 and G3 (n = 22 samples were used for biomarker discovery serving as surrogates of low and high recurrence risk, respectively. A novel biomarker selection workflow based on combining three different classification methods identified caveolin-1, NDKA, RPS6, and Ki-67 as top candidates. NDKA, RPS6, and Ki-67 were expressed at elevated levels in high risk tumors whereas caveolin-1 was observed as downregulated. The identified biomarker signature was subsequently analyzed using an independent test set (AUC = 0.78. Further evaluation of the identified biomarker panel by Western blot and mRNA profiling confirmed the proteomic signature obtained by RPPA. In conclusion, the biomarker signature introduced supports RPPA as a tool for cancer biomarker discovery.

  8. Detection of pAkt protein in imprint cytology of invasive breast cancer: Correlation with HER2/neu, hormone receptors, and other clinicopathological variables

    Directory of Open Access Journals (Sweden)

    Olympia Vasou

    2015-01-01

    Full Text Available Purpose: Akt is a serine/threonine protein kinase and has emerged as a crucial regulator of widely divergent cellular processes, including apoptosis, proliferation, differentiation, and metabolism. Activation of Akt/protein kinase B has been positively associated with human epidermal growth-factor receptor 2 (HER2/neu overexpression in breast carcinoma and a worse outcome among endocrine treated patients. The Akt signaling pathway currently attracts considerable attention as a new target for effective therapeutic strategies. We therefore investigated the relationship between activation of Akt and clinicopathologic variables including hormone receptor and HER2/neu status. Methods: Archival tumor tissues from 100 patients with invasive breast carcinoma were analyzed by immunocytochemistry. This study describes the results of immunocytochemical pAkt expression in breast carcinoma imprints, prepared from cut surfaces of freshly removed tumors . Both nuclear and cytoplasmic expressions were evaluated for pAkt. Results: Nuclear and cytoplasmic positive scores of 72% (72/100 and 42% (42/100, respectively, were found. Coexistence of nuclear and cytoplasmic staining was observed in 32 cases (32/100. Nuclear positive staining correlated with HER2/neu overexpression (P = 0.043 and was significantly associated with positive involvement of axillary lymph nodes (P = 0.013. No correlation was found between cytoplasmic pAkt rate and clinicopathological parameters, estrogen receptor, progesterone receptor or HER2/neu expression. Conclusions: pAkt expression can be evaluated in cytological material and may add valuable information to current prognostic models for breast cancer. pAkt overexpression appears to be linked with potentially aggressive tumor phenotype in invasive breast carcinoma.

  9. A Molecular Case-Control Study on the Association of Melatonin Hormone and rs#10830963 Single Nucleotide Polymorphism in its Receptor MTNR1B Gene with Breast Cancer

    Directory of Open Access Journals (Sweden)

    Nadia A Abd El Moneim

    2015-01-01

    Full Text Available Background: The main function of the pineal hormone melatonin which is mediated via its two receptors, MTNR1A and MTNR1B, is to mediate dark signals in addition to anti-oxidation, immune system enhancement, protection from radiation, and anti-cancer functions. A common single nucleotide polymorphism in the MTNR1B gene is rs#10830963, which is well known as a risk factor for type 2 diabetes mellitus. This study intends to figure out the role of melatonin and its receptor MTNR1B gene rs#10830963 polymorphism in breast cancer incidence, diagnosis and prognosis. Methods: This study included 43 females with breast cancer and 45 apparently normal healthy females. Restriction fragment length polymorphism-PCR was used for amplification and genotyping of the MTNR1B gene rs#10830963 polymorphism in whole blood. Serum melatonin levels were measured using a ready-for-use radioimmunoassay kit. Results: For the MTNR1B gene rs#10830963 polymorphism, we observed a significantly higher GG genotype frequency among cases (72.1% than controls (13.3%, with a diagnostic sensitivity of 83.78% and specificity of 76.47%. The cases had a frequency of 11.6% for the CC genotype and 16.3% for the CG genotype which was significantly lower compared to controls that had a 44.4% frequency of the CC genotype and 42.2% frequency of the CG genotype. The GG genotype had a significant association with larger tumor volume (P=0.048. Serum melatonin levels were significantly lower among breast cancer patients than controls. Using the ROC curve analysis, serum melatonin showed a significant AUC (72.6%, P39.5 pg/ml. Conclusion: The risk for breast cancer incidence increased as the serum levels of melatonin decreased and in females homozygous for the G allele (GG genotype of the MTNR1B gene rs#10830963 polymorphism. The GG genotype was found to be associated with increased breast tumor volume as a marker of a poor prognosis breast cancer.

  10. [Metastatic hormone-sensitive prostate cancer].

    Science.gov (United States)

    Gravis, Gwenaelle; Salem, Naji; Walz, Jochen

    2015-01-01

    The prostate cancer in its hormone-sensitive metastatic presentation is infrequent, it is either an initial presentation of the disease or an evolution after local treatment, without castration of the biological relapse. The surgical or biological castration remains the cornerstone of the treatment. The deadline of castration initiation and its modalities of administration, intermittent or continuous rest debated but consensual on the initiation is the appearance of the symptomatic disease. The chemotherapy by docetaxel in association with the castration increases significantly the survival of the patients having a high tumoral volume. The efficacy on the whole metastatic population requires additional analyses. Clinical prognostic factors as the bone localizations (axial or appendicular), the visceral involvement (liver, lung) are determining for the survival of these patients. Biological prognostic factors are in evaluation. Except the clodronate acid, which showed a survival improvement in the hormone-sensitive metastatic prostate cancer (HSMPC), the other treatments targeting the bone (zoledronic acid, rank-ligand inhibitor) demonstrated a benefit only in castrate resistant metastatic prostate cancer (MCRPC). The management of local disease lets suggest a benefit to at least symptomatic disease, but it requires to be estimated prospectively in clinical trials. The new hormonal treatments targeting the androgen receptor in CPMRC are in evaluation in CPMHS. The objective is to increase the survival and the quality of life of the CPMHS and to delay the evolution towards the castration resistant metastatic disease. PMID:25609491

  11. Role of androgen receptor in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    HiroyoshiSuzuki; HaruoIto

    1999-01-01

    The growth of prostate cancer is sensitive to androgen, and hormonal therapy has been used for treatment of ad-vanced cancer. About 80 % of prostate cancers initially respond to hormonal therapy, howcrver, more than half of the re-sponders gradtmlly become resistant to this therapy. Changes in tumors from an androgen-responsive to an androgen-unre-sponsive state have been widely discussed. Since androgen action is mediated by androgen receptor (AR), abnonnalitiesof AR is believed to play an important role of the loss of androgen responsiveness in prostate cancer. "Ilais article focusedon the role of AR in the progression of prostate cancer.

  12. Thyroid hormone receptors bind to defined regions of the growth hormone and placental lactogen genes.

    OpenAIRE

    Barlow, J W; Voz, M L; Eliard, P H; Mathy-Harter, M; De Nayer, Philippe; Economidis, I V; Belayew, A; Martial, J A; Rousseau, Guy

    1986-01-01

    The intracellular receptor for thyroid hormone is a protein found in chromatin. Since thyroid hormone stimulates transcription of the growth hormone gene through an unknown mechanism, the hypothesis that the thyroid hormone-receptor complex interacts with defined regions of this gene has been investigated in a cell-free system. Nuclear extracts from human lymphoblastoid IM-9 cells containing thyroid hormone receptors were incubated with L-3,5,3'-tri[125I]iodothyronine and calf thymus DNA-cell...

  13. Screening and association testing of common coding variation in steroid hormone receptor co-activator and co-repressor genes in relation to breast cancer risk: the Multiethnic Cohort

    International Nuclear Information System (INIS)

    Only a limited number of studies have performed comprehensive investigations of coding variation in relation to breast cancer risk. Given the established role of estrogens in breast cancer, we hypothesized that coding variation in steroid receptor coactivator and corepressor genes may alter inter-individual response to estrogen and serve as markers of breast cancer risk. We sequenced the coding exons of 17 genes (EP300, CCND1, NME1, NCOA1, NCOA2, NCOA3, SMARCA4, SMARCA2, CARM1, FOXA1, MPG, NCOR1, NCOR2, CALCOCO1, PRMT1, PPARBP and CREBBP) suggested to influence transcriptional activation by steroid hormone receptors in a multiethnic panel of women with advanced breast cancer (n = 95): African Americans, Latinos, Japanese, Native Hawaiians and European Americans. Association testing of validated coding variants was conducted in a breast cancer case-control study (1,612 invasive cases and 1,961 controls) nested in the Multiethnic Cohort. We used logistic regression to estimate odds ratios for allelic effects in ethnic-pooled analyses as well as in subgroups defined by disease stage and steroid hormone receptor status. We also investigated effect modification by established breast cancer risk factors that are associated with steroid hormone exposure. We identified 45 coding variants with frequencies ≥ 1% in any one ethnic group (43 non-synonymous variants). We observed nominally significant positive associations with two coding variants in ethnic-pooled analyses (NCOR2: His52Arg, OR = 1.79; 95% CI, 1.05–3.05; CALCOCO1: Arg12His, OR = 2.29; 95% CI, 1.00–5.26). A small number of variants were associated with risk in disease subgroup analyses and we observed no strong evidence of effect modification by breast cancer risk factors. Based on the large number of statistical tests conducted in this study, the nominally significant associations that we observed may be due to chance, and will need to be confirmed in other studies. Our findings suggest that common coding

  14. Screening and association testing of common coding variation in steroid hormone receptor co-activator and co-repressor genes in relation to breast cancer risk: the Multiethnic Cohort

    Directory of Open Access Journals (Sweden)

    Stallcup Michael R

    2009-01-01

    Full Text Available Abstract Background Only a limited number of studies have performed comprehensive investigations of coding variation in relation to breast cancer risk. Given the established role of estrogens in breast cancer, we hypothesized that coding variation in steroid receptor coactivator and corepressor genes may alter inter-individual response to estrogen and serve as markers of breast cancer risk. Methods We sequenced the coding exons of 17 genes (EP300, CCND1, NME1, NCOA1, NCOA2, NCOA3, SMARCA4, SMARCA2, CARM1, FOXA1, MPG, NCOR1, NCOR2, CALCOCO1, PRMT1, PPARBP and CREBBP suggested to influence transcriptional activation by steroid hormone receptors in a multiethnic panel of women with advanced breast cancer (n = 95: African Americans, Latinos, Japanese, Native Hawaiians and European Americans. Association testing of validated coding variants was conducted in a breast cancer case-control study (1,612 invasive cases and 1,961 controls nested in the Multiethnic Cohort. We used logistic regression to estimate odds ratios for allelic effects in ethnic-pooled analyses as well as in subgroups defined by disease stage and steroid hormone receptor status. We also investigated effect modification by established breast cancer risk factors that are associated with steroid hormone exposure. Results We identified 45 coding variants with frequencies ≥ 1% in any one ethnic group (43 non-synonymous variants. We observed nominally significant positive associations with two coding variants in ethnic-pooled analyses (NCOR2: His52Arg, OR = 1.79; 95% CI, 1.05–3.05; CALCOCO1: Arg12His, OR = 2.29; 95% CI, 1.00–5.26. A small number of variants were associated with risk in disease subgroup analyses and we observed no strong evidence of effect modification by breast cancer risk factors. Based on the large number of statistical tests conducted in this study, the nominally significant associations that we observed may be due to chance, and will need to be confirmed in other

  15. Hormone therapy and different ovarian cancers

    DEFF Research Database (Denmark)

    Mørch, Lina Steinrud; Løkkegaard, Ellen; Andreasen, Anne Helms;

    2012-01-01

    Postmenopausal hormone therapy use increases the risk of ovarian cancer. In the present study, the authors examined the risks of different histologic types of ovarian cancer associated with hormone therapy. Using Danish national registers, the authors identified 909,946 women who were followed from...... 1995-2005. The women were 50-79 years of age and had no prior hormone-sensitive cancers or bilateral oophorectomy. Hormone therapy prescription data were obtained from the National Register of Medicinal Product Statistics. The National Cancer and Pathology Register provided data on ovarian cancers......, including information about tumor histology. The authors performed Poisson regression analyses that included hormone exposures and confounders as time-dependent covariates. In an average of 8.0 years of follow up, 2,681 cases of epithelial ovarian cancer were detected. Compared with never users, women...

  16. Emerging roles of orphan nuclear receptors in cancer.

    Science.gov (United States)

    Baek, Sung Hee; Kim, Keun Il

    2014-01-01

    A growing body of evidence suggests that a subset of orphan nuclear receptors are amplified and prognostic for some human cancers. However, the specific roles of these orphan nuclear receptors in tumor progression and their utility as drug targets are not fully understood. In this review, we summarize recent progress in elucidating the direct and indirect involvement of orphan nuclear receptors in cancer as well as their therapeutic potential in a variety of human cancers. Furthermore, we contrast the role of orphan nuclear receptors in cancer with the known roles of estrogen receptor and androgen receptor in hormone-dependent cancers. PMID:24215441

  17. Hormone therapy and different ovarian cancers

    DEFF Research Database (Denmark)

    Mørch, Lina Steinrud; Løkkegaard, Ellen; Andreasen, Anne Helms;

    2012-01-01

    Postmenopausal hormone therapy use increases the risk of ovarian cancer. In the present study, the authors examined the risks of different histologic types of ovarian cancer associated with hormone therapy. Using Danish national registers, the authors identified 909,946 women who were followed fr...

  18. Substantial expression of luteinizing hormone-releasing hormone (LHRH) receptor type I in human uveal melanoma

    Science.gov (United States)

    Schally, Andrew V.; Block, Norman L; Dezso, Balazs; Olah, Gabor; Rozsa, Bernadett; Fodor, Klara; Buglyo, Armin; Gardi, Janos; Berta, Andras; Halmos, Gabor

    2013-01-01

    Uveal melanoma is the most common primary intraocular malignancy in adults, with a very high mortality rate due to frequent liver metastases. Consequently, the therapy of uveal melanoma remains a major clinical challenge and new treatment approaches are needed. For improving diagnosis and designing a rational and effective therapy, it is essential to elucidate molecular characteristics of this malignancy. The aim of this study therefore was to evaluate as a potential therapeutic target the expression of luteinizing hormone-releasing hormone (LHRH) receptor in human uveal melanoma. The expression of LHRH ligand and LHRH receptor transcript forms was studied in 39 human uveal melanoma specimens by RT-PCR using gene specific primers. The binding charachteristics of receptors for LHRH on 10 samples were determined by ligand competition assays. The presence of LHRH receptor protein was further evaluated by immunohistochemistry. The expression of mRNA for type I LHRH receptor was detected in 18 of 39 (46%) of tissue specimens. mRNA for LHRH-I ligand could be detected in 27 of 39 (69%) of the samples. Seven of 10 samples investigated showed high affinity LHRH-I receptors. The specific presence of full length LHRH receptor protein was further confirmed by immunohistochemistry. A high percentage of uveal melanomas express mRNA and protein for type-I LHRH receptors. Our results support the merit of further investigation of LHRH receptors in human ophthalmological tumors. Since diverse analogs of LHRH are in clinical trials or are already used for the treatment of various cancers, these analogs could be considered for the LHRH receptor-based treatment of uveal melanoma. PMID:24077773

  19. Intake of whole grain products and risk of breast cancer by hormone receptor status and histology among postmenopausal women

    DEFF Research Database (Denmark)

    Egeberg, Rikke; Olsen, Anja; Loft, Steffen;

    2009-01-01

    in intake of total whole grain products of 50 g per day the adjusted incidence rate ratio (95% confidence interval) was 1.01 (0.96-1.07). Intake of rye bread, oatmeal and whole grain bread was not associated with breast cancer risk. No association was observed between the intake of total or specific whole...

  20. Synthesis and in vitro anti-cancer evaluation of luteinizing hormone-releasing hormone-conjugated peptide.

    Science.gov (United States)

    Deng, Xin; Qiu, Qianqian; Ma, Ke; Huang, Wenlong; Qian, Hai

    2015-11-01

    Luteinizing hormone-releasing hormone (LHRH) is a decapeptide hormone released from the hypothalamus and shows high affinity binding to the LHRH receptors. It is reported that several cancer cells also express LHRH receptors such as breast, ovarian, prostatic, bladder and others. In this study, we linked B1, an anti-cancer peptide, to LHRH and its analogs to improve the activity against cancer cells with LHRH receptor. Biological evaluation revealed that TB1, the peptide contains triptorelin sequence, present favorable anti-cancer activity as well as plasma stability. Further investigations disclosed that TB1 trigger apoptosis by activating the mitochondria-cytochrome c-caspase apoptotic pathway, it also exhibited the anti-migratory effect on cancer cells. PMID:26058357

  1. Nuclear T-STAR protein expression correlates with HER2 status, hormone receptor negativity and prolonged recurrence free survival in primary breast cancer and decreased cancer cell growth in vitro.

    Directory of Open Access Journals (Sweden)

    Sandra Sernbo

    Full Text Available T-STAR (testis-signal transduction and activation of RNA is an RNA binding protein, containing an SH3-binding domain and thus potentially playing a role in integration of cell signaling and RNA metabolism. The specific function of T-STAR is unknown and its implication in cancer is poorly characterized. Expression of T-STAR has been reported in human testis, muscle and brain tissues, and is associated with a growth-inhibitory role in immortalized fibroblasts. The aim of this paper was to investigate the functional role of T-STAR through (i survival analysis of patients with primary invasive breast cancer and (ii experimental evaluation of the effect of T-STAR on breast cancer cell growth. T-STAR protein expression was analysed by immunohistochemistry (IHC in tissue microarrays with tumors from 289 patients with primary invasive breast cancer, and correlations to clinicopathological characteristics, recurrence-free and overall survival (RFS and OS and established tumor markers such as HER2 and ER status were evaluated. In addition, the function of T-STAR was investigated using siRNA-mediated knock-down and overexpression of the gene in six breast cancer cell lines. Of the tumors analysed, 86% showed nuclear T-STAR expression, which was significantly associated with an improved RFS and strongly associated with positive HER2 status and negative hormone receptor status. Furthermore, experimental data showed that overexpression of T-STAR decreased cellular growth while knock-down increased it, as shown both by thymidine incorporation and metabolic activity. In summary, we demonstrate that T-STAR protein expression correlates with an improved RFS in primary breast cancer. This is supported by functional data, indicating that T-STAR regulation is of importance both for breast cancer biology and clinical outcome but future studies are needed to determine a potential role in patient stratification.

  2. Recovery of hormone sensitivity after salvage brachytherapy for hormone refractory localized prostate cancer

    Directory of Open Access Journals (Sweden)

    Dan Smith

    2010-06-01

    Full Text Available PURPOSE: Recent work has demonstrated the return of hormone sensitivity after palliative chemotherapy in androgen independent prostate cancer. We wished to establish whether a similar phenomenon existed in patients with no exposure to chemotherapy. MATERIALS AND METHODS: A review of “hormone resistant” patients who had received salvage brachytherapy for localized prostate cancer after previous external beam radiotherapy was undertaken. Three patients with subsequent biochemical relapse responded to the rechallenge with hormonal treatment. RESULTS: The series of patients presented here demonstrates this phenomenon occurs after salvage brachytherapy with no exposure to chemotherapy. Recovery of sensitivity is demonstrated both to androgen deprivation and to androgen receptor antagonism. The recovery of hormone sensitivity was surprisingly durable, ranging from eight months to over twenty-one months. CONCLUSIONS: Hormone sensitivity may be recovered after salvage brachytherapy. Potential mechanisms underlying these observations are discussed and the likely central role of the activity of the androgen receptor highlighted. The relevance of these findings to the management of advanced prostate cancer is considered including thoughts on the practice of intermittent anti-androgen therapy.

  3. Nuclear hormone receptors put immunity on sterols.

    Science.gov (United States)

    Santori, Fabio R

    2015-10-01

    Nuclear hormone receptors (NHRs) are transcription factors regulated by small molecules. The functions of NHRs range from development of primary and secondary lymphoid organs, to regulation of differentiation and function of DCs, macrophages and T cells. The human genome has 48 classic (hormone and vitamin receptors) and nonclassic (all others) NHRs; 17 nonclassic receptors are orphans, meaning that the endogenous ligand is unknown. Understanding the function of orphan NHRs requires the identification of their natural ligands. The mevalonate pathway, including its sterol and nonsterol intermediates and derivatives, is a source of ligands for many classic and nonclassic NHRs. For example, cholesterol biosynthetic intermediates (CBIs) are natural ligands for RORγ/γt. CBIs are universal endogenous metabolites in mammalian cells, and to study NHRs that bind CBIs requires ligand-free reporters system in sterol auxotroph cells. Furthermore, RORγ/γt shows broad specificity to sterol lipids, suggesting that RORγ/γt is either a general sterol sensor or specificity is defined by an abundant endogenous ligand. Unlike other NHRs, which regulate specific metabolic pathways, there is no connection between the genetic programs induced by RORγ/γt and ligand biosynthesis. In this review, we summarize the roles of nonclassic NHRs and their potential ligands in the immune system.

  4. Comparison of hormonal receptor and HER2 status between ultrasound-guided 14-gauge core needle biopsy and surgery in breast cancer patients

    Energy Technology Data Exchange (ETDEWEB)

    Park, Yun Joo; Youk, Ji Hyun; Son, Eun Ji; Gweon, Hye Mi; Kim, Jeong Ah [Dept. of Radiology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2014-10-15

    To evaluate the concordance of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) statuses between ultrasound (US)-guided 14-gauge core needle biopsy (CNB) and surgery and to analyze whether the clinicopathological and imaging features including those from mammography and ultrasonography can predict the concordance in breast cancer patients. The concordance of receptor status between CNB and surgery was assessed for 55 breast cancers in 55 women who underwent CNB before treatment. The clinicopathological and imaging features and the concordance rates were compared between the non-neoadjuvant chemotherapy (non-NAC) group and the NAC group according to the initial treatment. The concordance rates were analyzed according to the clinicopathological and imaging features, by using the chi-square or Fisher exact test and McNemar test for the categorical and the independent t-test for continuous variables. Among 55 women, 22 women (40%) were part of the non-NAC group and 33 women (60%) were part of the NAC group. The concordance rates were 0.86-1.00 in the non-NAC group and 0.76-0.88 in the NAC group. In all three receptors, the difference in the concordance rate between the two groups was not significant. In the NAC group, the absence of axillary lymph node metastasis (1.00, P=0.02) and visibility of cancer on mammography (0.93, P=0.04) showed the higher concordance of the HER2 status. Concordance of the receptor status between surgery and US-guided 14-gauge CNB was feasible in breast cancer patients. The absence of axillary lymph node metastasis after NAC and the visibility of cancer on mammography prior to NAC may be helpful for predicting the concordance of HER2 in breast cancer patients.

  5. Quality assessment of estrogen receptor and progesterone receptor testing in breast cancer using a tissue microarray-based approach

    NARCIS (Netherlands)

    Dekker, T. J. A.; ter Borg, S.; Hooijer, G. K. J.; Meijer, S. L.; Wesseling, J.; Boers, J. E.; Schuuring, E.; Bart, J.; van Gorp, J.; Bult, P.; Riemersma, S. A.; van Deurzen, C. H. M.; Sleddens, H. F. B. M.; Mesker, W. E.; Kroep, J. R.; Smit, V. T. H. B. M.; van de Vijver, M. J.

    2015-01-01

    Assessing hormone receptor status is an essential part of the breast cancer diagnosis, as this biomarker greatly predicts response to hormonal treatment strategies. As such, hormone receptor testing laboratories are strongly encouraged to participate in external quality control schemes to achieve op

  6. Menopausal hormone use and ovarian cancer risk

    DEFF Research Database (Denmark)

    Beral, V; Gaitskell, K; Hermon, C;

    2015-01-01

    BACKGROUND: Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy...... on ovarian cancer risk. METHODS: Individual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies....... Adjusted Poisson regressions yielded relative risks (RRs) versus never-use. FINDINGS: During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with

  7. Management of Hormone Deprivation Symptoms After Cancer.

    Science.gov (United States)

    Faubion, Stephanie S; Loprinzi, Charles L; Ruddy, Kathryn J

    2016-08-01

    Cancer survivors often experience symptoms related to hormone deprivation, including vasomotor symptoms, genitourinary symptoms, and sexual health concerns. These symptoms can occur due to natural menopause in midlife women, or they can be brought on by oncologic therapies in younger women or men. We searched PubMed for English-language studies from January 1990 through January 2016 to identify relevant articles on the management of hormone deprivation symptoms, including vasomotor, genitourinary, and sexual symptoms in patients with cancer. The search terms used included hormone deprivation, vasomotor symptoms, hot flash, vaginal dryness, sexual dysfunction, and breast cancer. This manuscript provides a comprehensive description of data supporting the treatment of symptoms associated with hormone deprivation. PMID:27492917

  8. Thyroid Hormone Receptor beta Mediates Acute Illness-Induced Alterations in Central Thyroid Hormone Metabolism

    NARCIS (Netherlands)

    A. Boelen; J. Kwakkel; O. Chassande; E. Fliers

    2009-01-01

    Acute illness in mice profoundly affects thyroid hormone metabolism in the hypothalamus and pituitary gland. It remains unknown whether the thyroid hormone receptor (TR)-beta is involved in these changes. In the present study, we investigated central thyroid hormone metabolism during lipopolysacchar

  9. Hormone Therapy for Prostate Cancer

    Science.gov (United States)

    ... agonists , which are sometimes called LHRH analogs, are synthetic proteins that are structurally similar to LHRH and ... gland to stop producing luteinizing hormone, which prevents testosterone from being produced. Treatment with an LHRH agonist ...

  10. Management of hormone-sensitive metastatic prostate cancer.

    Science.gov (United States)

    Agarwal, Neeraj; Hussain, Maha

    2013-12-01

    Targeting gonadal androgen synthesis (often in conjunction with blockade of androgen receptor) is the cornerstone of treatment of hormone-sensitive metastatic prostate cancer (HSPC). Despite the failure of androgen deprivation therapy, most tumors maintain some dependence on androgen or androgen receptor signaling for proliferation. This article reviews the current standard of care for metastatic HSPC, mechanisms of treatment resistance, novel drugs targeting the androgen signaling pathway, biomarkers predicting response to treatment and survival, future directions, and ongoing clinical trials in HSPC. PMID:24188260

  11. Fast evolution of growth hormone receptor in primates and ruminants

    Institute of Scientific and Technical Information of China (English)

    HOU Zhenfang; LI Ying; ZHANG Yaping

    2005-01-01

    Pituitary growth hormone (GH) evolves very slowly in most of mammals, but the evolutionary rates appear to have increased markedly on two occasions during the evolution of primates and ruminants. To investigate the evolutionary pattern of growth hormone receptor (GHR), we sequenced the extracellular domain of GHR genes from four primate species. Our results suggested that GHR in mammal also shows an episodic evolutionary pattern, which is consistent with that observed in pituitary growth hormone. Further analysis suggested that this pattern of rapid evolution observed in primates and ruminants is likely the result of coevolution between pituitary growth hormone and its receptor.

  12. Mortality risk of black women and white women with invasive breast cancer by hormone receptors, HER2, and p53 status

    International Nuclear Information System (INIS)

    Black women are more likely than white women to have an aggressive subtype of breast cancer that is associated with higher mortality and this may contribute to the observed black-white difference in mortality. However, few studies have investigated the black-white disparity in mortality risk stratified by breast cancer subtype, defined by estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status. Furthermore, it is not known whether additional consideration of p53 protein status influences black-white differences in mortality risk observed when considering subtypes defined by ER, PR and HER2 status. Four biomarkers were assessed by immunohistochemistry in paraffin-embedded breast tumor tissue from 1,204 (523 black, 681 white) women with invasive breast cancer, aged 35–64 years at diagnosis, who accrued a median of 10 years’ follow-up. Multivariable Cox proportional hazards regression models were fit to assess subtype-specific black-white differences in mortality risk. No black-white differences in mortality risk were observed for women with triple negative (ER-negative [ER-], PR-, and HER2-) subtype. However, older (50–64 years) black women had greater overall mortality risk than older white women if they had been diagnosed with luminal A (ER-positive [ER+] or PR+ plus HER2-) breast cancer (all-cause hazard ratio, HR, 1.88; 95% confidence interval, CI, 1.18 to 2.99; breast cancer-specific HR, 1.51; 95% CI, 0.83 to 2.74). This black-white difference among older women was further confined to those with luminal A/p53- tumors (all-cause HR, 2.22; 95% CI, 1.30 to 3.79; breast cancer-specific HR, 1.89; 95% CI, 0.93 to 3.86). Tests for homogeneity of race-specific HRs comparing luminal A to triple negative subtype and luminal A/p53- to luminal A/p53+ subtype did not achieve statistical significance, although statistical power was limited. Our findings suggest that the subtype-specific black-white difference in

  13. Dietary flavonoid and lignan intake and breast cancer risk according to menopause and hormone receptor status in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study

    DEFF Research Database (Denmark)

    Zamora-Ros, Raul; Ferrari, Pietro; González, Carlos A.;

    2013-01-01

    Evidence on the association between dietary flavonoids and lignans and breast cancer (BC) risk is inconclusive, with the possible exception of isoflavones in Asian countries. Therefore, we investigated prospectively dietary total and subclasses of flavonoid and lignan intake and BC risk according...

  14. The reciprocal regulation of stress hormones and GABAA receptors

    Directory of Open Access Journals (Sweden)

    Istvan eMody

    2012-01-01

    Full Text Available Stress-derived steroid hormones regulate the expression and function of GABAA receptors (GABAARs. Changes in GABAAR subunit expression have been demonstrated under conditions of altered steroid hormone levels, such as stress, as well as following exogenous steroid hormone administration. In addition to the effects of stress-derived steroid hormones on GABAAR subunit expression, stress hormones can also be metabolized to neuroactive derivatives which can alter the function of GABAARs. Neurosteroids allosterically modulate GABAARs at concentrations comparable to those during stress. In addition to the actions of stress-derived steroid hormones on GABAARs, GABAARs reciprocally regulate the production of stress hormones. The stress response is mediated by the hypothalamic-pituitary-adrenal (HPA axis, the activity of which is governed by corticotropin releasing hormone (CRH neurons. The activity of CRH neurons is largely controlled by robust GABAergic inhibition. Recently, it has been demonstrated that CRH neurons are regulated by neurosteroid-sensitive, GABAAR δ subunit-containing receptors representing a novel feedback mechanism onto the HPA axis. Further, it has been demonstrated that neurosteroidogenesis and neurosteroid actions on GABAAR δ subunit-containing receptors on CRH neurons are necessary to mount the physiological response to stress. Here we review the literature describing the effects of steroid hormones on GABAARs as well as the importance of GABAARs in regulating the production of steroid hormones. This review incorporates what we currently know about changes in GABAARs following stress and the role in HPA axis regulation.

  15. Profile of thyroid hormones in breast cancer patients

    Directory of Open Access Journals (Sweden)

    Saraiva P.P.

    2005-01-01

    Full Text Available Estrogen involvement in breast cancer has been established; however, the association between breast cancer and thyroid diseases is controversial. Estrogen-like effects of thyroid hormone on breast cancer cell growth in culture have been reported. The objective of the present study was to determine the profile of thyroid hormones in breast cancer patients. Serum aliquots from 26 patients with breast cancer ranging in age from 30 to 85 years and age-matched normal controls (N = 22 were analyzed for free triiodothyronine (T3F, free thyroxine (T4F, thyroid-stimulating hormone (TSH, antiperoxidase antibody (TPO, and estradiol (E2. Estrogen receptor ß (ERß was determined in tumor tissues by immunohistochemistry. Thyroid disease incidence was higher in patients than in controls (58 vs 18%, P < 0.05. Subclinical hyperthyroidism was the most frequent disorder in patients (31%; hypothyroidism (8% and positive anti-TPO antibodies (19% were also found. Subclinical hypothyroidism was the only dysfunction (18% found in controls. Hyperthyroidism was associated with postmenopausal patients, as shown by significantly higher mean T3 and T4 values and lower TSH levels in this group of breast cancer patients than in controls. The majority of positive ERß tumors were clustered in the postmenopausal patients and all cases presenting subclinical hyperthyroidism in this subgroup concomitantly exhibited Erß-positive tumors. Subclinical hyperthyroidism was present in only one of 6 premenopausal patients. We show here that postmenopausal breast cancer patients have a significantly increased thyroid hormone/E2 ratio (P < 0.05, suggesting a possible tumor growth-promoting effect caused by this misbalance.

  16. Membrane progesterone receptors in reproduction and cancer.

    Science.gov (United States)

    Valadez-Cosmes, Paulina; Vázquez-Martínez, Edgar Ricardo; Cerbón, Marco; Camacho-Arroyo, Ignacio

    2016-10-15

    Progesterone is a sexual steroid hormone that has a critical role in reproductive processes in males and females of several species, including humans. Furthermore, progesterone has been associated with pathological diseases such as breast, gynecological and brain cancer, regulating cell proliferation, apoptosis, and metastasis. In the past, progesterone actions were thought to be only mediated by its intracellular receptor (PR). However, recent evidence has demonstrated that membrane progesterone receptors (mPRs) mediate most of the non-classical progesterone actions. The role of the different mPRs subtypes in progesterone effects in reproduction and cancer is an emerging and exciting research area. Here we review studies to date regarding mPRs role in reproduction and cancer and discuss their functions and clinical relevance, suggesting mPRs as putative pharmacological targets and disease markers in cancer and diseases associated with reproduction. PMID:27368976

  17. Molecular identification of the first insect ecdysis triggering hormone receptors

    DEFF Research Database (Denmark)

    Iversen, Annette; Cazzamali, Giuseppe; Williamson, Michael;

    2002-01-01

    be activated by low concentrations of Drosophila ecdysis triggering hormones-1 and -2. Ecdysis (cuticle shedding) is an important behaviour, allowing growth and metamorphosis in insects and other arthropods. Our paper is the first report on the molecular identification of ecdysis triggering hormone receptors...

  18. Cloning of partial putative gonadotropin hormone receptor sequence from fish

    Indian Academy of Sciences (India)

    G Kumaresan; T Venugopal; A Vikas; T J Pandian; S M Athavan

    2000-03-01

    A search for the presence of mariner-like elements in the Labeo rohita genome by polymerase chain reaction led to the amplification of a partial DNA sequence coding for a putative transmembrane domain of gonadotropin hormone receptor. The amplified DNA sequence shows a high degree of homology to the available turkey and human luteinizing and follicle stimulating hormone receptor coding sequences. This is the first report on cloning such sequences of piscine origin.

  19. Activation of the chicken gonadotropin-inhibitory hormone receptor reduces gonadotropin releasing hormone receptor signaling.

    Science.gov (United States)

    Shimizu, Mamiko; Bédécarrats, Grégoy Y

    2010-06-01

    Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic peptide from the RFamide peptide family that has been identified in multiple avian species. Although GnIH has clearly been shown to reduce LH release from the anterior pituitary gland, its mechanism of action remains to be determined. The overall objectives of this study were (1) to characterize the GnIH receptor (GnIH-R) signaling pathway, (2) to evaluate potential interactions with gonadotropin releasing hormone type III receptor (GnRH-R-III) signaling, and (3) to determine the molecular mechanisms by which GnIH and GnRH regulate pituitary gonadotrope function during a reproductive cycle in the chicken. Using real-time PCR, we showed that in the chicken pituitary gland, GnIH-R mRNA levels fluctuate in an opposite manner to GnRH-R-III, with higher and lower levels observed during inactive and active reproductive stages, respectively. We demonstrated that the chicken GnIH-R signals by inhibiting adenylyl cyclase cAMP production, most likely by coupling to G(alphai). We also showed that this inhibition is sufficient to significantly reduce GnRH-induced cAMP responsive element (CRE) activation in a dose-dependent manner, and that the ratio of GnRH/GnIH receptors is a significant factor. We propose that in avian species, sexual maturation is characterized by a change in GnIH/GnRH receptor ratio, resulting in a switch in pituitary sensitivity from inhibitory (involving GnIH) to stimulatory (involving GnRH). In turn, decreasing GnIH-R signaling, combined with increasing GnRH-R-III signaling, results in significant increases in CRE activation, possibly initiating gonadotropin synthesis. PMID:20350548

  20. Thyroid Hormone Receptor alpha Modulates Lipopolysaccharide-Induced Changes in Peripheral Thyroid Hormone Metabolism

    NARCIS (Netherlands)

    J. Kwakkel; O. Chassande; H.C. van Beeren; E. Fliers; W.M. Wiersinga; A. Boelen

    2010-01-01

    Acute inflammation is characterized by low serum T-3 and T-4 levels accompanied by changes in liver type 1 deiodinase (D1), liver D3, muscle D2, and muscle D3 expression. It is unknown at present whether thyroid hormone receptor alpha (TR alpha) plays a role in altered peripheral thyroid hormone met

  1. Evaluation of the ability of adjuvant tamoxifen-benefit gene signatures to predict outcome of hormone-naive estrogen receptor-positive breast cancer patients treated with tamoxifen in the advanced setting

    DEFF Research Database (Denmark)

    Sieuwerts, Anieta M; Lyng, Maria Bibi; Meijer-van Gelder, Marion E;

    2014-01-01

    To identify molecular markers indicative of response to tamoxifen and easily implemented in the routine setting, we recently reported three gene signatures that could stratify post-menopausal tamoxifen-treated, estrogen receptor-positive (ER+) patients according to outcome in the adjuvant setting....... Here, we evaluated the predictive potential of the total of 14 genes included in the 3 gene signatures using 2 hormone-naïve Dutch ER+ cohorts of a total of 285 recurrent breast cancer patients treated with first-line tamoxifen. mRNA levels were measured by reverse transcriptase quantitative PCR (RT......-qPCR) and the length of progression-free survival (PFS) was used as the primary endpoint. A Mann-Whitney U test was used to select for differentially expressed genes between tumors of patients who showed or did not show progressive disease within 6 months after start of tamoxifen treatment. Cox univariate...

  2. The role of the expression of bcl-2, p53 gene in tamoxifen-induced apoptosis of breast cancer cells and its relationship with hormone receptor status

    Energy Technology Data Exchange (ETDEWEB)

    Noh, Woo Chul; Ham, Yong Ho [Korea Cancer Center Hospital, Seoul (Korea, Republic of)

    1998-01-01

    To investigate the relationship of bcl-2, p53, ER and tamoxifen-induced apoptosis of breast cancer cells, MCF-7 (ER+/bcl-2+/p53-) and MB MDA 468 (ER-/bcl-2-/p53+) cell line were cultured in estrogen-free condition. E2(10`-`9M) and tamoxifen (10`-`5M) were added to the media. The changes of bcl-2 and mutant p53 protein were checked by Western blot and apoptosis were measured by flowcytometry. In MCF-7 cells, we found that treatment with tamoxifen resulted in a decrease in bcl-2 protein level, but produced no change in mutant p53. In MB MDA 468 cell however, there were no changes of bcl-2 and mutant p53 protein level when E2 or tamoxifen were added. Apoptotic cells increased with time-dependent pattern when tamoxifen was added to MCF-7 cells. According to these result, ER+/blc-2+/mutant p53- cells, when treated with tamoxifen, were converted into bcl-2/mutant p53- cells which were more prone to apoptosis than bcl-2-/mutant p53+ cells. The paradoxical correlation of bcl-2 and ER which had been observed in clinical studies might be explained with this results and bcl-2 protein seems to be one of important factors that can predict the effect of hormone therapy. (author). 26 refs., 5 figs

  3. Hormonal therapy might be a better choice asmaintenance treatment thancapecitabine afterresponse toifrst-line capecitabine-based combination chemotherapy forpatients withhormone receptor-positive andHER2-negative, metastatic breast cancer

    Institute of Scientific and Technical Information of China (English)

    Xue-LianChen; FengDu; Ruo-XiHong; Jia-YuWang; YangLuo; QingLi; YingFan; Bing-HeXu

    2016-01-01

    Background:Both hormonal therapy (HT) and maintenance capecitabine monotherapy (MCT) have been shown to extend time to progression (TTP) in patients with metastatic breast cancer (MBC) after failure of taxanes and anthracycline‑containing regimens. However, no clinical trials have directly compared the effcacy of MCT and HT after response to ifrst‑line capecitabine‑based combination chemotherapy (FCCT) in patients with hormone receptor (HR)‑positive and human epidermal growth factor receptor 2 (HER2)‑negative breast cancer. Methods:We retrospectively analyzed the charts of 138 HR‑positive and HER2‑negative MBC patients who were in non‑progression status after FCCT and who were treated between 2003 and 2012 at the Cancer Institute and Hospital, Chinese Academy of Medical Sciences, in Beijing, China. The median number of ifrst‑line chemotherapy cycles was 6 (range, 4–8); combined agents included taxanes, vinorelbine, or gemcitabine. Of these 138 patients, 79 received MCT, and 59 received HT. Single‑agent capecitabine was administered at a dose of 1250mg/m2 twice daily for 14days, followed by a 7‑day rest period, repeated every 3weeks. Of the 59 patients who received HT, 37 received aromatase inhibitors (AIs), 8 received selective estrogen receptor modulators (SERMs), and 14 received goserelin plus either AIs or SERMs. We then compared the MCT group and HT group in terms of treatment effcacy. Results:With a median follow‑up of 43months, patients in the HT group had a much longer TTP than patients in the MCT group (13 vs. 8months,P=0.011). When TTP was adjusted for age, menopausal status, Karnofsky performance status score, disease‑free survival, site of metastasis, number of metastatic sites, and response status after FCCT, extended TTP was still observed for patients in the HT group (hazard ratio: 0.63; 95% conifdence interval: 0.44–0.93;P=0.020). We also observed a trend of overall survival advantage for patients in the HT group vs

  4. Hormonal replacement therapy and gynecological cancer.

    Science.gov (United States)

    Onnis, A; Marchetti, M

    1999-01-01

    The problem of quality of life and lifestyle in elderly women is today a very important social problem all over the world but particularly in rich western countries. Life expectancy of the population will be longer and longer in the future and for both females and males the biological involution correlated with the aging process must be delayed. The gonadal hormones stimulate the healthy state of the entire body (heart, skin, brain, bones, urogenital apparatus and so on) and consequently hormonal replacement therapy (HRT) is mandatory. In women the biological clock of menopause allows us to intervene at the right time, with personalized estrogenic, estroprogestinic or estroandrogenic treatments. Health benefits and groundless risks allow today a careful hormonal management even in women treated for gynaecological cancers (breast and endometrium as well). PMID:10412612

  5. Molecular identification of the insect adipokinetic hormone receptors

    DEFF Research Database (Denmark)

    Staubli, Frank; Jørgensen, Thomas J. D.; Cazzamali, Giuseppe;

    2002-01-01

    The insect adipokinetic hormones (AKHs) are a large family of peptide hormones that are involved in the mobilization of sugar and lipids from the insect fat body during energy-requiring activities such as flight and locomotion, but that also contribute to hemolymph sugar homeostasis. Here, we have...... identified the first insect AKH receptors, namely those from the fruitfly Drosophila melanogaster and the silkworm Bombyx mori. These results represent a breakthrough for insect molecular endocrinology, because it will lead to the cloning of all AKH receptors from all model insects used in AKH research, and......, therefore, to a better understanding of AKH heterogeneity and actions. Interestingly, the insect AKH receptors are structurally and evolutionarily related to the gonadotropin-releasing hormone receptors from vertebrates....

  6. Selective Cancer Targeting via Aberrant Behavior of Cancer Cell-associated Glucocorticoid Receptor

    OpenAIRE

    Mukherjee, Amarnath; Narayan, Kumar P; Pal, Krishnendu; Kumar, Jerald M.; Rangaraj, Nandini; Shasi V Kalivendi; Banerjee, Rajkumar

    2009-01-01

    Glucocorticoid receptors (GRs) are ubiquitous, nuclear hormone receptors residing in cell types of both cancer and noncancerous origin. It is not known whether cancer cell–associated GR alone can be selectively manipulated for delivery of exogenous genes to its nucleus for eliciting anticancer effect. We find that GR ligand, dexamethasone (Dex) in association with cationic lipoplex (termed as targeted lipoplex) could selectively manipulate GR in cancer cells alone for the delivery of transgen...

  7. Update of NUREBASE: nuclear hormone receptor functional genomics

    OpenAIRE

    Ruau, David; Duarte, Jorge; Ourjdal, Tarik; Perrière, Guy; Laudet, Vincent; Robinson-Rechavi, Marc

    2004-01-01

    Nuclear hormone receptors are an abundant class of ligand-activated transcriptional regulators, found in varying numbers in all animals. Based on our experience of managing the official nomenclature of nuclear receptors, we have developed NUREBASE, a database containing protein and DNA sequences, reviewed protein alignments and phylogenies, taxonomy and annotations for all nuclear receptors. New developments in NUREBASE include explicit declaration of alternative transcripts of each gene, and...

  8. Selective induction of apoptosis by the cytotoxic analog AN-207 in cells expressing recombinant receptor for luteinizing hormone-releasing hormone

    OpenAIRE

    Danila, Daniel C; Schally, Andrew V.; Nagy, Attila; Alexander, Joseph M

    1999-01-01

    The selectivity of ligands specific for certain cells can be used to preferentially target chemotherapeutic compounds to neoplastic cells. Human breast, ovarian, endometrial, and prostatic cancers express receptors that can mediate the delivery of targeted cytotoxic compounds to neoplastic cells. Recently, a potent derivative of 2-pyrrolinodoxorubicin (AN-201) conjugated to [d-Lys6] luteinizing hormone-releasing hormone (LH-RH) (AN-207), was demonstrated to be less toxic than the nonconjugate...

  9. Luteinizing hormone-releasing hormone receptor-mediated delivery of mitoxantrone using LHRH analogs modified with PEGylated liposomes

    Directory of Open Access Journals (Sweden)

    Yingna He

    2010-09-01

    Full Text Available Yingna He, Linhua Zhang, Cunxian SongKey Laboratory of Biomedical Material of Tianjin, Institute of Biomedical Engineering, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin, ChinaAbstract: A sterically stabilized, mitoxantrone-loaded liposome, tailored to target luteinizing hormone-releasing hormone (LHRH receptor overexpressing cells, was developed to promote the efficiency of intracellular delivery of mitoxantrone through receptor-mediated endocytosis. Liposomes were prepared by lipid film hydration and an ultrasound dispersion process. Thiolated gonadorelin with affinity for the LHRH receptor was chemically coupled to N-[(3-maleimide-1-oxopropyl aminopropyl polyethylene glycol-carbamyl] distearoyl-l-phosphatidyl-ethanolamine via a thioether bond and subsequently inserted into polyethylene glycol-grafted liposomes. The liposome was characterized in terms of its size, ligand density, drug loading, and leakage properties. The targeting nature and antitumor effects of the liposomes were evaluated in vitro using cultured MCF-7 breast cancer cells. A protein assay of ligand coupling to the liposomal surface indicated that more than 60% of the LHRH peptides were inserted into the liposome bilayer. Up to 1.0 mg/mL of stable liposomal mitoxantrone loading was achieved, with approximately 98% of this being entrapped within the liposomes. In vitro cell culture studies revealed that the gonadorelin-modified liposomes bound to their target cells had significantly higher affinity and better antitumor efficiency than generic drug-loaded liposomes. These events were presumed to occur through specific interactions of the LHRH with its cognate receptors on the cell surface. It was concluded that the targeting properties of the delivery system would potentially improve the therapeutic benefits of mitoxantrone, as compared with nontargeted liposomes.Keywords: mitoxantrone, liposome, luteinizing hormone-releasing hormone receptor

  10. Redefining Hormone Sensitive Disease in Advanced Prostate Cancer

    OpenAIRE

    Xiaoyu Hou; Flaig, Thomas W.

    2012-01-01

    Prostate cancer is the most common cancer among men in the United States. For decades, the cornerstone of medical treatment for advanced prostate cancer has been hormonal therapy, intended to lower testosterone levels, known as Androgen Deprivation Therapy (ADT). The development of hormone-resistant prostate cancer (now termed castration-resistant prostate cancer:CRPC) remains the key roadblock in successful long-term management of prostate cancer. New advancements in medical therapy for pros...

  11. Synthesis of Analogues of Thyroid Hormones: Nuclear Receptor Modulators

    Directory of Open Access Journals (Sweden)

    Guilherme Vieira de Castro

    2015-09-01

    Full Text Available Thyroid hormones are essential for the development and differentiation of all cells of the human body. This work reports the synthesis of some synthetic structural analogues of thyroid hormones, which may be modulators of the thyroid hormone receptor. The known compounds GC-1 (Sobetirome and CG-24 were successfully prepared and two novel analogous molecules were also synthesized by a new and efficient synthetic methodology. DOI: http://dx.doi.org/10.17807/orbital.v7i3.739  

  12. Coffee consumption modifies risk of estrogen-receptor negative breast cancer

    OpenAIRE

    Li, Jingmei; Seibold, Petra; Chang-Claude, Jenny; Flesch-Janys, Dieter; Liu, Jianjun; Czene, Kamila; Humphreys, Keith; Hall, Per

    2011-01-01

    Introduction Breast cancer is a complex disease and may be sub-divided into hormone-responsive (estrogen receptor (ER) positive) and non-hormone-responsive subtypes (ER-negative). Some evidence suggests that heterogeneity exists in the associations between coffee consumption and breast cancer risk, according to different estrogen receptor subtypes. We assessed the association between coffee consumption and postmenopausal breast cancer risk in a large population-based study (2,818 cases and 3,...

  13. Effectiveness and adverse effects of hormonal therapy for prostate cancer: Japanese experience and perspective

    Institute of Scientific and Technical Information of China (English)

    Mikio Namiki; Satoru Ueno; Yasuhide Kitagawa; Takashi Fukagai; Hideyuki Akaza

    2012-01-01

    Recently,novel anti-androgens and inhibitors of androgen biosynthesis have been developed through the elucidation of mechanisms of castration resistance of prostate cancer.We believe that these new developments will improve hormonal therapy.On the other hand,there has been an increase in criticism of hormonal therapy,because hormonal therapy is supposed to induce adverse effects such as cardiovascular disease.In this review,we have introduced the Japanese experience of hormonal therapy,because we believe that there may be ethnic differences between Caucasians and Asian people in the efficacy and adverse effects of hormonal therapy.First,we showed that primary hormonal therapy can achieve long-term control of localized prostate cancer in some cases and that quality of life of patients receiving hormonal therapy is rather better than previously thought.Neoadjuvant and adjuvant hormonal therapy in cases undergoing radical prostatectomy or radiotherapy are very useful for high-risk or locally advanced prostate cancer.Further clinical trials are required to confirm the efficacy of neoadjuvant or adjuvant hormonal therapy.We showed that the death from cardiovascular diseases in Japanese patients receiving hormonal therapy was not higher than that in the general population.However,efforts should be made to decrease the adverse effects of hormonal therapy,because life-style change may increase the susceptibility to adverse effects by hormonal therapy even in Japan.Managements of endocrine and metabolic dysfunction,such as diabetes mellitus,are essential.New hormonal compounds such as selective androgen receptor modulators capable of specifically targeting prostate cancer are expected to be developed.

  14. Thyroid hormone receptor binds to a site in the rat growth hormone promoter required for induction by thyroid hormone

    International Nuclear Information System (INIS)

    Transcription of the rat growth hormone (rGH) gene in pituitary cells is increased by addition of thyroid hormone (T3). This induction is dependent on the presence of specific sequences just upstream of the rGH promoter. The authors have partially purified T3 receptor from rat liver and examined its interaction with these rGH sequences. They show here that T3 receptor binds specifically to a site just upstream of the basal rGH promoter. This binding site includes two copies of a 7-base-pair direct repeat, the centers of which are separated by 10 base pairs. Deletions that specifically remove the T3 receptor binding site drastically reduce response to T3 in transient transfection experiments. These results demonstrate that T3 receptor can recognize specific DNA sequences and suggest that it can act directly as a positive transcriptional regulatory factor

  15. Androgen Deprivation Therapy and Secondary Hormone Therapy in the Management of Hormone-sensitive and Castration-resistant Prostate Cancer.

    Science.gov (United States)

    Saad, Fred; Fizazi, Karim

    2015-11-01

    Androgen deprivation therapy (ADT) is the standard of care for patients with metastatic prostate cancer (mPC). However, nearly all patients with mPC progress to castration-resistant PC (CRPC). Arrays of treatments, including secondary hormonal therapies, are available for the treatment of mPC and CRPC, which show efficacy when administered with ADT. Continuation of ADT is recommended for CRPC treatment as therapies are added. New secondary hormonal therapies include abiraterone, targeting the CYP17 enzyme family, and enzalutamide, an androgen receptor inhibitor with heightened binding specificity. The optimal decision-making process for CRPC treatment option remains unclear, pending further research and experience. PMID:26282624

  16. Model for growth hormone receptor activation based on subunit rotation within a receptor dimer

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Richard J.; Adams, Julian J.; Pelekanos, Rebecca A.; Wan, Yu; McKinstry, William J.; Palethorpe, Kathryn; Seeber, Ruth M.; Monks, Thea A.; Eidne, Karin A.; Parker, Michael W.; Waters, Michael J. (UWA); (St. Vincent); (Queensland)

    2010-07-13

    Growth hormone is believed to activate the growth hormone receptor (GHR) by dimerizing two identical receptor subunits, leading to activation of JAK2 kinase associated with the cytoplasmic domain. However, we have reported previously that dimerization alone is insufficient to activate full-length GHR. By comparing the crystal structure of the liganded and unliganded human GHR extracellular domain, we show here that there is no substantial change in its conformation on ligand binding. However, the receptor can be activated by rotation without ligand by inserting a defined number of alanine residues within the transmembrane domain. Fluorescence resonance energy transfer (FRET), bioluminescence resonance energy transfer (BRET) and coimmunoprecipitation studies suggest that receptor subunits undergo specific transmembrane interactions independent of hormone binding. We propose an activation mechanism involving a relative rotation of subunits within a dimeric receptor as a result of asymmetric placement of the receptor-binding sites on the ligand.

  17. Redefining Hormone Sensitive Disease in Advanced Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Xiaoyu Hou

    2012-01-01

    Full Text Available Prostate cancer is the most common cancer among men in the United States. For decades, the cornerstone of medical treatment for advanced prostate cancer has been hormonal therapy, intended to lower testosterone levels, known as Androgen Deprivation Therapy (ADT. The development of hormone-resistant prostate cancer (now termed castration-resistant prostate cancer:CRPC remains the key roadblock in successful long-term management of prostate cancer. New advancements in medical therapy for prostate cancer have added to the hormonal therapy armamentarium. These new therapeutic agents not only provide a survival benefit but also show potential for reversing hormonal resistance in metastatic CRPC, and thus redefining hormonally sensitive disease.

  18. 新辅助化疗对乳腺癌激素受体 ER、PR 表达的影响%Influence of Neoadjuvant Chemotherapy on the Expression of Hormone Receptors ER、PR in Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    赵波涛; 罗庆丰; 高玟; 黄传生; 涂侃

    2014-01-01

    Objective To explore the influence of neoadjuvant chemotherapy on the expression of hormone receptors ER、PR in breast cancer .Methods Expression of ER、PR of 32 infitrating ductal carcinoma .patients before and after new adju-vant chemotherapy were detected by Maxvinsion immunohistochemistry .Results Expression of ER、PR of 32 infitrating ductal carcinoma patients before and after new adjuvant chemotherapy were the same .Negative expression of ER was observed in 5,ex-pression of ER +was observed in 8,ER ++in 12 and ER +++in 7.Negative expression of PR was observed in 6,expres-sion of PR +was observed in 7,PR ++in 12 and PR +++in 7.The positive expression of ER and PR was consistent ,and correlation comparison of the positive expression rate of ER and PR was important .Conclusion Expression of hormone receptors ER、PR in breast cancer before and after new adjuvant chemotherapy are the same .Neoadjuvant chemotherapy is safe .%目的:探讨新辅助化疗对乳腺癌激素受体ER、PR表达的影响。方法应用MaxVinsion免疫组织化学技术,检测32例浸润性导管癌乳腺患者新辅助化疗前、新辅助化疗后ER、PR表达情况。结果32例乳腺浸润性导管癌新辅助化疗前与化疗后检测结果完全相同:5例不表达ER,8例ER +,12例ER ++,7例ER +++;6例不表达PR,7例PR +,12例PR ++,7例PR +++。同时ER、PR阳性表达具有良好一致性,32例患者中ER、PR阳性表达间具有显著相关性。结论乳腺癌患者新辅助化疗前后激素受体ER、PR表达结果完全一致,新辅助化疗安全可行。

  19. Epidemiological trends of hormone-related cancers in Slovenia.

    Science.gov (United States)

    Zadnik, Vesna; Krajc, Mateja

    2016-06-01

    The incidence of hormone-related cancers tends to be higher in the developed world than in other countries. In Slovenia, six hormone-related cancers (breast, ovarian, endometrial, prostate, testicular, and thyroid) account for a quarter of all cancers. Their incidence goes up each year, breast and prostate cancer in particular. The age at diagnosis is not decreasing for any of the analysed cancer types. The risk of breast cancer is higher in the western part of the country, but no differences in geographical distribution have been observed for other hormone-related cancers. Furthermore, areas polluted with endocrine-disrupting chemicals that affect hormone balance such as PCBs, dioxins, heavy metals, and pesticides, do not seem to involve a greater cancer risk. We know little about how many cancers can be associated with endocrine disruptors, as there are too few reliable exposure studies to support an association. PMID:27331295

  20. Breast cancer with different prognostic characteristics developing in Danish women using hormone replacement therapy

    DEFF Research Database (Denmark)

    Stahlberg, Claudia; Pedersen, A T; Andersen, Zorana Jovanovic;

    2004-01-01

    The aim of this study is to investigate the risk of developing prognostic different types of breast cancer in women using hormone replacement therapy (HRT). A total of 10 874 postmenopausal Danish Nurses were followed since 1993. Incident breast cancer cases and histopathological information were...... retrieved through the National Danish registries. The follow-up ended on 31 December 1999. Breast cancer developed in 244 women, of whom 172 were invasive ductal carcinomas. Compared to never users, current users of HRT had an increased risk of a hormone receptor-positive breast cancer, but a neutral risk...... of receptor-negative breast cancer, relative risk (RR) 3.29 (95% confidence interval (CI): 2.27-4.77) and RR 0.99 (95% CI: 0.42-2.36), respectively (P for difference=0.013). The risk of being diagnosed with low histological malignancy grade was higher than high malignancy grade with RR 4.13 (95% CI...

  1. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Wang, Xianshu; Fredericksen, Zachary S;

    2010-01-01

    diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P(trend) = 2.3 × 10¿¿ to P(trend) = 3.9 × 10¿7), two of which showed independent...... associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR......) = 0.83, 95% CI 0.75-0.92, P(trend) = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P(trend) = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases...

  2. Transcriptional activation by the thyroid hormone receptor through ligand-dependent receptor recruitment and chromatin remodelling

    DEFF Research Database (Denmark)

    Grøntved, Lars; Waterfall, Joshua J; Kim, Dong Wook;

    2015-01-01

    A bimodal switch model is widely used to describe transcriptional regulation by the thyroid hormone receptor (TR). In this model, the unliganded TR forms stable, chromatin-bound complexes with transcriptional co-repressors to repress transcription. Binding of hormone dissociates co-repressors and...

  3. Hormone therapy use, sex hormone concentrations and gene expression : The Norwegian Women and Cancer study (NOWAC)

    OpenAIRE

    Waaseth, Marit

    2010-01-01

    According to sales statistics, the use of hormone therapy (HT) increased markedly in Norway through the 1990s, but decreased from 2002. Both endogenous and exogenous sex hormones are known risk factors for cancer among women. Cancer is characterized by uncontrolled cell growth which develops gradually through genomic alterations. Technological developments provide the opportunity to investigate relationships between sex hormones and blood gene expression in a population based cohort like the ...

  4. Elevated insulin receptor content in human breast cancer.

    OpenAIRE

    Papa, V.; Pezzino, V; Costantino, A.; Belfiore, A.; D. Giuffrida; Frittitta, L; Vannelli, G.B.; Brand, R.; Goldfine, I D; Vigneri, R

    1990-01-01

    The growth of breast cancer cells is under the regulation of hormones, growth factors, and their receptors. In the present study, we have employed a new, sensitive, and specific radioimmunoassay for the direct measurement of insulin receptors in surgical specimens of breast cancers. In 159 specimens the insulin receptor content was 6.15 +/- 3.69 ng/0.1 mg protein. This value was more than sixfold higher than the mean value found in both 27 normal breast tissues obtained at total mastectomy (0...

  5. 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.

  6. Neither bovine somatotropin nor growth hormone-releasing factor alters expression of thyroid hormone receptors in liver and mammary tissues.

    Science.gov (United States)

    Capuco, A V; Binelli, M; Tucker, H A

    2011-10-01

    Physiological effects of thyroid hormones are mediated primarily by binding of triiodothyronine to specific nuclear receptors. Organ-specific changes in production of triiodothyronine from its prohormone, thyroxine, have been hypothesized to target the action of thyroid hormones on the mammary gland and play a role in mediating or augmenting a galactopoietic response to bovine somatotropin (bST). Additionally, tissue responsiveness to thyroid hormones may be altered by changes in the number or affinity of nuclear receptors for thyroid hormones. In the present study, effects of bST and bovine growth hormone-releasing factor (bGRF) on thyroid hormone receptors in liver and mammary gland were studied. Lactating Holstein cows received continuous infusions of bST or bGRF for 63 d or served as uninfused controls. Nuclei were isolated from harvested mammary and liver tissues and incubated with [(125)I]-triiodothyronine. Treatments did not alter the capacity or affinity of specific binding sites for triiodothyronine in liver or mammary nuclei. Evaluation of transcript abundance for thyroid hormone receptors showed that isoforms of thyroid hormone receptor or retinoid receptor (which may influence thyroid receptor action) expressed in the mammary gland were not altered by bST or bGRF treatment. Data do not support the hypothesis that administration of bST or bGRF alters sensitivity of mammary tissue by changing expression of thyroid hormone receptors.

  7. Polypeptide hormone receptor phosphorylation: is there a role in receptor-mediated endocytosis of human growth hormone

    International Nuclear Information System (INIS)

    To determine whether receptor phosphorylation is a critical step in the internalization of polypeptide hormones and their receptors, the authors have studied a model system wherein insulin stimulates phosphorylation of its receptor and is also internalized. Using insulin as a positive control, they found that it stimulated a partially purified plasma membrane preparation of IM-9 lymphocytes to autophosphorylate its receptor and to catalyze the phosphorylation of a tyrosine-containing substrate. The human GH (hGH) receptor of the IM-9 lymphocytes, when coupled to [125I]iodo-hGH, migrated as a 140,000-dalton protein on polyacrylamide gel electrophoresis. This protein, in contrast to the insulin receptor, was not phosphorylated by the addition of hGH, nor did hGH stimulate this preparation to phosphorylate the tyrosine-containing substrate poly-(GluNa,Tyr)4:1, casein, or histone f2b under a variety of conditions. The authors conclude that receptor phosphorylation is not a critical intermediate in the receptor-mediated endocytosis of hGH and probably other polypeptide hormones and growth factors

  8. Absence of serum growth hormone binding protein in patients with growth hormone receptor deficiency (Laron dwarfism).

    OpenAIRE

    Daughaday, W H; Trivedi, B

    1987-01-01

    It has recently been recognized that human serum contains a protein that specifically binds human growth hormone (hGH). This protein has the same restricted specificity for hGH as the membrane-bound GH receptor. To determine whether the GH-binding protein is a derivative of, or otherwise related to, the GH receptor, we have examined the serum of three patients with Laron-type dwarfism, a condition in which GH refractoriness has been attributed to a defect in the GH receptor. The binding of 12...

  9. Molecular characterization of human thyroid hormone receptor β isoform 4.

    Science.gov (United States)

    Moriyama, Kenji; Yamamoto, Hiroyuki; Futawaka, Kumi; Atake, Asami; Kasahara, Masato; Tagami, Tetsuya

    2016-01-01

    Thyroid hormone exerts a pleiotropic effect on development, differentiation, and metabolism through thyroid hormone receptor (TR). A novel thyroid hormone receptor β isoform (TRβ4) was cloned using PCR from a human pituitary cDNA library as a template. We report here the characterization of TRβ4 from a molecular basis. Temporal expression of TRβ4 during the fetal period is abundant in the brain and kidney, comparable with the adult pattern. Western blot analysis revealed that TRs are ubiquitination labile proteins, while TRβ1 is potentially stable. TRβ1, peroxisome proliferator-activated receptors (PPAR), and vitamin D receptor (VDR), which belong to class II transcription factors that function via the formation of heterodimeric complexes with retinoid X receptor (RXR), were suppressed by TRβ4 in a dose-dependent manner. Thus, TRβ4 exhibits ligand-independent transcriptional silencing, possibly as a substitute for dimerized RXR. In this study, TRβ1 and TRβ4 transcripts were detected in several cell lines. Quantitative RT-PCR assay showed that the expression of TRβ4 in human embryonic carcinoma cells of the testis was suppressed by sex hormone in a reciprocal manner to TRβ1. In contrast, TRβ4 was expressed under a high dose of triiodothyronine (T3) in a reciprocal manner to TRβ1. Finally, in transiently transfected NIH-3T3 cells, green fluorescence protein (GFP)-tagged TRβ4 was mostly nuclear in both the absence and the presence of T3. By mutating defined regions of both TRβs, we found that both TRβ1 and TRβ4 had altered nuclear/cytoplasmic distribution as compared with wild-type, and different to T3 and the nuclear receptor corepressor (NCoR). Thus, site-specific DNA binding is not essential for maintaining TRβs within the nucleus. PMID:26513165

  10. Expression of functional growth hormone receptor in a mouse L cell line infected with recombinant vaccinia virus

    NARCIS (Netherlands)

    Strous, G J; van Kerkhof, P; Verheijen, C; Rossen, J W; Liou, W; Slot, J W; Roelen, C A; Schwartz, A L

    1994-01-01

    The growth hormone receptor is a member of a large family of receptors including the receptors for prolactin and interleukins. Upon binding to one molecule of growth hormone two growth hormone receptor polypeptides dimerize. We have expressed the rabbit growth hormone receptor DNA in transfected mou

  11. Analysis of Paired Primary-Metastatic Hormone-Receptor Positive Breast Tumors (HRPBC Uncovers Potential Novel Drivers of Hormonal Resistance.

    Directory of Open Access Journals (Sweden)

    Luis Manso

    Full Text Available We sought to identify genetic variants associated with disease relapse and failure to hormonal treatment in hormone-receptor positive breast cancer (HRPBC. We analyzed a series of HRPBC with distant relapse, by sequencing pairs (n = 11 of tumors (primary and metastases at >800X. Comparative genomic hybridization was performed as well. Top hits, based on the frequency of alteration and severity of the changes, were tested in the TCGA series. Genes determining the most parsimonious prognostic signature were studied for their functional role in vitro, by performing cell growth assays in hormonal-deprivation conditions, a setting that mimics treatment with aromatase inhibitors. Severe alterations were recurrently found in 18 genes in the pairs. However, only MYC, DNAH5, CSFR1, EPHA7, ARID1B, and KMT2C preserved an independent prognosis impact and/or showed a significantly different incidence of alterations between relapsed and non-relapsed cases in the TCGA series. The signature composed of MYC, KMT2C, and EPHA7 best discriminated the clinical course, (overall survival 90,7 vs. 144,5 months; p = 0.0001. Having an alteration in any of the genes of the signature implied a hazard ratio of death of 3.25 (p<0.0001, and early relapse during the adjuvant hormonal treatment. The presence of the D348N mutation in KMT2C and/or the T666I mutation in the kinase domain of EPHA7 conferred hormonal resistance in vitro. Novel inactivating mutations in KMT2C and EPHA7, which confer hormonal resistance, are linked to adverse clinical course in HRPBC.

  12. Starting Hormone Therapy at Menopause Increases Breast Cancer Risk

    Science.gov (United States)

    According to a January 28, 2011 article in the Journal of the National Cancer Institute, women who start taking menopausal hormone therapy around the time of menopause have a higher risk of breast cancer than women who begin taking hormones a few years later.

  13. Tyrosine kinase signalling in breast cancer: ErbB family receptor tyrosine kinases

    International Nuclear Information System (INIS)

    ERBB family receptor tyrosine kinases are overexpressed in a significant subset of breast cancers. One of these receptors, HER2/neu, or ErbB-2, is the target for a new rational therapeutic antibody, Herceptin. Other inhibitors that target this receptor, and another family member, the epidermal growth factor (EGF) receptor, are moving into clinical trials. Both of these receptors are sometimes overexpressed in breast cancer, and still subject to regulation by hormones and other physiological regulators. Optimal use of therapeutics targeting these receptors will require consideration of the several modes of regulation of these receptors and their interactions with steroid receptors

  14. Prediction of nuclear hormone receptor response elements.

    Science.gov (United States)

    Sandelin, Albin; Wasserman, Wyeth W

    2005-03-01

    The nuclear receptor (NR) class of transcription factors controls critical regulatory events in key developmental processes, homeostasis maintenance, and medically important diseases and conditions. Identification of the members of a regulon controlled by a NR could provide an accelerated understanding of development and disease. New bioinformatics methods for the analysis of regulatory sequences are required to address the complex properties associated with known regulatory elements targeted by the receptors because the standard methods for binding site prediction fail to reflect the diverse target site configurations. We have constructed a flexible Hidden Markov Model framework capable of predicting NHR binding sites. The model allows for variable spacing and orientation of half-sites. In a genome-scale analysis enabled by the model, we show that NRs in Fugu rubripes have a significant cross-regulatory potential. The model is implemented in a web interface, freely available for academic researchers, available at http://mordor.cgb.ki.se/NHR-scan. PMID:15563547

  15. Menopausal hormone therapy in cancer survivors: A narrative review of the literature.

    Science.gov (United States)

    Kuhle, Carol L; Kapoor, Ekta; Sood, Richa; Thielen, Jacqueline M; Jatoi, Aminah; Faubion, Stephanie S

    2016-10-01

    Decision making regarding the use of menopausal hormone therapy (MHT) for the treatment of bothersome menopausal symptoms in a cancer survivor can be complex, and includes assessment of its impact on disease-free or overall survival. Estrogen receptors are present in several cancer types, but this does not always result in estrogen-mediated tumor proliferation and adverse cancer-related outcomes. Estrogen may even be protective against certain cancers. Menopausal hormone therapy is associated with an increased risk of recurrence and mortality after diagnosis of some cancer types, but not others. We provide a narrative review of the medical literature regarding the risk of cancer recurrence and associated mortality with initiation of MHT after the diagnosis of breast, gynecologic, lung, colorectal, hematologic cancers, and melanoma. Menopausal hormone therapy may be considered for management of bothersome menopausal symptoms in women with some cancer types (e.g., colorectal and hematologic cancer, localized melanoma, and most cervical, vulvar and vaginal cancers), while nonhormonal treatment options may be preferred for others (e.g., breast cancer). In women with other cancer types, recommendations are less straightforward, and the use of MHT must be individualized. PMID:27621244

  16. A Comprehensive Nuclear Receptor Network for Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Ralf Kittler

    2013-02-01

    Full Text Available In breast cancer, nuclear receptors (NRs play a prominent role in governing gene expression, have prognostic utility, and are therapeutic targets. We built a regulatory map for 24 NRs, six chromatin state markers, and 14 breast-cancer-associated transcription factors (TFs that are expressed in the breast cancer cell line MCF-7. The resulting network reveals a highly interconnected regulatory matrix where extensive crosstalk occurs among NRs and other breast -cancer-associated TFs. We show that large numbers of factors are coordinately bound to highly occupied target regions throughout the genome, and these regions are associated with active chromatin state and hormone-responsive gene expression. This network also provides a framework for stratifying and predicting patient outcomes, and we use it to show that the peroxisome proliferator-activated receptor delta binds to a set of genes also regulated by the retinoic acid receptors and whose expression is associated with poor prognosis in breast cancer.

  17. Sex Hormones and Their Receptors Regulate Liver Energy Homeostasis

    Directory of Open Access Journals (Sweden)

    Minqian Shen

    2015-01-01

    Full Text Available The liver is one of the most essential organs involved in the regulation of energy homeostasis. Hepatic steatosis, a major manifestation of metabolic syndrome, is associated with imbalance between lipid formation and breakdown, glucose production and catabolism, and cholesterol synthesis and secretion. Epidemiological studies show sex difference in the prevalence in fatty liver disease and suggest that sex hormones may play vital roles in regulating hepatic steatosis. In this review, we summarize current literature and discuss the role of estrogens and androgens and the mechanisms through which estrogen receptors and androgen receptors regulate lipid and glucose metabolism in the liver. In females, estradiol regulates liver metabolism via estrogen receptors by decreasing lipogenesis, gluconeogenesis, and fatty acid uptake, while enhancing lipolysis, cholesterol secretion, and glucose catabolism. In males, testosterone works via androgen receptors to increase insulin receptor expression and glycogen synthesis, decrease glucose uptake and lipogenesis, and promote cholesterol storage in the liver. These recent integrated concepts suggest that sex hormone receptors could be potential promising targets for the prevention of hepatic steatosis.

  18. Mortality rates among early-stage hormone receptor-positive breast cancer patients: a population-based cohort study in Denmark

    DEFF Research Database (Denmark)

    Christiansen, Peer; Bjerre, Karsten; Ejlertsen, Bent Laursen;

    2011-01-01

    Indications for adjuvant endocrine treatment of breast cancer have gradually increased over the past several years. We aimed to define subgroups of patients who may or may not benefit from adjuvant endocrine therapy....

  19. Thyroid hormones and thyroid hormone receptors: Effects of thyromimetics on reverse cholesterol transport

    Institute of Scientific and Technical Information of China (English)

    Matteo; Pedrelli; Camilla; Pramfalk; Paolo; Parini

    2010-01-01

    Reverse cholesterol transport (RCT) is a complex process which transfers cholesterol from peripheral cells to the liver for subsequent elimination from the body via feces. Thyroid hormones (THs) affect growth, develop- ment, and metabolism in almost all tissues. THs exert their actions by binding to thyroid hormone receptors (TRs). There are two major subtypes of TRs, TRα and TRβ, and several isoforms (e.g. TRα1, TRα2, TRβ1, and TRβ2). Activation of TRα1 affects heart rate, whereas activation of TRβ1 has po...

  20. Homozygosity for a dominant negative thyroid hormone receptor gene responsible for generalized resistance to thyroid hormone.

    Science.gov (United States)

    Ono, S; Schwartz, I D; Mueller, O T; Root, A W; Usala, S J; Bercu, B B

    1991-11-01

    Generalized resistance to thyroid hormones (GRTH) commonly results from mutations in the T3-binding domain of the c-erbA beta thyroid hormone receptor gene. We have reported on a novel deletion mutation in c-erbA beta in a kindred, S, with GRTH. One patient from this kindred was the product of a consanguineous union from two affected members and was homozygous for the beta-receptor defect. This patient at 3.5 weeks of age had unprecedented elevations of TSH, free T4, and free T3 (TSH, 389 mU/L; free T4, 330.8 pmol/L; free T3, 82,719 fmol/L). He displayed a complex mixture of tissue-specific hyperthyroidism and hypothyroidism. He had delayed growth (height age, 1 3/12 yr at chronological age 2 9/12 yr) and skeletal maturation (bone age, 4 months), and developmental delay (developmental age, 8 months), but he was quite tachycardic. The homozygous patient of kindred S is markedly different from a recently reported patient with no c-erbA beta-receptor. This difference indicates that a dominant negative form of c-erbA beta in man can inhibit at least some thyroid hormone action mediated by the c-erbA alpha-receptors. PMID:1682340

  1. ICON 2013: practical consensus recommendations for hormone receptor-positive Her2-negative advanced or metastatic breastcancer.

    Science.gov (United States)

    Parikh, P M; Gupta, S; Dawood, S; Rugo, H; Bhattacharyya, G S; Agarwal, A; Chacko, R; Sahoo, T P; Babu, G; Agarwal, S; Munshi, A; Goswami, C; Smruti, B K; Bondarde, S; Desai, C; Rajappa, S; Somani, N; Singh, M; Nimmagadda, R; Pavitran, K; Mehta, A; Parmar, V; Desai, S; Nair, R; Doval, D

    2014-01-01

    The management of hormone receptor-positive Her2-negative breast cancer patients with advanced or metastatic disease is a common problem in India and other countries in this region. This expert group used data from published literature, practical experience, and opinion of a large group of academic oncologists, to arrive at practical consensus recommendations for use by the community oncologists.

  2. ICON 2013: Practical consensus recommendations for hormone receptor-positive Her2-negative advanced or metastatic breastcancer

    Directory of Open Access Journals (Sweden)

    P M Parikh

    2014-01-01

    Full Text Available The management of hormone receptor-positive Her2-negative breast cancer patients with advanced or metastatic disease is a common problem in India and other countries in this region. This expert group used data from published literature, practical experience, and opinion of a large group of academic oncologists, to arrive at practical consensus recommendations for use by the community oncologists.

  3. Hormonal regulation of AMPA receptor trafficking and memory formation

    Directory of Open Access Journals (Sweden)

    Harmen J Krugers

    2009-10-01

    Full Text Available Humans and rodents retain memories for stressful events very well. The facilitated retention of these memories is normally very useful. However, in susceptible individuals a variety of pathological conditions may develop in which memories related to stressful events remain inappropriately present, such as in post-traumatic stress disorder. The memory enhancing effects of stress are mediated by hormones, such as norepinephrine and glucocorticoids which are released during stressful experiences. Here we review recently identified molecular mechanisms that underlie the effects of stress hormones on synaptic efficacy and learning and memory. We discuss AMPA receptors as major target for stress hormones and describe a model in which norepinephrine and glucocorticoids are able to strengthen and prolong different phases of stressful memories.

  4. Thyroid hormone receptor can modulate retinoic acid-mediated axis formation in frog embryogenesis.

    OpenAIRE

    Banker, D E; Eisenman, R N

    1993-01-01

    Thyroid hormone receptor acts as a hormone-dependent transcriptional transactivator and as a transcriptional repressor in the absence of thyroid hormone. Specifically, thyroid hormone receptor can repress retinoic acid-induced gene expression through interactions with retinoic acid receptor. (Retinoic acid is a potent teratogen in the frog Xenopus laevis, acting at early embryonic stages to interfere with the formation of anterior structures. Endogenous retinoic acid is thought to act in norm...

  5. Role of chemotherapy in combination with hormonal therapy in first-line treatment of metastatic hormone-sensitive prostate cancer.

    Science.gov (United States)

    Ceresoli, G L; De Vincenzo, F; Sauta, M G; Bonomi, M; Zucali, P A

    2015-12-01

    Prostate cancer (PC) is a heterogeneous disease, whose growth is driven by androgens and androgen receptors. Androgen deprivation therapy (ADT) is the standard treatment of hormone-naïve metastatic disease. The majority of patients are treated with medical castration with GnRH agonists or antagonists, which usually determines a profound PSA decline and a radiological and clinical benefit. However, essentially all patients experience progression to castration-resistant prostate cancer (CRPC), and overall prognosis remains disappointing. Early targeting of cells that survive hormonal therapy may potentially prevent the development of CRPC. Several trials have explored the use of combination therapy with ADT and chemotherapy, targeting both the androgen dependent and independent cells simultaneously. Docetaxel was administered in combination with ADT to men with hormone-naïve metastatic prostate cancer, in the attempt to improve the duration and quality of patient survival. Three large randomized trials (the GETUG-15, CHAARTED and more recently the STAMPEDE study) have assessed these endpoints, with partially conflicting results. Overall, the results from these trials seem to support the use of early docetaxel combined with ADT in selected hormone-naïve metastatic PC patients. Full publication of the results of all studies, with longer follow-up, and the results of other ongoing trials in this setting will hopefully further define the role and the indications of this therapeutic strategy. PMID:26222275

  6. Regulation of growth hormone secretion by (pro)renin receptor

    OpenAIRE

    Tani, Yuji; Yamada, Shozo; Inoshita, Naoko; Hirata, Yukio; SHICHIRI, MASAYOSHI

    2015-01-01

    (Pro)renin receptor (PRR) has a single transmembrane domain that co-purifies with the vacuolar H+-ATPase (V-ATPase). In addition to its role in cellular acidification, V-ATPase has been implicated in membrane fusion and exocytosis via its Vo domain. Results from the present study show that PRR is expressed in pituitary adenoma cells and regulates growth hormone (GH) release via V-ATPase-induced cellular acidification. Positive PRR immunoreactivity was detected more often in surgically resecte...

  7. Steroid/thyroid hormone receptor genes in Caenorhabditis elegans.

    OpenAIRE

    Kostrouch, Z; Kostrouchova, M; Rall, J. E.

    1995-01-01

    The large family of steroid/thyroid hormone receptor (STR) genes has been extensively studied in vertebrates and insects but little information is available on it in more primitive organisms. All members possess a DNA binding domain of zinc fingers of the C2, C2 type. We have used the polymerase chain reaction with degenerate oligonucleotide primers covering this region to clone three distinct members of this family from the nematode Caenorhabditis elegans. All three belong to the retinoic ac...

  8. Hormone Replacement Therapy After Breast Cancer

    Directory of Open Access Journals (Sweden)

    Mueck AO

    2008-01-01

    Full Text Available So far, patient samples in all studies investigating hormone replacement therapy (HRT after breast cancer have been small.Therefore, HRT should only be used if alternatives such as specifically not contraindicated phytopreparations or selective sero-tonin reuptake inhibitors (SSRIs are not effective. This is primarily due to forensic reasons since clinical data on the risk ofalternatives (based on present evidence are even more sparse. Regarding HRT, four prospective randomized studies and at least15 observational studies after breast cancer are available. Only the HABITS study shows an increased risk of relapse. The authorssuggest that this is probably associated with the relatively high number of patients with HRT treatment after ER-positive cancersas well as due to the preferred use of estrogen/progestin-combined preparations. Based on the results of the randomized pla-cebo-controlled study Women’s Health Initiative (WHI as well as of at least 12 observational studies, the progestin componentseems to be mainly responsible for the probability of increased diagnosis frequency of primary breast cancer. However, no dataare available on the impact of progestin on the use of combined HRT after breast cancer. However, also with estrogen only anincreased risk of relapse must be expected and patients should be informed about it. This has to be concluded due to biologicalplausibility and observational studies although the estrogen-only arm in WHI did not show any increased primary risk. Thus, anyform of HRT should only be performed in exceptional cases, and treatment duration should be as short as possible with thelowest effective dose.

  9. Growth hormone action in rat insulinoma cells expressing truncated growth hormone receptors

    DEFF Research Database (Denmark)

    Møldrup, Annette; Allevato, G; Dyrberg, Thomas;

    1991-01-01

    Transfection of the insulin-producing rat islet tumor cell line RIN-5AH with a full length cDNA of the rat hepatic growth hormone (GH) receptor (GH-R1-638) augments the GH-responsive insulin synthesis in these cells. Using this functional system we analyzed the effect of COOH-terminal truncation...... a markedly reduced capability of GH internalization. In contrast to cells transfected with GH-R1-638, none of the cell lines expressing truncated GH receptors exhibited any increase of the GH-stimulated insulin production. We conclude that domains within the COOH-terminal half of the cytoplasmic part...... of the GH receptor are required for transduction of the signal for GH-stimulated insulin synthesis, whereas cytoplasmic domains proximal to the transmembrane region are involved in receptor-mediated GH internalization....

  10. Current status of primary pharmacotherapy and future perspectives toward upfront therapy for metastatic hormone-sensitive prostate cancer.

    Science.gov (United States)

    Shiota, Masaki; Eto, Masatoshi

    2016-05-01

    Since 1941, androgen deprivation therapy has been the primary treatment for metastatic hormone-sensitive prostate cancer. Androgen deprivation therapy consists of several regimens that vary according to therapeutic modality, as well as treatment schedule. Androgen deprivation therapy initially shows excellent antitumor effects, such as relief of cancer-related symptoms, tumor marker decline and tumor shrinking. However, most metastatic hormone-sensitive prostate cancer cases eventually develop castration resistance and become lethal. Taxanes, such as docetaxel and cabazitaxel, as well as novel androgen receptor-targeting agents, such as abiraterone acetate and enzalutamide, have emerged for metastatic castration-resistant prostate cancer. The concept and principle of primary therapy for metastatic hormone-sensitive prostate cancer has remained unchanged for decades. Recently, upfront docetaxel chemotherapy has been shown to prolong overall survival in men with metastatic hormone-sensitive prostate cancer, and would lead to a paradigm shift in primary pharmacotherapy for metastatic hormone-sensitive prostate cancer. This raises the possibility of upfront use of taxanes, as well as novel androgen receptor-targeting agents combined with androgen deprivation therapy. The present review summarizes the current status of primary pharmacotherapy for metastatic hormone-sensitive prostate cancer, and discusses future perspectives in this field. PMID:27062039

  11. Hormone receptor status of primary tumor as a prognostic factor in patients with liver metastases from breast cancer treated with transcatheter arterial chemoembolization

    Institute of Scientific and Technical Information of China (English)

    Kadri Altundag; Ozden Altundag; Serdal Aktolga; Ozlem Yavas; Cem Boruban

    2005-01-01

    @@ TO THE EDITOR We read with great interest the article by XP et al.[1] They reported the results of their experience with transcatheter arterial chemoembolization (TACE) and systemic chemotherapy for forty-five patients with liver metastases from breast cancer and evaluate the prognostic factors.In their study, the response and survival rates were significantly better in TACE group than in chemotherapy group.

  12. Pan-cancer analyses of the nuclear receptor superfamily

    Science.gov (United States)

    Long, Mark D.; Campbell, Moray J.

    2016-01-01

    Nuclear receptors (NR) act as an integrated conduit for environmental and hormonal signals to govern genomic responses, which relate to cell fate decisions. We review how their integrated actions with each other, shared co-factors and other transcription factors are disrupted in cancer. Steroid hormone nuclear receptors are oncogenic drivers in breast and prostate cancer and blockade of signaling is a major therapeutic goal. By contrast to blockade of receptors, in other cancers enhanced receptor function is attractive, as illustrated initially with targeting of retinoic acid receptors in leukemia. In the post-genomic era large consortia, such as The Cancer Genome Atlas, have developed a remarkable volume of genomic data with which to examine multiple aspects of nuclear receptor status in a pan-cancer manner. Therefore to extend the review of NR function we have also undertaken bioinformatics analyses of NR expression in over 3000 tumors, spread across six different tumor types (bladder, breast, colon, head and neck, liver and prostate). Specifically, to ask how the NR expression was distorted (altered expression, mutation and CNV) we have applied bootstrapping approaches to simulate data for comparison, and also compared these NR findings to 12 other transcription factor families. Nuclear receptors were uniquely and uniformly downregulated across all six tumor types, more than predicted by chance. These approaches also revealed that each tumor type had a specific NR expression profile but these were most similar between breast and prostate cancer. Some NRs were down-regulated in at least five tumor types (e.g. NR3C2/MR and NR5A2/LRH-1)) whereas others were uniquely down-regulated in one tumor (e.g. NR1B3/RARG). The downregulation was not driven by copy number variation or mutation and epigenetic mechanisms maybe responsible for the altered nuclear receptor expression. PMID:27200367

  13. Pan-Cancer Analyses of the Nuclear Receptor Superfamily

    Directory of Open Access Journals (Sweden)

    Mark D. Long

    2015-12-01

    Full Text Available Nuclear receptors (NR act as an integrated conduit for environmental and hormonal signals to govern genomic responses, which relate to cell fate decisions. We review how their integrated actions with each other, shared co-factors and other transcription factors are disrupted in cancer. Steroid hormone nuclear receptors are oncogenic drivers in breast and prostate cancer and blockade of signaling is a major therapeutic goal. By contrast to blockade of receptors, in other cancers enhanced receptor function is attractive, as illustrated initially with targeting of retinoic acid receptors in leukemia. In the post-genomic era large consortia, such as The Cancer Genome Atlas, have developed a remarkable volume of genomic data with which to examine multiple aspects of nuclear receptor status in a pan-cancer manner. Therefore to extend the review of NR function we have also undertaken bioinformatics analyses of NR expression in over 3000 tumors, spread across six different tumor types (bladder, breast, colon, head and neck, liver and prostate. Specifically, to ask how the NR expression was distorted (altered expression, mutation and CNV we have applied bootstrapping approaches to simulate data for comparison, and also compared these NR findings to 12 other transcription factor families. Nuclear receptors were uniquely and uniformly downregulated across all six tumor types, more than predicted by chance. These approaches also revealed that each tumor type had a specific NR expression profile but these were most similar between breast and prostate cancer. Some NRs were down-regulated in at least five tumor types (e.g., NR3C2/MR and NR5A2/LRH-1 whereas others were uniquely down-regulated in one tumor (e.g., NR1B3/RARG. The downregulation was not driven by copy number variation or mutation and epigenetic mechanisms maybe responsible for the altered nuclear receptor expression.

  14. The influence of hormone therapies on colon and rectal cancer.

    Science.gov (United States)

    Mørch, Lina Steinrud; Lidegaard, Øjvind; Keiding, Niels; Løkkegaard, Ellen; Kjær, Susanne Krüger

    2016-05-01

    Exogenous sex hormones seem to play a role in colorectal carcinogenesis. Little is known about the influence of different types or durations of postmenopausal hormone therapy (HT) on colorectal cancer risk. A nationwide cohort of women 50-79 years old without previous cancer (n = 1,006,219) were followed 1995-2009. Information on HT exposures was from the National Prescription Register and updated daily, while information on colon (n = 8377) and rectal cancers (n = 4742) were from the National Cancer Registry. Potential confounders were obtained from other national registers. Poisson regression analyses with 5-year age bands included hormone exposures as time-dependent covariates. Use of estrogen-only therapy and combined therapy were associated with decreased risks of colon cancer (adjusted incidence rate ratio 0.77, 95 % confidence interval 0.68-0.86 and 0.88, 0.80-0.96) and rectal cancer (0.83, 0.72-0.96 and 0.89, 0.80-1.00), compared to never users. Transdermal estrogen-only therapy implied more protection than oral administration, while no significant influence was found of regimen, progestin type, nor of tibolone. The benefit of HT was stronger for long-term hormone users; and hormone users were at lower risk of advanced stage of colorectal cancer, which seems supportive for a causal association between hormone therapy and colorectal cancer. PMID:26758900

  15. Advances in Variations of Estrogen Receptor, Progesterone Receptor and Human Epidermal Growth Factor Receptor-2 Status in Metastatic Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    Yuan Yuan; Zhang Lili

    2013-01-01

    Chemotherapy, endocrine therapy and molecular targeted therapy are vital means in the treatment of metastatic breast cancer (MBC), whose reasonable and standard applications are of great importance to prolong patients’ survival and improve the quality of life. The expressions of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) present signiifcant differences between primary and metastatic breast cancer. However, these differences may affect the selection of MBC patients for therapeutic strategies and judgment on the prognosis. Hence, the relevant researches on variations of hormone receptors and HER-2 in primary and metastatic breast cancer, discordant causes of ER, PR and HER-2 expression in primary and metastatic lesions and clinical value of biopsy to the metastases are reviewed in the study.

  16. Radioiodination of chicken luteinizing hormone without affecting receptor binding potency

    Energy Technology Data Exchange (ETDEWEB)

    Kikuchi, M.; Ishii, S. (Waseda Univ., Tokyo (Japan))

    1989-12-01

    By improving the currently used lactoperoxidase method, we were able to obtain radioiodinated chicken luteinizing hormone (LH) that shows high specific binding and low nonspecific binding to a crude plasma membrane fraction of testicular cells of the domestic fowl and the Japanese quail, and to the ovarian granulosa cells of the Japanese quail. The change we made from the original method consisted of (1) using chicken LH for radioiodination that was not only highly purified but also retained a high receptor binding potency; (2) controlling the level of incorporation of radioiodine into chicken LH molecules by employing a short reaction time and low temperature; and (3) fractionating radioiodinated chicken LH further by gel filtration using high-performance liquid chromatography. Specific radioactivity of the final {sup 125}I-labeled chicken LH preparation was 14 microCi/micrograms. When specific binding was 12-16%, nonspecific binding was as low as 2-4% in the gonadal receptors. {sup 125}I-Labeled chicken LH was displaced by chicken LH and ovine LH but not by chicken follicle-stimulating hormone. The equilibrium association constant of quail testicular receptor was 3.6 x 10(9) M-1. We concluded that chicken LH radioiodinated by the present method is useful for studies of avian LH receptors.

  17. Hormonal and molecular aspects of endometrioid endometrial cancer

    NARCIS (Netherlands)

    Jongen, Vincentius Hubertus Willibrordus Maria

    2008-01-01

    This thesis concerns the expression and prognostic value of various hormones and molecular markers playing a role n endometrioid endometrial cancer. Especially we were interested in the enzyme aromatase, its expression and (prognostic) role in endometrioid endometrial cancer. Endometrial cancer is t

  18. The influence of hormone therapies on colon and rectal cancer

    DEFF Research Database (Denmark)

    Mørch, Lina Steinrud; Lidegaard, Øjvind; Keiding, Niels;

    2016-01-01

    followed 1995-2009. Information on HT exposures was from the National Prescription Register and updated daily, while information on colon (n = 8377) and rectal cancers (n = 4742) were from the National Cancer Registry. Potential confounders were obtained from other national registers. Poisson regression...... analyses with 5-year age bands included hormone exposures as time-dependent covariates. Use of estrogen-only therapy and combined therapy were associated with decreased risks of colon cancer (adjusted incidence rate ratio 0.77, 95 % confidence interval 0.68-0.86 and 0.88, 0.80-0.96) and rectal cancer (0......Exogenous sex hormones seem to play a role in colorectal carcinogenesis. Little is known about the influence of different types or durations of postmenopausal hormone therapy (HT) on colorectal cancer risk. A nationwide cohort of women 50-79 years old without previous cancer (n = 1,006,219) were...

  19. Endometrial cancer, types, prognosis, female hormones and antihormones

    DEFF Research Database (Denmark)

    Ulrich, L S G

    2011-01-01

    . Prognosis is also dependent on tumor differentiation and stage, and treatment should be adjusted accordingly. In this paper, the different types of endometrial cancer, staging, prognosis, diagnosis, prevention, treatment and their relationship to estrogen and other female hormones are reviewed....

  20. Characterization of a thyroid hormone receptor expressed in human kidney and other tissues

    International Nuclear Information System (INIS)

    A cDNA encoding a specific form of thyroid hormone receptor expressed in human liver, kidney, placenta, and brain was isolated from a human kidney library. Identical clones were found in human placenta and HepG2 cDNA libraries. The cDNA encodes a 490-amino acid protein. When expressed and translated in vitro, the protein products binds triiodothyronine with K/sub a/ of 2.3 /times/ 109 M/sup /minus/1/. This protein, designated human thyroid hormone receptor type α2 (hTRα2), has the same domain structure as other members of the v-erbA-related superfamily of receptor genes. It is similar to thyroid hormone receptor type α described in chicken and rat and less similar to human thyroid hormone receptor type β (formerly referred to as c-erbAβ) from placenta. However, it is distinguished from these receptors by an extension of the C-terminal hormone binding domain making it 80 amino acids longer than rat thyroid hormone receptor type α1. Different sizes of mRNA found in liver and kidney suggest that there may be tissue-specific processing of the primary transcript of this gene. Identification of human thyroid hormone receptor type α2 indicates that two or more forms of thyroid hormone receptor exist in human tissues and may explain the normal variation in thyroid hormone responsiveness of various organs and the selective tissue abnormalities found in the thyroid hormone resistance syndromes

  1. 促甲状腺激素受体在甲状腺癌中的表达及其临床作用探讨%Discussion of the Expression of Thyroid Stimulating Hormone Receptor in Thyroid Cancer and Its Clinical Effect

    Institute of Scientific and Technical Information of China (English)

    郭红丽; 雷川云

    2015-01-01

    Objective To analyze and investigate the expression of thyroid stimulating hormone receptor in thyroid cancer patients. Methods A retrospective analysis was conducted on the clinical data of thyroid cancer patients admitted in the Oncology Depart-ment of our hospital from April 2011 to March 2015. And other 30 healthy people with normal thyroid function were selected as the control group. The thyroid tissues of the thyroid cancer patients and control group were stained by HE staining and measured by immunohistochemistry for detecting the expression of thyroid stimulating hormone receptor. Results The results showed that thy-roid stimulating hormone receptor in normal thyroid tissue and the thyroid tissue of thyroid cancer patients expressed, but the latter coloring was shallow, the expression site was located in the base side of the cell membrane. The positive expression rate of thyroid stimulating hormone receptor in the normal thyroid tissues was 100% (30/30), significantly higher than 84.84% (28/33) in thyroid tumor patients and 68.75%(22/32) in thyroid cancer patients. And the positive rate of thyroid stimulating hormone receptor in thy-roid tumor patients was significantly higher than that in thyroid cancer patients with statistically significant difference ( P<0.05). Conclusion The results suggested that the expression of thyroid stimulating hormone receptor in the normal thyroid tissue is high-er, but with the degree of differentiation of the thyroid tissue decreases, the expression decreases significantly, which provides an important reference for the TSH suppression therapy in differentiated thyroid cancer patients.%目的 分析和探讨甲状腺癌患者体内促甲状腺激素受体表达情况. 方法 对整群选取的2011年4月-2015年3月该院肿瘤科收治的65例甲状腺癌患者临床资料进行回顾性分析,选取30例甲状腺功能正常的健康人作为对照组,对采集的甲状腺组织进行HE染色观

  2. RXR alpha, a promiscuous partner of retinoic acid and thyroid hormone receptors.

    OpenAIRE

    Bugge, T H; Pohl, J.; Lonnoy, O; Stunnenberg, H G

    1992-01-01

    Retinoic acid receptor (RAR), thyroid hormone receptor (T3R) and vitamin D3 receptor (VD3R) differ from steroid hormone receptors in that they bind and transactivate through responsive elements organized as direct rather than inverted repeats. We now show that recombinant RAR and T3R are monomers in solution and cannot form stable homodimeric complexes on their responsive elements. Stable binding of the receptors to their responsive elements requires heterodimerization with a nuclear factor. ...

  3. Synthesis and Evaluation of Novel Gonadotropin-Releasing Hormone Receptor-Targeting Peptides

    OpenAIRE

    Guo, Haixun; Lu, Jie; Hathaway, Helen; Royce, Melanie E.; Prossnitz, Eric R.; Miao, Yubin

    2011-01-01

    The purpose of this study was to develop novel radiolabeled gonadotropin-releasing hormone (GnRH) receptor-targeting peptides for breast cancer imaging. Three novel 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated GnRH peptides were designed and synthesized. The radiometal chelator DOTA was conjugated to the epsilon or alpha amino group of D-lysine, or the epsilon amino group of L-lysine via an Ahx {aminohexanoic acid} linker to generate DOTA-Ahx-(D-Lys6-GnRH1), DOTA...

  4. Detection of two growth hormone receptor mRNAs and primary translation products in the mouse

    OpenAIRE

    Smith, W.C.; Linzer, D I; Talamantes, F

    1989-01-01

    Two mouse growth hormone-receptor primary translation products of Mr 95,900 and 31,800 were identified from in vitro-translated late pregnant mouse liver mRNA. RNA isolated from mouse liver was translated in a rabbit reticulocyte lysate system containing [35S]methionine, and the growth hormone receptor primary translation products were identified by immunoprecipitation with anti-mouse growth hormone receptor antiserum followed by sodium dodecyl sulfate/PAGE and fluorography. Detectable amount...

  5. The liver taxis of receptor mediated lactosaminated human growth hormone

    International Nuclear Information System (INIS)

    Radiography imaging is used to assess liver taxis mechanism of anti-dwarfism drug lactosaminated human growth hormone (L-rhGH). Both L-rhGH and rhGH labelled with 131I are used to study their biodistribution in animals (including rabbits, cocks and rats). The results show that L-rhGH is of specific hepatic targeting property, and the maximum hepatic concentration rate is 76.8%, which is two times of rhGH. Its hepatic binding is receptor mediated

  6. Introduction of exogenous growth hormone receptors augments growth hormone-responsive insulin biosynthesis in rat insulinoma cells.

    OpenAIRE

    Billestrup, N; Møldrup, A; Serup, P.; Mathews, L S; Norstedt, G; Nielsen, J H

    1990-01-01

    The stimulation of insulin biosynthesis in the pancreatic insulinoma cell line RIN5-AH by growth hormone (GH) is initiated by GH binding to specific receptors. To determine whether the recently cloned rat hepatic GH receptor is able to mediate the insulinotropic effect of GH, we have transfected a GH receptor cDNA under the transcriptional control of the human metallothionein promoter into RIN5-AH cells. The transfected cells were found to exhibit an increased expression of GH receptors and t...

  7. Luteinizing hormone-releasing hormone receptor-mediated delivery of mitoxantrone using LHRH analogs modified with PEGylated liposomes

    OpenAIRE

    Sun, Hongfan

    2010-01-01

    Yingna He, Linhua Zhang, Cunxian SongKey Laboratory of Biomedical Material of Tianjin, Institute of Biomedical Engineering, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin, ChinaAbstract: A sterically stabilized, mitoxantrone-loaded liposome, tailored to target luteinizing hormone-releasing hormone (LHRH) receptor overexpressing cells, was developed to promote the efficiency of intracellular delivery of mitoxantrone through receptor-mediated endocytosis. Liposome...

  8. Cell Cycle-dependent Expression of Thyroid Hormone Receptor-β Is a Mechanism for Variable Hormone SensitivityD⃞

    OpenAIRE

    Maruvada, Padma; Dmitrieva, Natalia I.; East-Palmer, Joyce; Yen, Paul M.

    2004-01-01

    Thyroid hormone receptors (TRs) are ligand-regulatable transcription factors. Currently, little is known about the expression of TRs or other nuclear hormone receptors during the cell cycle. We thus developed a stable expression system to express green fluorescent protein-TRβ in HeLa cells under tetracycline regulation, and studied TR expression during the cell cycle by laser scanning cytometry. Only ∼9-15% of the nonsynchronized cell population expressed TR because the majority of cells were...

  9. Avoidable cancers in the Nordic countries. Exogenous hormones

    DEFF Research Database (Denmark)

    Winther, J F; Dreyer, L; Tryggvadottir, L

    1997-01-01

    The well-described influence of several aspects of reproductive life on the risk for cancer in the reproductive organs has raised concern regarding the safety of exogenous hormones, particularly since sex hormones have become one of the most widely used drugs among women in the western world....... The major areas of application include oral contraception and hormone replacement therapy in women with menopausal symptoms. Since the introduction of oral contraceptives onto the Nordic market in the late 1960s, the number of users has grown steadily, to reach proportions of long-term users among women...... years) of hormone replacement therapy among Nordic women aged 40-69 in 1995 was estimated to be 10-11%, which on the basis of an associated relative risk for breast cancer ranging from 1.2-1.5 suggests than an annual total of 260 cases of breast cancer could be avoided in the Nordic countries around...

  10. Aromatase Inhibitor-Induced Erythrocytosis in a Patient Undergoing Hormonal Treatment for Breast Cancer

    Directory of Open Access Journals (Sweden)

    Sri Lakshmi Hyndavi Yeruva

    2015-01-01

    Full Text Available Aromatase inhibitors (AIs are most commonly used for breast cancer patients with hormone receptor positive disease. Although the side effect profile of aromatase inhibitors is well known, including common side effects like arthralgia, bone pain, arthritis, hot flashes, and more serious problems like osteoporosis, we present a case of an uncommon side effect of these medications. We report the case of a postmenopausal woman on adjuvant hormonal therapy with anastrozole after completing definitive therapy for stage IIIB estrogen receptor-positive breast cancer, who was referred to hematology service for evaluation of persistent erythrocytosis. Primary and known secondary causes of polycythemia were ruled out. On further evaluation, we found that her erythrocytosis began after initiation of anastrozole and resolved after it was discontinued. We discuss the pathophysiology of aromatase inhibitor-induced erythrocytosis and reference of similar cases reported in the literature.

  11. Antiproliferative effect of growth hormone-releasing hormone (GHRH antagonist on ovarian cancer cells through the EGFR-Akt pathway

    Directory of Open Access Journals (Sweden)

    Varga Jozsef

    2010-05-01

    Full Text Available Abstract Background Antagonists of growth hormone-releasing hormone (GHRH are being developed for the treatment of various human cancers. Methods MTT assay was used to test the proliferation of SKOV3 and CaOV3. The splice variant expression of GHRH receptors was examined by RT-PCR. The expression of protein in signal pathway was examined by Western blotting. siRNA was used to block the effect of EGFR. Results In this study, we investigated the effects of a new GHRH antagonist JMR-132, in ovarian cancer cell lines SKOV3 and CaOV3 expressing splice variant (SV1 of GHRH receptors. MTT assay showed that JMR-132 had strong antiproliferative effects on SKOV3 and CaOV3 cells in both a time-dependent and dose-dependent fashion. JMR-132 also induced the activation and increased cleaved caspase3 in a time- and dose-dependent manner in both cell lines. In addition, JMR-132 treatments decreased significantly the epidermal growth factor receptor (EGFR level and the phosphorylation of Akt (p-Akt, suggesting that JMR-132 inhibits the EGFR-Akt pathway in ovarian cancer cells. More importantly, treatment of SKOV3 and CaOV3 cells with 100 nM JMR-132 attenuated proliferation and the antiapoptotic effect induced by EGF in both cell lines. After the knockdown of the expression of EGFR by siRNA, the antiproliferative effect of JMR-132 was abolished in SKOV3 and CaOV3 cells. Conclusions The present study demonstrates that the inhibitory effect of the GHRH antagonist JMR-132 on proliferation is due, in part, to an interference with the EGFR-Akt pathway in ovarian cancer cells.

  12. Inhibitory effects of antagonists of growth hormone-releasing hormone on growth and invasiveness of PC3 human prostate cancer.

    Science.gov (United States)

    Muñoz-Moreno, Laura; Arenas, M Isabel; Schally, Andrew V; Fernández-Martínez, Ana B; Zarka, Elías; González-Santander, Marta; Carmena, María J; Vacas, Eva; Prieto, Juan C; Bajo, Ana M

    2013-02-15

    New approaches are needed to the therapy of advanced prostate cancer. This study determined the effect of growth hormone-releasing hormone (GHRH) antagonists, JMR-132 and JV-1-38 on growth of PC3 tumors as well as on angiogenesis and metastasis through the evaluation of various factors that contribute largely to the progression of prostate cancer. Human PC3 androgen-independent prostate cancer cells were injected subcutaneously into nude mice. The treatment with JMR-132 (10 μg/day) or JV-1-38 (20 μg/day) lasted 41 days. We also evaluated the effects of JMR-132 and JV-1-38 on proliferation, cell adhesion and migration in PC-3 cells in vitro. Several techniques (Western blot, reverse transcription polymerase chain reaction, immunohistochemistry, ELISA and zymography) were used to evaluate the expression levels of GHRH receptors and its splice variants, GHRH, vascular endothelial growth factor (VEGF), hypoxia inducible factor (HIF)-1α, metalloproteinases (MMPs) -2 and -9, β-catenin and E-cadherin. GHRH antagonists suppressed the proliferation of PC-3 cells in vitro and significantly inhibited growth of PC3 tumors. After treatment with these analogues, we found an increase in expression of GHRH receptor accompanied by a decrease of GHRH levels, a reduction in both VEGF and HIF-1α expression and in active forms of MMP-2 and MMP-9, a significant increase in levels of membrane-associated β-catenin and a significant decline in E-cadherin. These results support that the blockade of GHRH receptors can modulate elements involved in angiogenesis and metastasis. Consequently, GHRH antagonists could be considered as suitable candidates for therapeutic trials in the management of androgen-independent prostate cancer.

  13. Binding of 125I-human growth hormone to specific receptors in human cultured lymphocytes

    International Nuclear Information System (INIS)

    The interaction of human growth hormone with human lymphocytes from an established culture (IM-9) was studied using 125I- human growth hormone. The binding of 125I-human growth hormone was rapid; with human growth hormone at 0.1 nM a steady state was observed in 90 min at 300. Bound labeled human growth hormone was dissociated rapidly by addition of excess unlabeled human growth hormone. Binding of 125I-human growth hormone to cultured lymphocytes was relatively insensitive to alterations in the pH and in the concentrations of Ca2+, Mg2+, EDTA. At 800 there was very little degradation of labeled human growth hormone or of the specific receptor sites. Tryptic digestion destroyed the capacity of cells to bind human growth hormone. The IM-9 cells bound all human growth hormone preparations but not unrelated hormones or nonprimate growth hormones. The binding of 125I-human growth hormone was inhibited 10 to 14 percent with 1 to 2 ng per ml of unlabeled human growth hormone and 50 percent with 30 to 40 ng per ml, well within the range of hormone concentrations in vivo. Analysis of steady state data revealed a single order of binding sites with an affinity constant of 1.3 x 109 M-1 and about 4000 binding sites per cell. Numerous human growth hormone preparations were assayed by use of this receptor system as well as by immunoassay and by bioassay in vivo. The po

  14. The thyroid hormone receptors modulate the skin response to retinoids.

    Directory of Open Access Journals (Sweden)

    Laura García-Serrano

    Full Text Available BACKGROUND: Retinoids play an important role in skin homeostasis and when administered topically cause skin hyperplasia, abnormal epidermal differentiation and inflammation. Thyroidal status in humans also influences skin morphology and function and we have recently shown that the thyroid hormone receptors (TRs are required for a normal proliferative response to 12-O-tetradecanolyphorbol-13-acetate (TPA in mice. METHODOLOGY/PRINCIPAL FINDINGS: We have compared the epidermal response of mice lacking the thyroid hormone receptor binding isoforms TRα1 and TRβ to retinoids and TPA. Reduced hyperplasia and a decreased number of proliferating cells in the basal layer in response to 9-cis-RA and TPA were found in the epidermis of TR-deficient mice. Nuclear levels of proteins important for cell proliferation were altered, and expression of keratins 5 and 6 was also reduced, concomitantly with the decreased number of epidermal cell layers. In control mice the retinoid (but not TPA induced parakeratosis and diminished expression of keratin 10 and loricrin, markers of early and terminal epidermal differentiation, respectively. This reduction was more accentuated in the TR deficient animals, whereas they did not present parakeratosis. Therefore, TRs modulate both the proliferative response to retinoids and their inhibitory effects on skin differentiation. Reduced proliferation, which was reversed upon thyroxine treatment, was also found in hypothyroid mice, demonstrating that thyroid hormone binding to TRs is required for the normal response to retinoids. In addition, the mRNA levels of the pro-inflammatory cytokines TNFα and IL-6 and the chemotactic proteins S1008A and S1008B were significantly elevated in the skin of TR knock-out mice after TPA or 9-cis-RA treatment and immune cell infiltration was also enhanced. CONCLUSIONS/SIGNIFICANCE: Since retinoids are commonly used for the treatment of skin disorders, these results demonstrating that TRs

  15. The Neuroendocrine Functions of the Parathyroid Hormone 2 Receptor

    Directory of Open Access Journals (Sweden)

    Arpad eDobolyi

    2012-10-01

    Full Text Available The G-protein coupled parathyroid hormone 2 receptor (PTH2R is concentrated in endocrine and limbic regions in the forebrain. Its endogenous ligand,tuberoinfundibular peptide of 39 residues (TIP39, is synthesized in only 2 brain regions, within the posterior thalamus and the lateral pons. TIP39-expressing neurons have a widespread projection pattern, which matches the PTH2R distribution in the brain. Neuroendocrine centers including the preoptic area, the periventricular, paraventricular, and arcuate nuclei contain the highest density of PTH2R-positive networks. The administration of TIP39 and an antagonist of the PTH2R as well as the investigation of mice that lack functional TIP39 and PTH2R revealed the involvement of the PTH2R in a variety of neural and neuroendocrine functions. TIP39 acting via the PTH2R modulates several aspects of the stress response. It evokes corticosterone release by activating corticotropin-releasing hormone-containing neurons in the hypothalamic paraventricular nucleus. Block of TIP39 signaling elevates the anxiety state of animals and their fear response, and increases stress-induced analgesia. TIP39 has also been suggested to affect the release of additional pituitary hormones including arginine vasopressin and growth hormone. A role of the TIP39-PTH2R system in thermoregulation was also identified. TIP39 may play a role in maintaining body temperature in a cold environment via descending excitatory pathways from the preoptic area. Anatomical and functional studies also implicated the TIP39-PTH2R system in nociceptive information processing. Finally, TIP39 induced in postpartum dams may play a role in the release of prolactin during lactation. Potential mechanisms leading to the activation of TIP39 neurons and how they influence the neuroendocrine system are also described. The unique TIP39-PTH2R neuromodulator system provides the possibility for developing drugs with a novel mechanism of action to control

  16. Effects of sex and pregnancy hormones on growth hormone and prolactin receptor gene expression in insulin-producing cells

    DEFF Research Database (Denmark)

    Møldrup, Annette; Petersen, Elisabeth D.; Nielsen, Jens Høiriis

    1993-01-01

    During pregnancy, marked hyperplasia of the pancreatic islet cells has been observed. This effect may be mediated by the pregnancy-associated peptide hormones, placental lactogen, PRL, and GH, which were previously shown to be mitogenic to beta-cells in vitro. To study whether the responsiveness...... of islet cells to these hormones is regulated on the receptor level, GH and PRL receptor gene expression was studied in pancreata from male rats and virgin, pregnant, and lactating female rats and in cultured islets and insulinoma cells (RIN-5AH) in response to various hormones. The mRNA levels were...... of exposure. The effective doses were within the physiological ranges. In conclusion, these results show a differential hormonal regulation of GH and PRL receptor gene expression in the pancreatic islets, which may play a role in the adaptive beta-cell growth during pregnancy....

  17. Abiraterone acetate for prostate cancer: a new era of hormonal therapies

    Institute of Scientific and Technical Information of China (English)

    Emmanuel S Antonarakis

    2011-01-01

    @@ Therapies targeting the androgen receptor (AR) axis have constituted the Holy Grail in the management of advanced prostate cancer for seven decades.1 These hormonal therapies have traditionally taken two main forms: those that suppress gonadal androgen synthesis (e.g.,the gonadotropin releasing hormone agonists/antagonists,such as leuprolide),and those that inhibit the AR directly (e.g.,the anti-androgens,such asbicalutamide).However,although the vast majority of patients with prostate cancer initially respond favorably to androgen-ablative therapies (manifested by tumor regressions and symptomatic improvements),all patients will eventually develop further disease progression after a median of 18-24 months.This transformed disease state,known as castration-resistant prostate cancer (CRPC),is invariably fatal.

  18. Birth weight, breast cancer and the potential mediating hormonal environment.

    LENUS (Irish Health Repository)

    Bukowski, Radek

    2012-01-01

    Previous studies have shown that woman\\'s risk of breast cancer in later life is associated with her infants birth weights. The objective of this study was to determine if this association is independent of breast cancer risk factors, mother\\'s own birth weight and to evaluate association between infants birth weight and hormonal environment during pregnancy. Independent association would have implications for understanding the mechanism, but also for prediction and prevention of breast cancer.

  19. Anti-idiotypic antibody: A new strategy for the development of a growth hormone receptor antagonist.

    Science.gov (United States)

    Lan, Hainan; Zheng, Xin; Khan, Muhammad Akram; Li, Steven

    2015-11-01

    In general, traditional growth hormone receptor antagonist can be divided into two major classes: growth hormone (GH) analogues and anti-growth hormone receptor (GHR) antibodies. Herein, we tried to explore a new class of growth hormone receptor (GHR) antagonist that may have potential advantages over the traditional antagonists. For this, we developed a monoclonal anti-idiotypic antibody growth hormone, termed CG-86. A series of experiments were conducted to characterize and evaluate this antibody, and the results from a competitive receptor-binding assay, Enzyme Linked Immunosorbent Assays (ELISA) and epitope mapping demonstrate that CG-86 behaved as a typical Ab2β. Next, we examined its antagonistic activity using in vitro cell models, and the results showed that CG-86 could effectively inhibit growth hormone receptor-mediated signalling and effectively inhibit growth hormone-induced Ba/F3-GHR638 proliferation. In summary, these studies show that an anti-idiotypic antibody (CG-86) has promise as a novel growth hormone receptor antagonist. Furthermore, the current findings also suggest that anti-idiotypic antibody may represent a novel strategy to produce a new class of growth hormone receptor antagonist, and this strategy may be applied with other cytokines or growth factors.

  20. The Role of the Enterohepatic Circulation of Bile Salts and Nuclear Hormone Receptors in the Regulation of Cholesterol Homeostasis: Bile Salts as Ligands for Nuclear Hormone Receptors

    OpenAIRE

    Redinger, Richard N.

    2003-01-01

    The coordinated effect of lipid activated nuclear hormone receptors; liver X receptor (LXR), bound by oxysterol ligands and farnesoid X receptor (FXR), bound by bile acid ligands, act as genetic transcription factors to cause feed-forward cholesterol catabolism to bile acids and feedback repression of bile acid synthesis, respectively. It is the coordinated action of LXR and FXR, each dimerized to retinoid X receptor, that signal nuclear DNA response elements to encode proteins that prevent e...

  1. Evidence for association of the cloned liver growth hormone receptor with a tyrosine kinase

    DEFF Research Database (Denmark)

    Wang, X; Uhler, M D; Billestrup, N;

    1992-01-01

    The ability of the cloned liver growth hormone (GH) receptor, when expressed in mammalian cell lines, to copurify with tyrosine kinase activity and be tyrosyl phosphorylated was examined. 125I-human growth hormone-GH receptor complexes isolated from COS-7 cells transiently expressing high levels ...

  2. Management of Hormone-Sensitive and Hormone-Refractory Metastatic Prostate Cancer.

    Science.gov (United States)

    Rago

    1998-11-01

    BACKGROUND: Prostate cancer is a significant health problem in the United States and is the focus of increasing attention in our society. With the aging of the US population, it is likely that prostate cancer will continue to grow in importance. The options for systemic therapy of metastatic prostate cancer should be familiar to physicians, including nonspecialists, whose patients seek their advice and counsel. METHODS: Past and recent literature was surveyed to provide an understanding of the systemic treatment of advanced prostate cancer. The author presents a review of the systemic treatment of metastatic prostate cancer in different clinical circumstances and addresses the current status of chemotherapy in the management of advanced prostate cancer. RESULTS: Early androgen deprivation used over prolonged periods appears to be modestly superior to delayed androgen deprivation with a small potential survival advantage and an advantage in delaying disease progression in advanced prostate cancer. Patients with hormone-refractory prostate cancer may benefit from secondary hormonal therapy (eg, adrenal enzyme inhibitors, antiandrogens, glucocorticoids) and chemotherapy. CONCLUSIONS: The choices of therapy for metastatic prostate cancer depend on individual patient preference. Patients and physicians should be aware of the possible side effects associated with the therapeutics options for treatment of metastatic prostate cancer. PMID:10761100

  3. Advances in breast cancer treatment and prevention: preclinical studies on aromatase inhibitors and new selective estrogen receptor modulators (SERMs)

    OpenAIRE

    Schiff, Rachel; Chamness, Gary C.; Brown, Powel H.

    2003-01-01

    Intensive basic and clinical research over the past 20 years has yielded crucial molecular understanding into how estrogen and the estrogen receptor act to regulate breast cancer and has led to the development of more effective, less toxic, and safer hormonal therapy agents for breast cancer management and prevention. Selective potent aromatase inhibitors are now challenging the hitherto gold standard of hormonal therapy, the selective estrogen-receptor modulator tamoxifen. Furthermore, new s...

  4. Increased survival in men with metastatic prostate cancer receiving chemo and hormone therapy

    Science.gov (United States)

    Men with hormone-sensitive metastatic prostate cancer who received the chemotherapy drug docetaxel given at the start of standard hormone therapy lived longer than patients who received hormone therapy alone, according to early results from a NIH-supporte

  5. Analysis of estrogen receptor transcriptional enhancement by a nuclear hormone receptor coactivator.

    OpenAIRE

    McInerney, E M; Tsai, M J; O'Malley, B W; Katzenellenbogen, B S

    1996-01-01

    The estrogen receptor (ER), a member of a large superfamily of nuclear hormone receptors, is a ligand-inducible transcription factor that regulates the expression of estrogen-responsive genes. The ER, in common with other members of this superfamily, contains two transcription activation functions (AFs)--one located in the amino-terminal region (AF-1) and the second located in the carboxyl-terminal region (AF-2). In most cell contexts, the synergistic activity of AF-1 and AF-2 is required for...

  6. Inverse Relationship between Progesterone Receptor and Myc in Endometrial Cancer.

    Directory of Open Access Journals (Sweden)

    Tamar Kavlashvili

    Full Text Available Endometrial cancer, the most common gynecologic malignancy, is a hormonally-regulated disease. Response to progestin therapy positively correlates with hormone receptor expression, in particular progesterone receptor (PR. However, many advanced tumors lose PR expression. We recently reported that the efficacy of progestin therapy can be significantly enhanced by combining progestin with epigenetic modulators, which we term "molecularly enhanced progestin therapy." What remained unclear was the mechanism of action and if estrogen receptor α (ERα, the principle inducer of PR, is necessary to restore functional expression of PR via molecularly enhanced progestin therapy. Therefore, we modeled advanced endometrial tumors that have lost both ERα and PR expression by generating ERα-null endometrial cancer cell lines. CRISPR-Cas9 technology was used to delete ERα at the genomic level. Our data demonstrate that treatment with a histone deacetylase inhibitor (HDACi was sufficient to restore functional PR expression, even in cells devoid of ERα. Our studies also revealed that HDACi treatment results in marked downregulation of the oncogene Myc. We established that PR is a negative transcriptional regulator of Myc in endometrial cancer in the presence or absence of ERα, which is in contrast to studies in breast cancer cells. First, estrogen stimulation augmented PR expression and decreased Myc in endometrial cancer cell lines. Second, progesterone increased PR activity yet blunted Myc mRNA and protein expression. Finally, overexpression of PR by adenoviral transduction in ERα-null endometrial cancer cells significantly decreased expression of Myc and Myc-regulated genes. Analysis of the Cancer Genome Atlas (TCGA database of endometrial tumors identified an inverse correlation between PR and Myc mRNA levels, with a corresponding inverse correlation between PR and Myc downstream transcriptional targets SRD5A1, CDK2 and CCNB1. Together, these data

  7. Gene specific actions of thyroid hormone receptor subtypes.

    Directory of Open Access Journals (Sweden)

    Jean Z Lin

    Full Text Available There are two homologous thyroid hormone (TH receptors (TRs α and β, which are members of the nuclear hormone receptor (NR family. While TRs regulate different processes in vivo and other highly related NRs regulate distinct gene sets, initial studies of TR action revealed near complete overlaps in their actions at the level of individual genes. Here, we assessed the extent that TRα and TRβ differ in target gene regulation by comparing effects of equal levels of stably expressed exogenous TRs +/- T(3 in two cell backgrounds (HepG2 and HeLa. We find that hundreds of genes respond to T(3 or to unliganded TRs in both cell types, but were not able to detect verifiable examples of completely TR subtype-specific gene regulation. TR actions are, however, far from identical and we detect TR subtype-specific effects on global T(3 response kinetics in HepG2 cells and many examples of TR subtype specificity at the level of individual genes, including effects on magnitude of response to TR +/- T(3, TR regulation patterns and T(3 dose response. Cycloheximide (CHX treatment confirms that at least some differential effects involve verifiable direct TR target genes. TR subtype/gene-specific effects emerge in the context of widespread variation in target gene response and we suggest that gene-selective effects on mechanism of TR action highlight differences in TR subtype function that emerge in the environment of specific genes. We propose that differential TR actions could influence physiologic and pharmacologic responses to THs and selective TR modulators (STRMs.

  8. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population

    NARCIS (Netherlands)

    Antoniou, Antonis C.; Wang, Xianshu; Fredericksen, Zachary S.; McGuffog, Lesley; Tarrell, Robert; Sinilnikova, Olga M.; Healey, Sue; Morrison, Jonathan; Kartsonaki, Christiana; Lesnick, Timothy; Ghoussaini, Maya; Barrowdale, Daniel; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Eccles, Diana; Evans, D. Gareth; Eeles, Ros; Izatt, Louise; Chu, Carol; Douglas, Fiona; Paterson, Joan; Stoppa-Lyonnet, Dominique; Houdayer, Claude; Mazoyer, Sylvie; Giraud, Sophie; Lasset, Christine; Remenieras, Audrey; Caron, Olivier; Hardouin, Agnes; Berthet, Pascaline; Hogervorst, Frans B. L.; Rookus, Matti A.; Jager, Agnes; van den Ouweland, Ans; Hoogerbrugge, Nicoline; van der Luijt, Rob B.; Meijers-Heijboer, Hanne; Garcia, Encarna B. Gomez; Devilee, Peter; Vreeswijk, Maaike P. G.; Lubinski, Jan; Jakubowska, Anna; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Gorski, Bohdan; Cybulski, Cezary; Spurdle, Amanda B.; Holland, Helene; Goldgar, David E.; John, Esther M.; Hopper, John L.; Southey, Melissa; Buys, Saundra S.; Daly, Mary B.; Terry, Mary-Beth; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Preisler-Adams, Sabine; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy; Blum, Joanne L.; Piedmonte, Marion; Rodriguez, Gustavo C.; Wakeley, Katie; Boggess, John F.; Basil, Jack; Blank, Stephanie V.; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Kirchhoff, Tomas; Vijai, Joseph; Gaudet, Mia M.; Altshuler, David; Guiducci, Candace; Loman, Niklas; Harbst, Katja; Rantala, Johanna; Ehrencrona, Hans; Gerdes, Anne-Marie; Thomassen, Mads; Sunde, Lone; Peterlongo, Paolo; Manoukian, Siranoush; Bonanni, Bernardo; Viel, Alessandra; Radice, Paolo; Caldes, Trinidad; de la Hoya, Miguel; Singer, Christian F.; Fink-Retter, Anneliese; Greene, Mark H.; Mai, Phuong L.; Loud, Jennifer T.; Guidugli, Lucia; Lindor, Noralane M.; Hansen, Thomas V. O.; Nielsen, Finn C.; Blanco, Ignacio; Lazaro, Conxi; Garber, Judy; Ramus, Susan J.; Gayther, Simon A.; Phelan, Catherine; Narod, Stephen; Szabo, Csilla I.; Benitez, Javier; Osorio, Ana; Nevanlinna, Heli; Heikkinen, Tuomas; Caligo, Maria A.; Beattie, Mary S.; Hamann, Ute; Godwin, Andrew K.; Montagna, Marco; Casella, Cinzia; Neuhausen, Susan L.; Karlan, Beth Y.; Tung, Nadine; Toland, Amanda E.; Weitzel, Jeffrey; Olopade, Olofunmilayo; Simard, Jacques; Soucy, Penny; Rubinstein, Wendy S.; Arason, Adalgeir; Rennert, Gad; Martin, Nicholas G.; Montgomery, Grant W.; Chang-Claude, Jenny; Flesch-Janys, Dieter; Brauch, Hiltrud; Severi, Gianluca; Baglietto, Laura; Cox, Angela; Cross, Simon S.; Miron, Penelope; Gerty, Sue M.; Tapper, William; Yannoukakos, Drakoulis; Fountzilas, George; Fasching, Peter A.; Beckmann, Matthias W.; Silva, Isabel dos Santos; Peto, Julian; Lambrechts, Diether; Paridaens, Robert; Ruediger, Thomas; Foersti, Asta; Winqvist, Robert; Pylkaes, Katri; Diasio, Robert B.; Lee, Adam M.; Eckel-Passow, Jeanette; Vachon, Celine; Blows, Fiona; Driver, Kristy; Dunning, Alison; Pharoah, Paul P. D.; Offit, Kenneth; Pankratz, V. Shane; Hakonarson, Hakon; Chenevix-Trench, Georgia; Easton, Douglas F.; Couch, Fergus J.

    2010-01-01

    Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosi

  9. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Wang, Xianshu; Fredericksen, Zachary S;

    2010-01-01

    Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagn...

  10. Development and validation of in vitro bioassays for thyroid hormone receptor mediated endocrine disruption

    NARCIS (Netherlands)

    Freitas, de J.

    2012-01-01

    Thyroid hormones regulate crucial processes in vertebrates such as reproduction, development and energy metabolism. Endocrine disruption via the thyroid hormone system is gaining more attention both from scientists and regulators, because of the increasing incidence of hormone-related cancers and de

  11. Role of the extracellular and intracellular loops of follicle stimulating hormone receptor in its function

    Directory of Open Access Journals (Sweden)

    Antara A Banerjee

    2015-07-01

    Full Text Available Follicle stimulating hormone receptor (FSHR is a leucine rich repeat containing class A G-protein coupled receptor belonging to the subfamily of glycoprotein hormone receptors, which includes luteinizing hormone/choriogonadotropin receptor (LH/CGR and thyroid stimulating hormone receptor (TSHR. Its cognate ligand, follicle stimulating hormone (FSH binds to and activates FSHR expressed on the surface of granulosa cells of the ovary, in females, and Sertoli cells of the testis, in males, to bring about folliculogenesis and spermatogenesis, respectively. FSHR contains a large extracellular domain (ECD consisting of leucine rich repeats at the N-terminal end and a hinge region at the C-terminus that connects the ECD to the membrane spanning transmembrane domain (TMD. The TMD consists of seven α-helices that are connected to each other by means of three extracellular loops (ELs and three intracellular loops (ILs and ends in a short cytoplasmic tail. It is well established that the extracellular domain (ECD is the primary hormone binding domain, whereas the TMD is the signal transducing domain. However, several studies on the ELs and ILs employing site directed mutagenesis, generation of chimeric receptors and in vitro characterization of naturally occurring mutations have proven their indispensable role in FSHR function. Their role in every phase of the life cycle of the receptor like post translational modifications, cell surface trafficking, hormone binding, activation of downstream signaling, receptor phosphorylation, hormone-receptor internalization, recycling of hormone receptor complex have been documented. Mutations in the loops causing dysregulation of these processes lead to pathophysiological conditions. In other GPHRs as well, the loops have been convincingly shown to contribute to various aspects of receptor function. This review article attempts to summarize the extensive contributions of FSHR loops and C-terminal tail to its function.

  12. Characterization of the hormone-binding domain of the chicken c-erbA/thyroid hormone receptor protein

    DEFF Research Database (Denmark)

    Muñoz, A; Zenke, M; Gehring, U;

    1988-01-01

    To identify and characterize the hormone-binding domain of the thyroid hormone receptor, we analyzed the ligand-binding capacities of proteins representing chimeras between the normal receptor and P75gag-v-erbA, the retrovirus-encoded form deficient in binding ligand. Our results show that severa......gag-v-erbA and that renders it biologically inactive fails to affect hormone binding by the c-erbA protein. These results suggest that the mutation changed the ability of P75gag-v-erbA to affect transcription since it also had no effect on DNA binding. Our data also suggest that hormone......-independent activity of P75gag-v-erbA provided a selective advantage to the avian erythroblastosis virus during the original selection for a highly oncogenic strain of the virus....

  13. Intercellular interactions and progression of hormonal resistance of breast cancer cells

    Directory of Open Access Journals (Sweden)

    S. E. Semina

    2015-01-01

    Full Text Available The main goal of the study is the analysis of the role of cell-cell interactions in the formation of the tumor cell resistance to hormonal drugs. About 70 % of breast tumors contain estrogen receptor (ER, a key molecular target for hormone (endocrine therapy. However, the efficiency of endocrine therapy of breast cancer is limited by the development of hormone resistance which leads to progression of tumor cells to hormone-independent phenotype, increase in tumor malignancy and worse prognosis. Hormonal independence may be accompanied with the loss of the receptors, as well as with the another mechanisms including ligand-independent receptor activation, disbalance between receptor activators and repressors, stimulation of hormone-independent pathways. It is less known about the role of the intercellular interactions in the progression of hormonal resistance. Several studies demonstrate the involvement of cell junctions in the mediating of cell response to (anti estrogens, however the significance of cell-cell contacts in the formation of hormonal resistance still not clear. Here we have hypothesized that the formation of the hormone resistance of tumors may be based, at least in part, on the transferring of the resistant phenotype from the resistant to hormone-sensitive cells – as a result of the secretion of the specific factors acting in the paracrine manner or via the direct cell-cell contacts. Using the estrogen-dependent breast cancer cells MCF-7 and the resistant subline MCF-7 / T developed by long-term cultivation of MCF-7 cells in the presence of antiestrogen tamoxifen, we investigated the possible changes in the hormonal sensitivity of these cells caused by the co-cultivation in vitro. To discern the cell cultures, the MCF-7 / T cells were previously transfected with the plasmid containing the gene of the green fluorescent protein (GFP, and GFP-positive hormone-resistant subline MCF-7 / T / GFP+ was developed. We showed that the co

  14. Estrogen signalling and the DNA damage response in hormone dependent breast cancers

    Directory of Open Access Journals (Sweden)

    C Elizabeth Caldon

    2014-05-01

    Full Text Available Estrogen is necessary for the normal growth and development of breast tissue, but high levels of estrogen are a major risk factor for breast cancer. One mechanism by which estrogen could contribute to breast cancer is via the induction of DNA damage. This perspective discusses the mechanisms by which estrogen alters the DNA damage response (DDR and DNA repair through the regulation of key effector proteins including ATM, ATR, CHK1, BRCA1 and p53 and the feedback on estrogen receptor signalling from these proteins. We put forward the hypothesis that estrogen receptor signalling converges to suppress effective DNA repair and apoptosis in favour of proliferation. This is important in hormone-dependent breast cancer as it will affect processing of estrogen-induced DNA damage, as well as other genotoxic insults. DDR and DNA repair proteins are frequently mutated or altered in estrogen responsive breast cancer which will further change the processing of DNA damage. Finally the action of estrogen signalling on DNA damage is also relevant to the therapeutic setting as the suppression of a DNA damage response by estrogen has the potential to alter the response of cancers to anti-hormone treatment or chemotherapy that induces DNA damage.

  15. (−) Arctigenin and (+) Pinoresinol Are Antagonists of the Human Thyroid Hormone Receptor β

    OpenAIRE

    Ogungbe, Ifedayo Victor; Crouch, Rebecca A.; Demeritte, Teresa

    2014-01-01

    Lignans are important biologically active dietary polyphenolic compounds. Consumption of foods that are rich in lignans is associated with positive health effects. Using modeling tools to probe the ligand-binding pockets of molecular receptors, we found that lignans have high docking affinity for the human thyroid hormone receptor β. Follow-up experimental results show that lignans (−) arctigenin and (+) pinoresinol are antagonists of the human thyroid hormone receptor β. The modeled complexe...

  16. Enzalutamide monotherapy: Phase II study results in patients with hormone-naive prostate cancer

    DEFF Research Database (Denmark)

    Tombal, Bertrand; Borre, Michael; Rathenborg, Per Zier;

    2013-01-01

    Background: Enzalutamide (ENZA) is an oral androgen receptor inhibitor that has been approved in the US and shown to increase overall survival by 4.8 months over a placebo (HR,0.63) in patients with metastatic castration resistant prostate cancer (CRPC) previously treated with docetaxel (Scher et...... al, N Engl J Med 2012;367:1187). Compared with bicalutamide in nonclinical studies, enzalutamide had higher androgen receptor– binding affinity, prevented nuclear translocation, showed no DNA binding, and induced apoptosis (Tran et al, Science 2009;324:787). In contrast to previous phase II and III....../dL). Methods: This was a 25-wk, open-label, single-arm study of patients with hormone-naïve, histologically confirmed prostate cancer (all stages) requiring hormonal treatment, an ECOG PS score of 0,and a life expectancy .1 y. All patients received ENZA 160 mg/d without concomitment castration. Primary endpoint...

  17. Exploratory Cost-Effectiveness Analysis of Response-Guided Neoadjuvant Chemotherapy for Hormone Positive Breast Cancer Patients

    OpenAIRE

    Anna Miquel-Cases; Retèl, Valesca P; Bianca Lederer; Gunter von Minckwitz; Steuten, Lotte M.G.; van Harten, Wim H

    2016-01-01

    Purpose Guiding response to neoadjuvant chemotherapy (guided-NACT) allows for an adaptative treatment approach likely to improve breast cancer survival. In this study, our primary aim is to explore the expected cost-effectiveness of guided-NACT using as a case study the first randomized controlled trial that demonstrated effectiveness (GeparTrio trial). Materials and Methods As effectiveness was shown in hormone-receptor positive (HR+) early breast cancers (EBC), our decision model compared t...

  18. Hormone-replacement therapy influences gene expression profiles and is associated with breast-cancer prognosis: a cohort study

    OpenAIRE

    Skoog Lambert; Shaw Peter; Pawitan Yudi; Nordgren Hans; Miller Lance D; Liu Edison T; Lin Chin-Yo; Huang Fei; Bjöhle Judith; Ploner Alexander; Hall Per; Smeds Johanna; Wedrén Sara; Öhd John; Bergh Jonas

    2006-01-01

    Abstract Background Postmenopausal hormone-replacement therapy (HRT) increases breast-cancer risk. The influence of HRT on the biology of the primary tumor, however, is not well understood. Methods We obtained breast-cancer gene expression profiles using Affymetrix human genome U133A arrays. We examined the relationship between HRT-regulated gene profiles, tumor characteristics, and recurrence-free survival in 72 postmenopausal women. Results HRT use in patients with estrogen receptor (ER) pr...

  19. Hormonal treatment of obstructed kidneys in patients with prostatic cancer

    DEFF Research Database (Denmark)

    Honnens de Lichtenberg, M; Miskowiak, J; Rolff, H

    1993-01-01

    A review of 1288 patients with previously untreated prostatic cancer revealed 209 patients (16%) with ureteric obstruction; the obstruction was bilateral in 36%. The effect of hormonal treatment was assessed in 88 patients with 120 obstructed kidneys: 77 patients had androgen deprivation...

  20. SRC-3 Has a Role in Cancer Other Than as a Nuclear Receptor Coactivator

    Directory of Open Access Journals (Sweden)

    Gang Ma, Yu Ren, Ke Wang, Jianjun He

    2011-01-01

    Full Text Available Steroid receptor coactivator-3 (SRC-3, also known as AIB1, is a member of the p160 steroid receptor coactivator family. Since SRC-3 was found to be amplified in breast cancer in 1997, the role of SRC-3 in cancer has been broadly investigated. SRC-3 initially was identified as a transcriptional coactivator for nuclear receptors such as the estrogen receptor (ER, involved in the proliferation of hormone-dependent cancers. However, increasing clinical evidence shows that dysregulation of SRC-3 expression in several human hormone-independent cancers is correlated with pathological factors and clinical prognosis. Recently, both in vivo and in vitro studies demonstrate that SRC-3 may influence a number of cancer cellular processes in several ways independent of nuclear receptor signaling. In addition, an SRC-3 transgenic mice model shows that SRC-3 induces tumors in several mouse tissues. These results indicate that the role of SRC-3 in cancer is not just as a nuclear receptor coactivator. The focus of this review is to examine possible SRC-3 roles in cancer, other than as a nuclear receptor coactivator.

  1. Hormonal contraception and risk of cancer

    DEFF Research Database (Denmark)

    Cibula, D; Gompel, A; Mueck, A O;

    2010-01-01

    Fear from increased cancer risk is one of the most significant reasons for low acceptance of reliable contraceptive methods and low compliance.......Fear from increased cancer risk is one of the most significant reasons for low acceptance of reliable contraceptive methods and low compliance....

  2. THYROID HORMONE PROFILE IN EARLY BREAST CANCER PATIENTS

    Directory of Open Access Journals (Sweden)

    Renija Valiya

    2016-06-01

    Full Text Available BACKGROUND Breast cancer is the most common malignant tumour in women worldwide. The relationship between breast cancer and thyroid disease is a controversy. Many of the studies showed hypothyroidism as the commonly found thyroid abnormality in breast cancer. [1] There is considerable evidence for an increased risk of thyroid and breast cancer in patients with iodine deficiency. This ability of iodine to reduce the risk of breast cancer is attributed to the ability of iodine and its compounds to induce apoptosis so that appropriate cell death occurs. Instead, in the absence of optimum level of iodine in the body the transformed cells continue to grow and divide resulting in cancer. AIMS 1. To find out the association of thyroid hormones and breast cancer in early breast cancer patients. 2. To find out the association of thyroid peroxidase antibodies in early breast cancer patients. Settings Cases: 82 breast cancer patients in early stage who attended the breast clinic. Controls: 82 age matched controls (Between 25-80 years. Design: Case control study. MATERIALS AND METHOD In this study, investigated for thyroid function test (T3, T4, TSH and thyroid peroxide antibody level in 82 early breast cancer patients. STATISTICAL ANALYSIS SPSS 16. RESULTS Statistically significant low T4 and high TSH in breast cancer patients, along with elevated thyroid peroxidase antibody. CONCLUSION Compared to hyperthyroidism, hypothyroidism was found to be clinically significant in breast cancer patients

  3. Hormone receptors in gills of smolting Atlantic salmon, Salmo salar

    DEFF Research Database (Denmark)

    Kiilerich, Pia; Kristiansen, Karsten; Madsen, Steffen

    2007-01-01

    This is the first study to report concurrent dynamics in mRNA expression of growth hormone receptor (GHR), prolactin receptor (PRLR), gluco- and mineralocorticoid receptor (GR and MR) and the 11beta-hydroxysteroid dehydrogenase type-2 enzyme (11beta-HSD2) in Atlantic salmon (Salmo salar) gill...

  4. Genomic organization of the human thyroid hormone receptor alpha (c-erbA-1) gene.

    OpenAIRE

    Laudet, V; Begue, A; Henry-Duthoit, C; Joubel, A; P. Martin; Stehelin, D.; Saule, S.

    1991-01-01

    The thyroid hormone receptor alpha (THRA or c-erbA-1) gene belongs to a family of genes which encode nuclear receptors for various hydrophobic ligands such as steroids, vitamin D, retinoic acid and thyroid hormones. These receptors are composed of several domains important for hormone-binding, DNA-binding, dimerization and activation of transcription. We show here that the human THRA gene is organized in 10 exons distributed along 27 kbp of genomic DNA on chromosome 17. The position of the in...

  5. Muscarinic Receptor Signaling in Colon Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Rosenvinge, Erik C. von, E-mail: evonrose@medicine.umaryland.edu; Raufman, Jean-Pierre [University of Maryland School of Medicine, Division of Gastroenterology & Hepatology, 22 S. Greene Street, N3W62, Baltimore, MD 21201 (United States); Department of Veterans Affairs, VA Maryland Health Care System, 10 North Greene Street, Baltimore, MD 21201 (United States)

    2011-03-02

    According to the adenoma-carcinoma sequence, colon cancer results from accumulating somatic gene mutations; environmental growth factors accelerate and augment this process. For example, diets rich in meat and fat increase fecal bile acids and colon cancer risk. In rodent cancer models, increased fecal bile acids promote colon dysplasia. Conversely, in rodents and in persons with inflammatory bowel disease, low-dose ursodeoxycholic acid treatment alters fecal bile acid composition and attenuates colon neoplasia. In the course of elucidating the mechanism underlying these actions, we discovered that bile acids interact functionally with intestinal muscarinic receptors. The present communication reviews muscarinic receptor expression in normal and neoplastic colon epithelium, the role of autocrine signaling following synthesis and release of acetylcholine from colon cancer cells, post-muscarinic receptor signaling including the role of transactivation of epidermal growth factor receptors and activation of the ERK and PI3K/AKT signaling pathways, the structural biology and metabolism of bile acids and evidence for functional interaction of bile acids with muscarinic receptors on human colon cancer cells. In murine colon cancer models, deficiency of subtype 3 muscarinic receptors attenuates intestinal neoplasia; a proof-of-concept supporting muscarinic receptor signaling as a therapeutic target for colon cancer.

  6. Muscarinic Receptor Signaling in Colon Cancer

    Directory of Open Access Journals (Sweden)

    Jean-Pierre Raufman

    2011-03-01

    Full Text Available According to the adenoma-carcinoma sequence, colon cancer results from accumulating somatic gene mutations; environmental growth factors accelerate and augment this process. For example, diets rich in meat and fat increase fecal bile acids and colon cancer risk. In rodent cancer models, increased fecal bile acids promote colon dysplasia. Conversely, in rodents and in persons with inflammatory bowel disease, low-dose ursodeoxycholic acid treatment alters fecal bile acid composition and attenuates colon neoplasia. In the course of elucidating the mechanism underlying these actions, we discovered that bile acids interact functionally with intestinal muscarinic receptors. The present communication reviews muscarinic receptor expression in normal and neoplastic colon epithelium, the role of autocrine signaling following synthesis and release of acetylcholine from colon cancer cells, post-muscarinic receptor signaling including the role of transactivation of epidermal growth factor receptors and activation of the ERK and PI3K/AKT signaling pathways, the structural biology and metabolism of bile acids and evidence for functional interaction of bile acids with muscarinic receptors on human colon cancer cells. In murine colon cancer models, deficiency of subtype 3 muscarinic receptors attenuates intestinal neoplasia; a proof-of-concept supporting muscarinic receptor signaling as a therapeutic target for colon cancer.

  7. Monoclonal antibodies against rabbit mammary prolactin receptors. Specific antibodies to the hormone binding domain

    International Nuclear Information System (INIS)

    Three monoclonal antibodies (M110, A82, and A917) were obtained by fusing myeloma cells and spleen cells from mice immunized with partially purified rabbit mammary gland prolactin (PRL) receptors. All 3 antibodies were capable of complete inhibition of 125I-ovine prolactin (oPRL) binding to rabbit mammary PRL receptors in either particulate or soluble form. M110 showed slightly greater potency than oPRL in competing for 125I-oPRL binding. These antibodies also inhibited PRL binding to microsomal fractions from rabbit liver, kidney, adrenal, ovary, and pig mammary gland, although A82 showed poor inhibition in pig mammary gland. There was no cross-reaction of any of the 3 monoclonal antibodies (mAbs) for the other species tested: human (T-47D breast cancer cells) and rat (liver, ovary). In order to confirm that these antibodies are specific to the binding domain, antibodies were purified, iodinated, and binding characteristics were investigated. 125I-M110 and 125I-A82 binding was completely inhibited by lactogenic hormones, whereas nonlactogenic hormones did not cross-react. Competition of 125I-M110 by oPRL was comparable to that of 125I-oPRL by unlabeled oPRL, while 125I-A917 binding was only partially competed (30-60%) by lactogenic hormones. Tissue and species specificity of labeled antibody binding paralleled results of binding inhibition experiments using 125I-oPRL. In addition, A82 and A917 completely inhibited 125I-M110 binding. In contrast, 125I-A82 binding was stimulated by A917 and 125I-A917 binding was stimulated by A82

  8. Peroxisome Proliferator-Activated Receptor and Vitamin D Receptor Signaling Pathways in Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Matsuda, Satoru, E-mail: smatsuda@cc.nara-wu.ac.jp; Kitagishi, Yasuko [Department of Food Science and Nutrition, Nara Women’s University, Kita-Uoya Nishimachi, Nara 630-8506 (Japan)

    2013-10-21

    Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation, but also by cross-talk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, PPARs and vitamin D receptor (VDR) signaling pathways regulate a multitude of genes that are of importance for cellular functions including cell proliferation and cell differentiation. Interaction of the PPARs and VDR signaling pathways has been shown at the level of molecular cross-regulation of their transcription factor. A variety of ligands influencing the PPARs and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in human cancers. Use of these compounds may represent a potential novel strategy to prevent cancers. This review summarizes the roles of the PPARs and the VDR in pathogenesis and progression of cancer.

  9. Peroxisome Proliferator-Activated Receptor and Vitamin D Receptor Signaling Pathways in Cancer Cells

    International Nuclear Information System (INIS)

    Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation, but also by cross-talk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, PPARs and vitamin D receptor (VDR) signaling pathways regulate a multitude of genes that are of importance for cellular functions including cell proliferation and cell differentiation. Interaction of the PPARs and VDR signaling pathways has been shown at the level of molecular cross-regulation of their transcription factor. A variety of ligands influencing the PPARs and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in human cancers. Use of these compounds may represent a potential novel strategy to prevent cancers. This review summarizes the roles of the PPARs and the VDR in pathogenesis and progression of cancer

  10. Anthropometric and hormonal risk factors for male breast cancer

    DEFF Research Database (Denmark)

    Brinton, Louise A; Cook, Michael B; McCormack, Valerie;

    2014-01-01

    BACKGROUND: The etiology of male breast cancer is poorly understood, partly because of its relative rarity. Although genetic factors are involved, less is known regarding the role of anthropometric and hormonally related risk factors. METHODS: In the Male Breast Cancer Pooling Project, a consortium.......41; 95% CI = 1.07 to 1.86). CONCLUSIONS: Consistent findings across case-control and cohort investigations, complemented by pooled analyses, indicated important roles for anthropometric and hormonal risk factors in the etiology of male breast cancer. Further investigation should focus on potential roles...... significantly associated with risk, relations that were independent of BMI. Diabetes also emerged as an independent risk factor (OR = 1.19; 95% CI = 1.04 to 1.37). There were also suggestive relations with cryptorchidism (OR = 2.18; 95% CI = 0.96 to 4.94) and orchitis (OR = 1.43; 95% CI = 1.02 to 1...

  11. Circulating Thyroxine, Thyroid-Stimulating Hormone, and Hypothyroid Status and the Risk of Prostate Cancer

    OpenAIRE

    Mondul, Alison M.; Weinstein, Stephanie J.; Tracey Bosworth; Remaley, Alan T.; Jarmo Virtamo; Demetrius Albanes

    2012-01-01

    BACKGROUND: Thyroid hormones may influence risk of cancer through their role in cell differentiation, growth, and metabolism. One study of circulating thyroid hormones supports this hypothesis with respect to prostate cancer. We undertook a prospective analysis of thyroid hormones and prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. METHODS: Within the ATBC Study, a randomized controlled trial of α-tocopherol and β-carotene supplements and cancer inc...

  12. Alien, a Highly Conserved Protein with Characteristics of a Corepressor for Members of the Nuclear Hormone Receptor Superfamily

    OpenAIRE

    Dressel, Uwe; Thormeyer, Dorit; Altincicek, Boran; Paululat, Achim; Eggert, Martin; Schneider, Sandra; Tenbaum, Stephan P.; Renkawitz, Rainer; Baniahmad, Aria

    1999-01-01

    Some members of nuclear hormone receptors, such as the thyroid hormone receptor (TR), silence gene expression in the absence of the hormone. Corepressors, which bind to the receptor’s silencing domain, are involved in this repression. Hormone binding leads to dissociation of corepressors and binding of coactivators, which in turn mediate gene activation. Here, we describe the characteristics of Alien, a novel corepressor. Alien interacts with TR only in the absence of hormone. Addition of thy...

  13. Introduction of exogenous growth hormone receptors augments growth hormone-responsive insulin biosynthesis in rat insulinoma cells

    DEFF Research Database (Denmark)

    Billestrup, N; Møldrup, A; Serup, P;

    1990-01-01

    The stimulation of insulin biosynthesis in the pancreatic insulinoma cell line RIN5-AH by growth hormone (GH) is initiated by GH binding to specific receptors. To determine whether the recently cloned rat hepatic GH receptor is able to mediate the insulinotropic effect of GH, we have transfected...... of GH receptors in one clone (1.24) selected for detailed analysis was increased 2.6-fold compared to untransfected cells. The increased GH receptor expression was accompanied by an increased responsiveness to GH. Thus, the maximal GH-stimulated increase of insulin biosynthesis was 4.1-fold in 1...... magnitude of GH-stimulated insulin biosynthesis. A close stoichiometric relationship between the level of receptor expression and the level of GH-stimulated insulin biosynthesis was observed. We conclude from these results that the hepatic GH receptor is able to mediate the effect of GH on insulin...

  14. Identifying neuropeptide and protein hormone receptors in Drosophila melanogaster by exploiting genomic data

    DEFF Research Database (Denmark)

    Hauser, Frank; Williamson, Michael; Cazzamali, Giuseppe;

    2006-01-01

    Most neuropeptide and protein hormone receptors belong to the large superfamily of G-protein-coupled receptors (GPCRs). These cell membrane proteins steer many important processes such as development, reproduction, homeostasis and behaviour when activated by their corresponding ligands. The first...... insect genome, that of the fruitfly Drosophila melanogaster, was sequenced in 2000, and about 200 GPCRs have been annnotated in this model insect. About 50 of these receptors were predicted to have neuropeptides or protein hormones as their ligands. Since 2000, the cDNAs of most of these candidate...... receptors have been cloned and for many receptors the endogenous ligand has been identified. In this review, we will give an update about the current knowledge of all Drosophila neuropeptide and protein hormone receptors, and discuss their phylogenetic relationships. Udgivelsesdato: 2006-Feb...

  15. Enzalutamide monotherapy in hormone-naive prostate cancer

    DEFF Research Database (Denmark)

    Tombal, Bertrand; Borre, Michael; Rathenborg, Per;

    2014-01-01

    : This trial is an ongoing open-label, single-arm, phase 2 study, done across 12 European sites. Men aged over 18 years, with hormone-naive prostate cancer for whom hormone therapy was indicated, and who had non-castration levels of testosterone and prostate-specific antigen (PSA) of 2 ng/mL or greater......), nipple pain (n=13), and hot flush (n=12), all of which were of mild to moderate severity. Nine patients had a treatment-emergent adverse event of grade 3 or higher, most of which were reported in one patient each, except for pneumonia (grade 3, two patients) and hypertension (grade 3, four patients...

  16. Rabbit antibodies for hormone receptors and HER2 evaluation in breast cancer Anticorpos de coelho para avaliação de receptores hormonais e HER2 em câncer de mama

    Directory of Open Access Journals (Sweden)

    Rafael Malagoli Rocha

    2009-01-01

    Full Text Available BACKGROUND: Novel rabbit monoclonal antibodies (RabMab for estrogen (ER, progesterone (PR receptors and HER2 evaluation by immunohistochemistry have recently been commercially released. We compared the RabMab anti-ER, anti-PR and anti-HER2 to mouse monoclonal antibodies (Mab using tissue microarrays (TMA of breast carcinomas. METHODS: Two TMA containing breast carcinomas were built. Sections were immunostained using anti-ER and anti-PR, Mab and RabMab. The sections stained for ER and PR were evaluated considering positive those tumors in which more than 1% of the tumor cell nuclei stained moderate or strong. For HER2, the immunostained sections were evaluated using the ASCO/CAP guidelines for HER2. Chromogenic in situ hybridization (CISH was used as the gold standard for HER2 evaluation. CISH was evaluated using the Zymed HER2 CISH interpretation guidelines. RESULTS: RabMab against ER have similar staining patterns compared to the 6F11 (Mab, but stronger than 1D5 (Mab from three different suppliers. The RabMab against PR provide stronger and sharper immunohistochemical signals compared to Mab. The detection of HER2 protein overexpression was more prevalent with the polyclonal antibodies and RabMab than with the Mab. These were more specific than the RabMab, which were more sensitive when compared to CISH. CONCLUSION: The novel RabMab against ER and PR showed higher intensity of staining than the Mab. The RabMab against HER2 is more sensitive than Mab, however, Mab presented more specificity than RabMab when compared to CISH for HER2 evaluation of breast carcinomas.OBJETIVOS: Novos anticorpos monoclonais de coelho (RabMab para a avaliação imuno-histoquímica de receptores de estrógeno (RE, progesterona (RP e HER2 foram lançados comercialmente. Comparamos os RabMab anti-RE, anti-RP e anti-HER2 com os anticorpos monoclonais de camundongo (Mab utilizando tissue microarrays (TMA de carcinomas de mama. MÉTODOS: Foram construídos dois TMAs de

  17. Predicting Response to Hormonal Therapy and Survival in Men with Hormone Sensitive Metastatic Prostate Cancer

    OpenAIRE

    Grivas, Petros D; Robins, Diane M.; Hussain, Maha

    2012-01-01

    Androgen deprivation is the cornerstone of the management of metastatic prostate cancer. Despite several decades of clinical experience with this therapy there are no standard predictive biomarkers for response. Although several candidate genetic, hormonal, inflammatory, biochemical, metabolic biomarkers have been suggested as potential predictors of response and outcome, none has been prospectively validated nor has proven clinical utility to date. There is significant heterogeneity in the d...

  18. Hormones and breast and endometrial cancers: preventive strategies and future research.

    OpenAIRE

    Hulka, B S; Brinton, L. A.

    1995-01-01

    A number of hormonal approaches for prevention of endometrial and breast cancers have been proposed. Because of the hormonal responsiveness of both tumors, much attention has focused on effects of exogenous hormone use. Although estrogens in hormone replacement therapy increase the risk of endometrial cancer, the disease is substantially reduced by long-term use of oral contraceptives. The issues with breast cancer are more complex, mainly because of a variety of unresolved effects. Long-term...

  19. Postmenopausal hormone therapy and the risk of breast cancer: a contrary thought.

    Science.gov (United States)

    Speroff, Leon

    2008-01-01

    The most important unanswered question regarding postmenopausal hormone therapy and the risk of breast cancer is whether hormone therapy initiates the growth of new breast cancers or whether the epidemiologic data reflect a hormonal impact on preexisting tumors. In this perspective I review the evidence favoring hormonal effects on preexisting tumors and suggest that exposure to combined estrogen and progestin is beneficial, causing greater differentiation and earlier detection of breast cancers.

  20. Analysis of the hormone-binding domain of steroid receptors using chimeras generated by homologous recombination

    International Nuclear Information System (INIS)

    The glucocorticoid receptor and the mineralocorticoid receptor are members of the steroid receptor family that exhibit ligand cross-reactivity. Specificity of steroid receptor action is investigated in the present work by the construction and characterization of chimeras between the glucocorticoid receptor and the mineralocorticoid receptor. We used an innovative approach to make novel steroid receptor proteins in vivo that in general, contrary to our expectations, show increased ligand specificity compared to the parental receptors. We describe a receptor that is specific for the potent synthetic glucocorticoid triamcinolone acetonide and does not bind aldosterone. A further set of chimeras has an increased ability to discriminate between ligands, responding potently to mineralocorticoids and only very weakly to synthetic glucocorticoids. A chimera with the fusion site in the hinge highlights the importance of the region between the DNA-binding and the hormone-binding domains since, unlike both the glucocorticoid and mineralocorticoid receptors, it only responds to mineralocorticoids. One chimera has reduced specificity in that it acts as a general corticoid receptor, responding to glucocorticoids and mineralocorticoids with similar potency and efficacy. Our data suggest that regions of the glucocorticoid and mineralocorticoid receptor hormone-binding domains are functionally non-reciprocal. We present transcriptional, hormone-binding, and structure-modeling evidence that suggests that receptor-specific interactions within and across domains mediate aspects of specificity in transcriptional responses to steroids

  1. Effects of Phytoestrogen Extracts Isolated from Elder Flower on Hormone Production and Receptor Expression of Trophoblast Tumor Cells JEG-3 and BeWo, as well as MCF7 Breast Cancer Cells

    Science.gov (United States)

    Schröder, Lennard; Richter, Dagmar Ulrike; Piechulla, Birgit; Chrobak, Mareike; Kuhn, Christina; Schulze, Sandra; Abarzua, Sybille; Jeschke, Udo; Weissenbacher, Tobias

    2016-01-01

    Herein we investigated the effect of elderflower extracts (EFE) and of enterolactone/enterodiol on hormone production and proliferation of trophoblast tumor cell lines JEG-3 and BeWo, as well as MCF7 breast cancer cells. The EFE was analyzed by mass spectrometry. Cells were incubated with various concentrations of EFE. Untreated cells served as controls. Supernatants were tested for estradiol production with an ELISA method. Furthermore, the effect of the EFE on ERα/ERβ/PR expression was assessed by immunocytochemistry. EFE contains a substantial amount of lignans. Estradiol production was inhibited in all cells in a concentration-dependent manner. EFE upregulated ERα in JEG-3 cell lines. In MCF7 cells, a significant ERα downregulation and PR upregulation were observed. The control substances enterolactone and enterodiol in contrast inhibited the expression of both ER and of PR in MCF7 cells. In addition, the production of estradiol was upregulated in BeWo and MCF7 cells in a concentration dependent manner. The downregulating effect of EFE on ERα expression and the upregulation of the PR expression in MFC-7 cells are promising results. Therefore, additional unknown substances might be responsible for ERα downregulation and PR upregulation. These findings suggest potential use of EFE in breast cancer prevention and/or treatment and warrant further investigation. PMID:27740591

  2. (-) Arctigenin and (+) pinoresinol are antagonists of the human thyroid hormone receptor β.

    Science.gov (United States)

    Ogungbe, Ifedayo Victor; Crouch, Rebecca A; Demeritte, Teresa

    2014-11-24

    Lignans are important biologically active dietary polyphenolic compounds. Consumption of foods that are rich in lignans is associated with positive health effects. Using modeling tools to probe the ligand-binding pockets of molecular receptors, we found that lignans have high docking affinity for the human thyroid hormone receptor β. Follow-up experimental results show that lignans (-) arctigenin and (+) pinoresinol are antagonists of the human thyroid hormone receptor β. The modeled complexes show key plausible interactions between the two ligands and important amino acid residues of the receptor.

  3. Expression of Growth Hormone Receptors by Lymphocyte subpopulations in the Human tonsil

    OpenAIRE

    Olivier Thellin; Bernard Coumans; Willy Zorzi; Ross Barnard; Georges Hennen; Ernst Heinen; Ahmed Igout

    1998-01-01

    The ability of human tonsillar lymphoid cells to express growth hormone receptor (hGH-N-R) was analyzed by flow cytometry. FITC-coupled recombinant human growth hormone (hGH-N) was used to reveal the receptors, in combination with phenotype markers. Unlike T cells, tonsillar B cells constitutively express the hGH-N receptor. Quiescent cells separated from activated cells by Percoll-gradient centrifugation bear fewer receptors than activated ones. Activated T cells express hGH-N-R, but the typ...

  4. (−) Arctigenin and (+) Pinoresinol Are Antagonists of the Human Thyroid Hormone Receptor β

    Science.gov (United States)

    2015-01-01

    Lignans are important biologically active dietary polyphenolic compounds. Consumption of foods that are rich in lignans is associated with positive health effects. Using modeling tools to probe the ligand-binding pockets of molecular receptors, we found that lignans have high docking affinity for the human thyroid hormone receptor β. Follow-up experimental results show that lignans (−) arctigenin and (+) pinoresinol are antagonists of the human thyroid hormone receptor β. The modeled complexes show key plausible interactions between the two ligands and important amino acid residues of the receptor. PMID:25383984

  5. (-) Arctigenin and (+) pinoresinol are antagonists of the human thyroid hormone receptor β.

    Science.gov (United States)

    Ogungbe, Ifedayo Victor; Crouch, Rebecca A; Demeritte, Teresa

    2014-11-24

    Lignans are important biologically active dietary polyphenolic compounds. Consumption of foods that are rich in lignans is associated with positive health effects. Using modeling tools to probe the ligand-binding pockets of molecular receptors, we found that lignans have high docking affinity for the human thyroid hormone receptor β. Follow-up experimental results show that lignans (-) arctigenin and (+) pinoresinol are antagonists of the human thyroid hormone receptor β. The modeled complexes show key plausible interactions between the two ligands and important amino acid residues of the receptor. PMID:25383984

  6. Detection of thyroid hormone receptor disruptors by a novel stable in vitro reporter gene assay

    NARCIS (Netherlands)

    Freitas, de J.; Cano, P.; Craig-Veit, C.; Goodson, M.L.; Furlow, J.D.; Murk, A.J.

    2011-01-01

    A stable luciferase reporter gene assay was developed based on the thyroid hormone responsive rat pituitary tumor GH3 cell line that constitutively expresses both thyroid hormone receptor isoforms. Stable transfection of the pGL4CP-SV40-2xtaDR4 construct into the GH3 cells resulted in a highly sensi

  7. Growth hormone receptor antagonists: discovery and potential uses.

    Science.gov (United States)

    Kopchick, J J; Okada, S

    2001-06-01

    Serum levels of growth hormone (GH) in the human body vary and can influence the levels of insulin-like growth factor I (IGF-1). Low levels of GH can result in a dwarf phenotype and have been positively correlated with an increased life expectancy. High levels of GH can lead to gigantism or a clinical syndrome termed acromegaly, and also have been implicated in diabetic eye and kidney damage. Additionally, it has been postulated that the GH-IGF-I system can be involved in several types of cancers. Overall, both elevated and suppressed circulating levels of GH can have pronounced physiological effects. More than a decade ago a new class of drug, a GH antagonist, was discovered. It is now being tested for its ability to combat the effects of high circulating levels of GH. In this review, we will discuss some of the detrimental actions of GH and how a GH antagonist may be used to combat these effects. PMID:11527080

  8. Expression of oestrogen receptor-α and oestrogen receptor-β in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    YANG Guo-sheng; WANG Ying; WANG Ping; CHEN Zhao-dian

    2007-01-01

    Background Recent studies have suggested that estrogens are involved in normal and abnormal prostate growth,though their exact role is still controversial. Oestrogens exert inhibitory and stimulatory effects on prostate gland, but the expression of oestrogen receptor-α (ERα) and oestrogen receptor-β (ERβ) in malignant prostate tissue remains unresolved. We determined ERα and ERβ in prostate cancer and investigated the relationship between expression of ER and pathological features of prostate carcinoma.Methods Thirty-two cases of prostate cancer, 12 cases of normal prostate tissue and 32 cases of benign prostate hyperplasia were analyzed for the expression of ERα and ERβ using semiquantitative, reverse transcription polymerase chain reaction (RT-PCR) and the products sequenced.Results Comparisons of the normal, hyperplastic and tumour prostate tissues indicated an overexpression of ERα in tumour specimens (P<0.01). However, the expression of ERβ significantly reduced in tumour tissues compared with normal and hyperplastic specimens (P<0.01), suggesting that severe pathological features of prostate cancer were associated with lower ERβ expression. Spearman analysis showed negative correlation between ERβ expression and tumour stage, grade (-0.67, -0.43, respectively, both P<0.05), and a positive correlation between ERα expression and tumour stage, grade (0.51, 0.57, respectively, both P<0.01). Our analysis also showed that hormone refractory, prostate cancer, compared with hormone dependent, prostate cancer, displayed a decreased expression of ERβ (P<0.01) and an increased expression of ERα.Conclusions ERa and ERβ may play important roles in the development of prostate cancer. The decrease in ERβ expression is associated with higher Gleason grade tumours and prostate cancer with higher metastatic potential. The loss of ERβ could be one of the key processes leading to uncontrolled growth of prostate epithelial cells.

  9. Cancer cell gene expression modulated from plasma membrane integrin αvβ3 by thyroid hormone and nanoparticulate tetrac

    Directory of Open Access Journals (Sweden)

    Paul eDavis

    2015-01-01

    Full Text Available Integrin αvβ3 is generously expressed by cancer cells and rapidly dividing endothelial cells. The principal ligands of the integrin are extracellular matrix proteins, but we have described a cell surface small molecule receptor on αvβ3 that specifically binds thyroid hormone and thyroid hormone analogues. From this receptor, thyroid hormone (L-thyroxine, T4; 3,5,3’-triiodo-L-thyronine, T3 and tetraiodothyroacetic acid (tetrac regulate expression of specific genes by a mechanism that is initiated nongenomically. At the integrin, T4 and T3 at physiological concentrations are pro-angiogenic by multiple mechanisms that include gene expression, and T4 supports tumor cell proliferation. Tetrac blocks the transcriptional activities directed by T4 and T3 at αvβ3, but, independently of T4 and T3, tetrac modulates transcription of cancer cell genes that are important to cell survival pathways, control of the cell cycle, angiogenesis, apoptosis, cell export of chemotherapeutic agents and repair of double-strand DNA breaks. We have covalently bound tetrac to a 200 nm biodegradable nanoparticle that prohibits cell entry of tetrac and limits its action to the hormone receptor on the extracellular domain of plasma membrane αvβ3. This reformulation has greater potency than unmodified tetrac at the integrin and affects a broader range of cancer-relevant genes. In addition to these actions on intracellular kinase-mediated regulation of gene expression, hormone analogues at αvβ3 have additional effects on intracellular protein-trafficking (cytosol compartment to nucleus, nucleoprotein phosphorylation and generation of nuclear coactivator complexes that are relevant to traditional genomic actions of T3. Thus, previously unrecognized cell surface-initiated actions of thyroid hormone and tetrac formulations at αvβ3 offer opportunities to regulate angiogenesis and multiple aspects of cancer cell behavior.

  10. Immunologic analysis of human breast cancer progesterone receptors. 1. Immunonaffinity purification of transformed receptors and production of monoclonal antibodies

    International Nuclear Information System (INIS)

    A monoclonal antibody (MAb), designated PR-6, produced against chick oviduct progesterone receptors cross-reacts with the M/sub r/ 120,000 human B receptors. An immunomatrix prepared with PR-6 was used to purify progesterone receptors (PR) from T47D human breast cancer cells. Single-step immunoaffinity chromatography results in enrichment of B receptors (identified by immunoblot with PR-6 and by photoaffinity labeling with [3H]promegestone) to a specific activity of 1915 pmol/mg of protein (or 23% purity) and with 27% yield. Purity and yields as judged by gel electrophoresis and densitometric scanning of the B protein were approximately 1.7-fold higher due to partial loss in hormone binding activity at the elution step. B receptors purified under these conditions are transformed and biologically active. They were maintained as undergraded 120-kDa doublets and retained both hormone and DNA binding activities. These purified B receptors were used as immunogen for production of four monoclonal antibodies against human PR. Three of the MAbs, designated as B-30 (IgG1), B-64 (IgG1), and B-11 (IgM), are specific for B receptors. The fourth MAb, A/B-52 (IgG1), reacts with both A and B receptors. The IgG MAbs are monospecific for human PR since they recognize and absorb native receptor-hormone complexes, displace the sedimentation of 4S receptors on salt containing sucrose gradients, and, by immunoblot assay of crude T47D cytosol, react only with receptor polypeptides. Although mice were injected with B receptors only, production of A/B-52 which recognized both A and B receptors provides evidence that these two proteins share regions of structural homology

  11. Steroid hormone secretion in inflammatory breast cancer cell lines.

    Science.gov (United States)

    Illera, Juan Carlos; Caceres, Sara; Peña, Laura; de Andres, Paloma J; Monsalve, Beatriz; Illera, Maria J; Woodward, Wendy A; Reuben, James M; Silvan, Gema

    2015-12-01

    Inflammatory breast carcinoma (IBC) is a special type of breast cancer with a poor survival rate. Though several IBC cell lines have been established, recently a first IMC cell line was established. The aims of this study were: (1) to validate a highly sensitive, reliable, accurate and direct amplified enzyme immunoassay (EIA) to measure several cell-secreted steroid hormones: progesterone (P4), androstenedione (A4), testosterone (T), 17β-estradiol (E2) and estrone sulfate (SO4E1) in the culture medium. (2) To assess whether hormone production profile by IPC-366 cells validates the IMC model for human IBC. We validated a non-competitive amplified EIA for inflammatory breast cancer cell lines based on the results of accuracy, precision, sensitivity and parallelism. The low detection limits of the technique were: P4=13.2 pg/well, A4=2.3 pg/well, T=11.4 pg/well, E2=1.9 pg/well and SO4E1=4.5 pg/well. Intra- and inter-assay coefficient of variation percentages were 90%. In all hormones studied SUM149 have higher levels (1.4 times, but not significant) than IPC-366, and the correlation index between SUM149 and IPC-366 concentrations were >97%. We can coclude that cells of both cell lines, IPC-366 and SUM149, are capable to produce steroid hormone in culture media. The presented EIA methodology is very valuable for the detection of steroid production in culture media and could be used in hormone regulation studies and therapeutic agents in cell lines of inflammatory and non-inflammatory mammary carcinoma or other cancer cell lines in preclinical studies. PMID:26495931

  12. Endocrine therapy for hormone treatment-naïve advanced breast cancer.

    Science.gov (United States)

    Martin, Miguel; Lopez-Tarruella, Sara; Gilarranz, Yolanda Jerez

    2016-08-01

    A proportion of patients with hormone receptor-positive locally advanced or metastatic breast cancer will not have received prior endocrine therapy. However, there are limited clinical data specifically in these patients. We conducted a review of randomized phase II and III clinical studies of anastrozole, letrozole, exemestane, palbociclib, and fulvestrant to determine the evidence base supporting use of specific endocrine therapies in this patient population. From our findings, there is a paucity of clinical studies in patients with endocrine therapy-naïve disease; however, it appears that first-line treatment effects are consistent between patients who have and have not received prior endocrine treatment. PMID:27326977

  13. Bioluminescent Ligand-Receptor Binding Assays for Protein or Peptide Hormones.

    Science.gov (United States)

    Liu, Ya-Li; Guo, Zhan-Yun

    2016-01-01

    Bioluminescence has been widely used in biomedical research due to its high sensitivity, low background, and broad linear range. In recent studies, we applied bioluminescence to ligand-receptor binding assays for some protein or peptide hormones based on a newly developed small monomeric Nanoluciferase (NanoLuc) reporter that has the so far brightest bioluminescence. The conventional ligand-receptor binding assays rely on radioligands that have drawbacks, such as radioactive hazards and short shelf lives. In contrast, the novel bioluminescent binding assays use the NanoLuc-based protein or peptide tracers that are safe, stable, and ultrasensitive. Thus, the novel bioluminescent ligand-receptor binding assay would be applied to more and more protein or peptide hormones for ligand-receptor interaction studies in future. In the present article, we provided detailed protocols for setting up the novel bioluminescent ligand-receptor binding assays using two representative protein hormones as examples. PMID:27424896

  14. Management of metastatic hormone-sensitive prostate cancer.

    Science.gov (United States)

    Bernard, Brandon; Sweeney, Christopher J

    2015-03-01

    In 2014, prostate cancer will affect roughly 15 % of American men during their lifetimes with about 230,000 new cases and 29,000 deaths per year. If required, most can be treated with curative surgery or radiotherapy. Upon relapse, androgen deprivation therapy (intermittent or continuous) is the cornerstone of treatment for hormone-sensitive disease. Response is variable and treatment is associated with a significant risk of toxicity. Recently, significant advances in survival have been demonstrated with chemohormonal therapy in men with high-volume disease. In addition, new findings have informed the approach to preventing bone complications in patients on therapy for metastatic hormone-sensitive prostate cancer. Devising clinical prediction tools and biomarkers is needed to select patients most likely to benefit from certain therapies and allow for a personalized approach. PMID:25677237

  15. Expression and function of androgen receptor coactivator p44/Mep50/WDR77 in ovarian cancer.

    Directory of Open Access Journals (Sweden)

    Martin Ligr

    Full Text Available Hormones, including estrogen and progesterone, and their receptors play an important role in the development and progression of ovarian carcinoma. Androgen, its receptor and coactivators have also been implicated in these processes. p44/Mep50/WDR77 was identified as a subunit of the methylosome complex and lately characterized as a steroid receptor coactivator that enhances androgen receptor as well as estrogen receptor-mediated transcriptional activity in a ligand-dependent manner. We previously described distinct expression and function of p44 in prostate, testis, and breast cancers. In this report, we examined the expression and function of p44 in ovarian cancer. In contrast to findings in prostate and testicular cancer and similar to breast cancer, p44 shows strong cytoplasmic localization in morphologically normal ovarian surface and fallopian tube epithelia, while nuclear p44 is observed in invasive ovarian carcinoma. We observed that p44 can serve as a coactivator of both androgen receptor (AR and estrogen receptor (ER in ovarian cells. Further, overexpression of nuclear-localized p44 stimulates proliferation and invasion in ovarian cancer cells in the presence of estrogen or androgen. These findings strongly suggest that p44 plays a role in mediating the effects of hormones during ovarian tumorigenesis.

  16. Update in palliative management of hormone refractory cancer of prostate

    OpenAIRE

    Singh, Pratipal; Srivastava, Aneesh

    2007-01-01

    Hormone refractory prostate cancer (HRPC) is an incurable disease and as in the pressure sensitive adhesive era the median survival of patients is increasing, these men increasingly develop symptomatic problems as a result of advanced local and or metastatic disease during their progression to death. Recently, it has been shown that it is possible to improve survival in this group of patients with use of chemotherapy which reinforces the need of better options in palliative care. We discus th...

  17. PET Imaging of Steroid Receptor Expression in Breast and Prostate Cancer

    NARCIS (Netherlands)

    Hospers, G. A. P.; Helmond, F. A.; Dierckx, R. A.; de Vries, Emma; de Vries, Erik

    2008-01-01

    The vast majority of breast and prostate cancers express specific receptors for steroid hormones, which play a pivotal role in tumor progression. Because of the efficacy of endocrine therapy combined with its relatively mild side-effects, this intervention has nowadays become the treatment of choice

  18. Re-evaluation of the prolactin receptor expression in human breast cancer

    DEFF Research Database (Denmark)

    Galsgaard, Elisabeth Douglas; Rasmussen, Birgitte Bruun; Folkesson, Charlotta Grånäs;

    2009-01-01

    The pituitary hormone PRL is involved in tumorigenesis in rodents and humans. PRL promotes proliferation, survival and migration of cancer cells acting via the PRL receptor (PRLR). Aiming to perform a large-scale immunohistochemical (IHC) screening of human mammary carcinomas for PRLR expression,...

  19. Pentadecapeptide BPC 157 Enhances the Growth Hormone Receptor Expression in Tendon Fibroblasts

    Directory of Open Access Journals (Sweden)

    Chung-Hsun Chang

    2014-11-01

    Full Text Available BPC 157, a pentadecapeptide derived from human gastric juice, has been demonstrated to promote the healing of different tissues, including skin, muscle, bone, ligament and tendon in many animal studies. However, the underlying mechanism has not been fully clarified. The present study aimed to explore the effect of BPC 157 on tendon fibroblasts isolated from Achilles tendon of male Sprague-Dawley rat. From the result of cDNA microarray analysis, growth hormone receptor was revealed as one of the most abundantly up-regulated genes in tendon fibroblasts by BPC 157. BPC 157 dose- and time-dependently increased the expression of growth hormone receptor in tendon fibroblasts at both the mRNA and protein levels as measured by RT/real-time PCR and Western blot, respectively. The addition of growth hormone to BPC 157-treated tendon fibroblasts dose- and time-dependently increased the cell proliferation as determined by MTT assay and PCNA expression by RT/real-time PCR. Janus kinase 2, the downstream signal pathway of growth hormone receptor, was activated time-dependently by stimulating the BPC 157-treated tendon fibroblasts with growth hormone. In conclusion, the BPC 157-induced increase of growth hormone receptor in tendon fibroblasts may potentiate the proliferation-promoting effect of growth hormone and contribute to the healing of tendon.

  20. Molecular recognition of parathyroid hormone by its G protein-coupled receptor

    Energy Technology Data Exchange (ETDEWEB)

    Pioszak, Augen A.; Xu, H. Eric (Van Andel)

    2008-08-07

    Parathyroid hormone (PTH) is central to calcium homeostasis and bone maintenance in vertebrates, and as such it has been used for treating osteoporosis. It acts primarily by binding to its receptor, PTH1R, a member of the class B G protein-coupled receptor (GPCR) family that also includes receptors for glucagon, calcitonin, and other therapeutically important peptide hormones. Despite considerable interest and much research, determining the structure of the receptor-hormone complex has been hindered by difficulties in purifying the receptor and obtaining diffraction-quality crystals. Here, we present a method for expression and purification of the extracellular domain (ECD) of human PTH1R engineered as a maltose-binding protein (MBP) fusion that readily crystallizes. The 1.95-{angstrom} structure of PTH bound to the MBP-PTH1R-ECD fusion reveals that PTH docks as an amphipathic helix into a central hydrophobic groove formed by a three-layer {alpha}-{beta}-{beta}{alpha} fold of the PTH1R ECD, resembling a hot dog in a bun. Conservation in the ECD scaffold and the helical structure of peptide hormones emphasizes this hot dog model as a general mechanism of hormone recognition common to class B GPCRs. Our findings reveal critical insights into PTH actions and provide a rational template for drug design that targets this hormone signaling pathway.

  1. Somatostatin, somatostatin receptors, and pancreatic cancer.

    Science.gov (United States)

    Li, Min; Fisher, William E; Kim, Hee Joon; Wang, Xiaoping; Brunicardi, Charles F; Chen, Changyi; Yao, Qizhi

    2005-03-01

    Somatostatin may play an important role in the regulation of cancer growth including pancreatic cancer by interaction with somatostatin receptors (SSTRs) on the cell surface. Five SSTRs were cloned, and the function of these SSTRs is addressed in this review. SSTR-2, SSTR-5, and SSTR-1 are thought to play major roles in inhibiting pancreatic cancer growth both in vitro and in vivo. SSTR-3 may be involved in mediating apoptosis, but the role of SSTR-4 is not clear. In most pancreatic cancers, functional SSTRs are absent. Reintroduction of SSTR genes has been shown to inhibit pancreatic cancer growth in cell cultures and animal models. PMID:15706439

  2. Somatostatin, somatostatin receptors, and pancreatic cancer.

    Science.gov (United States)

    Li, Min; Fisher, William E; Kim, Hee Joon; Wang, Xiaoping; Brunicardi, Charles F; Chen, Changyi; Yao, Qizhi

    2005-03-01

    Somatostatin may play an important role in the regulation of cancer growth including pancreatic cancer by interaction with somatostatin receptors (SSTRs) on the cell surface. Five SSTRs were cloned, and the function of these SSTRs is addressed in this review. SSTR-2, SSTR-5, and SSTR-1 are thought to play major roles in inhibiting pancreatic cancer growth both in vitro and in vivo. SSTR-3 may be involved in mediating apoptosis, but the role of SSTR-4 is not clear. In most pancreatic cancers, functional SSTRs are absent. Reintroduction of SSTR genes has been shown to inhibit pancreatic cancer growth in cell cultures and animal models.

  3. Steroid hormone receptors in prostatic hyperplasia and prostatic carcinoma.

    Science.gov (United States)

    Khalid, B A; Nurshireen, A; Rashidah, M; Zainal, B Y; Roslan, B A; Mahamooth, Z

    1990-06-01

    One hundred and six prostatic tissue samples obtained from transurethral resection were analysed for androgen and estrogen receptors. In 62 of these, progesterone and glucocorticoid receptors were also assayed. Steroid receptors were assayed using single saturation dose 3H-labelled ligand assays. Ninety percent of the 97 prostatic hyperplasia tissues and six of the nine prostatic carcinoma tissues were positive for androgen receptors. Estrogen receptors were only present in 19% and 33% respectively. Progesterone receptors were present in 70% of the tissues, but glucocorticoid receptors were present in only 16% of prostatic hyperplasia and none in prostatic carcinoma. PMID:1725553

  4. Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease

    DEFF Research Database (Denmark)

    Brand, Oliver J; Barrett, Jeffrey C; Simmonds, Matthew J;

    2009-01-01

    Graves' disease (GD) is a common autoimmune disease (AID) that shares many of its susceptibility loci with other AIDs. The thyroid stimulating hormone receptor (TSHR) represents the primary autoantigen in GD, in which autoantibodies bind to the receptor and mimic its ligand, thyroid stimulating h...

  5. Steroid hormone synthetic pathways in prostate cancer.

    Science.gov (United States)

    Mostaghel, Elahe A

    2013-09-01

    While androgen deprivation therapy (ADT) remains the primary treatment for metastatic prostate cancer (PCa) since the seminal recognition of the disease as androgen-dependent by Huggins and Hodges in 1941, therapy is uniformly marked by progression to castration-resistant prostate cancer (CRPC) over a period of about 18 months, with an ensuing median survival of 1 to 2 years. Importantly, castration does not eliminate androgens from the prostate tumor microenvironment. Castration resistant tumors are characterized by elevated tumor androgens that are well within the range capable of activating the AR and AR-mediated gene expression, and by steroid enzyme alterations which may potentiate de novo androgen synthesis or utilization of circulating adrenal androgens. The dependence of CRPC on intratumoral androgen metabolism has been modeled in vitro and in vivo, and residual intratumoral androgens are implicated in nearly every mechanism by which AR-mediated signaling promotes castration-resistant disease. These observations suggest that tissue based alterations in steroid metabolism contribute to the development of CRPC and underscore these metabolic pathways as critical targets of therapy. Herein, we review the accumulated body of evidence which strongly supports intracrine (tumoral) androgen synthesis as an important mechanism underlying PCa progression. We first discuss the presence and significance of residual prostate tumor androgens in the progression of CRPC. We review the classical and non-classical pathways of androgen metabolism, and how dysregulated expression of these enzymes is likely to potentiate tumor androgen production in the progression to CRPC. Next we review the in vitro and in vivo data in human tumors, xenografts, and cell line models which demonstrate the capacity of prostate tumors to utilize cholesterol and adrenal androgens in the production of testosterone (T) and dihydrotestosterone (DHT), and briefly review the potential role of exogenous

  6. Estimation of hormone receptor status in fine-needle aspirates and paraffin-embedded sections from breast cancer using the novel rabbit monoclonal antibodies SP1 and SP2.

    Science.gov (United States)

    Cano, Guillerma; Milanezi, Fernanda; Leitão, Dina; Ricardo, Sara; Brito, Maria José; Schmitt, Fernando Carlos

    2003-10-01

    We describe a method of immunocytochemical assessment of estrogen receptor (ER) status on alcohol-fixed smears obtained by fine-needle aspiration (FNA) from breast cancer patients, using a commercially available rabbit monoclonal antibody anti-ER (SP1) without any antigen retrieval. A series of 40 aspirates were analyzed and the results of ER status were compared with the respective formalin-fixed tissue using the same procedure and with assessment by the classical method using the mouse monoclonal antibody 6F11 (anti-ER) with antigen retrieval on paraffin sections. Twenty-four out of the 40 cases examined were positive at least by two methods and 16 were negative for all three determinations. The results obtained in the ER immunocytochemical assay on aspirates and paraffin sections using the antibody SP1 and those obtained on paraffin sections using the antibody 6F11 were quite similar. In one case the material was insufficient to interpret the reaction in the cytological specimen and only one case, with focal positivity reaction on paraffin sections, was negative in the cytological specimen. The intensity of nuclei staining in cytological smears of breast cancer cells was stronger than that observed by traditional methods. We also assessed progesterone receptor (PR) status on 40 paraffin-sections from breast cancer patients, using a commercially available rabbit monoclonal antibody anti-PR (SP2), with the same characteristics described for anti-ER (SP1). The results were compared with assessment by the classic method with mouse monoclonal antibody 1A6 (PR) on paraffin sections and total agreement was observed. Of the 40 cases examined, 18 were positive and 22 were negative for the two determinations. We conclude that the application of the ER method on alcohol-fixed smears/paraffin sections with the rabbit monoclonal antibody SP1, and the PR method on paraffin sections with the rabbit monoclonal antibody SP2, provide several advantages, such as high sensitivity

  7. Toll-like Receptors and Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Shu eZhao

    2014-07-01

    Full Text Available Prostate cancer is the second leading cause of cancer-related death in men after lung cancer. Immune responses clearly play a critical role in the tumorigenesis and in the efficacy of radiation therapy and chemotherapy in prostate cancer; however, the underlying molecular mechanisms are still poorly understood. Toll-like receptors (TLRs are a well-known family of pattern recognition receptors that play a key role in host immune system. Recent studies demonstrate that there are links between TLRs and cancer; however, the function and biological importance of TLRs in prostate cancer seems complex. To elucidate the role of TLRs and innate immunity in prostate cancer might provide us with a better understanding of the molecular mechanisms of this disease. Moreover, utilizing the agonists or antagonists of TLRs might represent a promising new strategy against prostate cancer. In this review, we summarize recent advances on the studies of association between TLR signaling and prostate cancer, TLR polymorphisms and prostate cancer risk, and provide some insights about TLRs as potential targets for prostate cancer immunotherapy.

  8. Birth weight, breast cancer and the potential mediating hormonal environment.

    Directory of Open Access Journals (Sweden)

    Radek Bukowski

    Full Text Available BACKGROUND: Previous studies have shown that woman's risk of breast cancer in later life is associated with her infants birth weights. The objective of this study was to determine if this association is independent of breast cancer risk factors, mother's own birth weight and to evaluate association between infants birth weight and hormonal environment during pregnancy. Independent association would have implications for understanding the mechanism, but also for prediction and prevention of breast cancer. METHODS AND FINDINGS: Risk of breast cancer in relation to a first infant's birth weight, mother's own birth weight and breast cancer risk factors were evaluated in a prospective cohort of 410 women in the Framingham Study. Serum concentrations of estriol (E3, anti-estrogen alpha-fetoprotein (AFP, and pregnancy-associated plasma protein-A (PAPP-A were measured in 23,824 pregnant women from a separate prospective cohort, the FASTER trial. During follow-up (median, 14 years 31 women (7.6% were diagnosed with breast cancer. Women with large birth weight infants (in the top quintile had a higher breast cancer risk compared to other women (hazard ratio (HR, 2.5; 95% confidence interval (CI, 1.2-5.2; P = 0.012. The finding was not affected by adjustment for birth weight of the mother and traditional breast cancer risk factors (adjusted HR, 2.5; 95% CI, 1.2-5.6; P = 0.021. An infant's birth weight had a strong positive relationship with the mother's serum E3/AFP ratio and PAPP-A concentration during pregnancy. Adjustment for breast cancer risk factors did not have a material effect on these relationships. CONCLUSIONS: Giving birth to an infant with high birth weight was associated with increased breast cancer risk in later life, independently of mother's own birth weight and breast cancer risk factors and was also associated with a hormonal environment during pregnancy favoring future breast cancer development and progression.

  9. EFFICIENCY OF HORMONE THERAPY WITH LEIPRORELIN (LUCRIN DEPOT® IN PATIENTS WITH PROSTATE CANCER

    Directory of Open Access Journals (Sweden)

    B. Ya. Alekseev

    2014-07-01

    Full Text Available Prostate cancer (PC is one of the most common cancers. Hormone therapy (HT is the basic treatment for metastatic hormone-sensitive PC. HT with luteinizing-hormone-releasing hormone (LHRH analogues is considered to be an effective method for hormone exposure as monotherapy and in combination with other drugs. Lucrin depot® is a potent and safe LHRH analogue whose efficacy has been proven by a number of clinical trials. This drug may be recommended as monotherapy or in combination with other hormonal agents in patients with PC if there are indications for androgen deprivation.

  10. EFFICIENCY OF HORMONE THERAPY WITH LEIPRORELIN (LUCRIN DEPOT® IN PATIENTS WITH PROSTATE CANCER

    Directory of Open Access Journals (Sweden)

    B. Ya. Alekseev

    2011-01-01

    Full Text Available Prostate cancer (PC is one of the most common cancers. Hormone therapy (HT is the basic treatment for metastatic hormone-sensitive PC. HT with luteinizing-hormone-releasing hormone (LHRH analogues is considered to be an effective method for hormone exposure as monotherapy and in combination with other drugs. Lucrin depot® is a potent and safe LHRH analogue whose efficacy has been proven by a number of clinical trials. This drug may be recommended as monotherapy or in combination with other hormonal agents in patients with PC if there are indications for androgen deprivation.

  11. Expression of Obesity Hormone Leptin in Human Colorectal Cancer

    Institute of Scientific and Technical Information of China (English)

    Jin-chun Cong; Xian-wei Dai; Ming-yang Shen; Jun-jiang Wang; Chun-sheng Chen; Hong Zhang; Lei Qiao

    2009-01-01

    Objective: The obesity hormone, leptin, has been found to participate in the development and proliferation of normal and malignant tissues. The aim of this study was to evaluate the role of leptin in human colorectal cancer.Methods: Serum leptin levels were measured via ABC-ELLSA in 30 colorectal cancers and 24 normal controls. Leptin concentration in colorectal cancer was analyzed in terms of selected clinicopathological features and some oncogenes.Results: The mean concentration of leptin was significantly higher for colorectal cancers(3.54±1.46 ng/ml) than normal controls(2.27±0.99 ng/ml), no gender difference was observed in this study. Leptin expression in poorly differentiated tumors was obviously lower than those in moderately and well differentiated tumors. There were no statistically significant correlations between leptin and the serum CEA and CA199 in colorectal cancers (P>0.05), and between leptin and the expressions of K-RAS, P53, APC, DCC genes in tumor tissues (P>0.05).Conclusion: Leptin is overexpressed in human colorectal cancer, which is related to the differentiation degrees of the tumor. There is no correlation between leptin expression and chages of oncogenes in colorectal cancers.

  12. Characterization of the ligand-dependent transactivation domain of thyroid hormone receptor.

    OpenAIRE

    Barettino, D; Vivanco Ruiz, M M; Stunnenberg, H.G.

    1994-01-01

    Transcriptional activation by nuclear receptors is achieved through autonomous activation functions (AFs), a constitutive N-terminal AF-1 and a C-terminal, ligand-dependent AF-2 that comprises a motif conserved between nuclear receptors. We have performed an extensive mutational analysis of the putative AF-2 domain of chicken thyroid hormone receptor alpha (cT3R alpha). We show that the AF-2 region mediates transactivation as well as transcriptional interference (squelching), not only between...

  13. 性激素受体在胆囊癌中的表达研究%Expression of gonadal hormone receptors in gallbladder carcinoma

    Institute of Scientific and Technical Information of China (English)

    陈炯; 徐荣楠; 余建伟; 牛俊扬; 杨志伟; 王晓秋; 李巍松

    2001-01-01

    Objective To study the expression of sex hormone receptors in human gallbladder cancer.  Methods Using immunohistochemistry avidin biotin peroxidase complex(ABC) method, the expression of estrogen receptor (ER)、 progesterone receptor (PR) and androgen receptor (AR) was examined in paraffin embedded sections of gallbladder cancer in 106 cases and 61 benign controls. Results The positive expression rate of ER、 PR and AR in gallbladder cancer was 67%、57% and 44% respectively. The positive rates of sex hormone receptors had significant correlation with pathologic differentiation grade.  Conclusion There was significant correlations between sex hormones and the development of gallbladder cancer. Sex hormones might be implicated in the therapy of gallbladder cancer.%目的探讨性激素受体在胆囊癌中的表达。方法采用免疫组织化学Avidin Biotin Peroxidase Complex (ABC)方法对 106例胆囊癌和61例胆囊良性病变石蜡切片标本进行雌激素、孕激素及雄激素受体检测。结果胆囊癌中三种受体阳性率分别为67%、57%、44%。性激素受体阳性率与胆囊癌分化程度有密切关系。结论性激素与胆囊癌发展关系密切。内分泌治疗可能成为治疗胆囊癌的一种方法。

  14. ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer

    OpenAIRE

    Fizazi, Karim; Albiges, Laurence; Loriot, Yohann; Massard, Christophe

    2015-01-01

    Androgen deprivation therapy is the standard of care for patients with advanced hormone-sensitive prostate cancer. Despite an initial response, most patients progress to castration-resistant prostate cancer (CRPC). The realization that CRPC remains driven by androgen receptor (AR) signaling has formed the basis for a new generation of agents targeting the AR axis. Two of these agents, abiraterone acetate and enzalutamide, have been shown to prolong overall survival in patients with CRPC. Seve...

  15. Epidermal Growth Factor Receptor in Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Oliveira-Cunha, Melissa, E-mail: melissacunha@doctors.org.uk [Hepatobiliary Surgery Unit, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL (United Kingdom); Newman, William G. [Genetic Medicine, MAHSC, University of Manchester, St Mary' s Hospital, Oxford Road, Manchester, M13 9WL (United Kingdom); Siriwardena, Ajith K. [Hepatobiliary Surgery Unit, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL (United Kingdom)

    2011-03-24

    Pancreatic cancer is the fourth leading cause of cancer related death. The difficulty in detecting pancreatic cancer at an early stage, aggressiveness and the lack of effective therapy all contribute to the high mortality. Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein, which is expressed in normal human tissues. It is a member of the tyrosine kinase family of growth factors receptors and is encoded by proto-oncogenes. Several studies have demonstrated that EGFR is over-expressed in pancreatic cancer. Over-expression correlates with more advanced disease, poor survival and the presence of metastases. Therefore, inhibition of the EGFR signaling pathway is an attractive therapeutic target. Although several combinations of EGFR inhibitors with chemotherapy demonstrate inhibition of tumor-induced angiogenesis, tumor cell apoptosis and regression in xenograft models, these benefits remain to be confirmed. Multimodality treatment incorporating EGFR-inhibition is emerging as a novel strategy in the treatment of pancreatic cancer.

  16. The diversity of abnormal hormone receptors in adrenal Cushing's syndrome allows novel pharmacological therapies

    Directory of Open Access Journals (Sweden)

    Lacroix A.

    2000-01-01

    Full Text Available Recent studies from several groups have indicated that abnormal or ectopic expression and function of adrenal receptors for various hormones may regulate cortisol production in ACTH-independent hypercortisolism. Gastric inhibitory polypeptide (GIP-dependent Cushing's syndrome has been described in patients with either unilateral adenoma or bilateral macronodular adrenal hyperplasia; this syndrome results from the large adrenal overexpression of the GIP receptor without any activating mutation. We have conducted a systematic in vivo evaluation of patients with adrenal Cushing's syndrome in order to identify the presence of abnormal hormone receptors. In macronodular adrenal hyperplasia, we have identified, in addition to GIP-dependent Cushing's syndrome, other patients in whom cortisol production was regulated abnormally by vasopressin, ß-adrenergic receptor agonists, hCG/LH, or serotonin 5HT-4 receptor agonists. In patients with unilateral adrenal adenoma, the abnormal expression or function of GIP or vasopressin receptor has been found, but the presence of ectopic or abnormal hormone receptors appears to be less prevalent than in macronodular adrenal hyperplasia. The identification of the presence of an abnormal adrenal receptor offers the possibility of a new pharmacological approach to control hypercortisolism by suppressing the endogenous ligands or by using specific antagonists for the abnormal receptors.

  17. Hormone profiles in women treated for cervical cancer

    International Nuclear Information System (INIS)

    Some investigators believe that the protective effect of radiotherapy is hormonally mediated. To determine whether ovarian radiation affects serum hormone levels differently from surgical removal of the ovaries, serum estradiol, estrone, testosterone and androstenedione were evaluated by radioimmunoassay in 320 women (203 irradiated and 117 nonirradiated) from six US clinics participating in a large international cohort study of women treated for cervical cancer since the 1960's. Overall, estradiol levels were similar for both treatment groups, while estrone, testosterone and androstenedione levels were somewhat lower in irradiated women than in nonirradiated women after adjustment for year of birth. Notably, among women in both groups whose treatment included bilateral oophorectomy, irradiated women consistently had lower levels of androstenedione, testosterone and estrone but similar levels of estradiol

  18. Impaired hair growth and wound healing in mice lacking thyroid hormone receptors.

    Directory of Open Access Journals (Sweden)

    Constanza Contreras-Jurado

    Full Text Available Both clinical and experimental observations show that the skin is affected by the thyroidal status. In hypothyroid patients the epidermis is thin and alopecia is common, indicating that thyroidal status might influence not only skin proliferation but also hair growth. We demonstrate here that the thyroid hormone receptors (TRs mediate these effects of the thyroid hormones on the skin. Mice lacking TRα1 and TRβ (the main thyroid hormone binding isoforms display impaired hair cycling associated to a decrease in follicular hair cell proliferation. This was also observed in hypothyroid mice, indicating the important role of the hormone-bound receptors in hair growth. In contrast, the individual deletion of either TRα1 or TRβ did not impair hair cycling, revealing an overlapping or compensatory role of the receptors in follicular cell proliferation. In support of the role of the receptors in hair growth, TRα1/TRβ-deficient mice developed alopecia after serial depilation. These mice also presented a wound-healing defect, with retarded re-epithelialization and wound gaping, associated to impaired keratinocyte proliferation. These results reinforce the idea that the thyroid hormone nuclear receptors play an important role on skin homeostasis and suggest that they could be targets for the treatment of cutaneous pathologies.

  19. Behavioral Interventions to Enhance Adherence to Hormone Therapy in Breast Cancer Survivors: A Systematic Literature Review.

    Science.gov (United States)

    Hurtado-de-Mendoza, Alejandra; Cabling, Mark L; Lobo, Tania; Dash, Chiranjeev; Sheppard, Vanessa B

    2016-08-01

    Adjuvant hormone therapy contributes to reductions in recurrence and mortality for women with hormone receptor-positive breast cancer. However, adherence to hormone therapy is suboptimal. This is the first systematic literature review examining interventions aimed at improving hormone therapy adherence. Researchers followed the PRISMA guidelines. PubMed-Medline, CINAHL, PsychInfo, Ovid-Medline, and EMBASE were searched for behavioral interventions that aimed to enhance adherence to adjuvant hormone therapy in breast cancer survivors. A total of 376 articles were screened for eligibility. Five articles met the study criteria. All interventions presented adherence outcomes after 1-year follow-up. None significantly enhanced adherence compared to the usual care in the primary analysis (odds ratios ranged from 1.03 to 2.06 for adherence and from 1.11 to 1.18 for persistence). All studies targeted patients, and only 3 studies included postmenopausal breast cancer patients. Three tested the same intervention consisting of educational materials. Only one was conducted in the United States. Only one reported participants' ethnicity. Overall, it was unclear whether the studies contained bias. The use of different terminology and operationalization of adherence made comparisons challenging. Interventions to improve adherence to adjuvant hormone therapy in US breast cancer populations that include survivors who are ethnically diverse, premenopausal, and receiving tamoxifen therapy are necessary to inform future interventions. Adoption of consistent adherence definitions/measurements will provide a clearer framework to consolidate aggregate findings. Given the limited efficacy of tested interventions, it is important to engage oncologists and researchers to develop approaches that target different components associated with hormone therapy adherence, such as doctor-patient communication or social support. PMID:27133733

  20. Introduction of exogenous growth hormone receptors augments growth hormone-responsive insulin biosynthesis in rat insulinoma cells

    International Nuclear Information System (INIS)

    The stimulation of insulin biosynthesis in the pancreatic insulinoma cell line RIN5-AH by growth hormone (GH) is initiated by GH binding to specific receptors. To determine whether the recently cloned rat hepatic GH receptor is able to mediate the insulinotropic effect of GH, the authors have transfected a GH receptor cDNA under the transcriptional control of the human metallothionein promoter into RIN5-AH cells. The transfected cells were found to exhibit an increased expression of GH receptors and to contain a specific GH receptor mRNA that was not expressed in the parent cell line. The expression of GH receptors in one clone (1.24) selected for detailed analysis was increased 2.6-fold compared to untransfected cells. The increased GH receptor expression was accompanied by an increased responsiveness to GH. Thus, the maximal GH-stimulated increase of insulin biosynthesis was 4.1-fold in 1.24 cells compared to 1.9-fold in the nontransfected RIN5-AH cells. The expression of the transfected receptor was stimulated 1.6- and 2.3-fold when cells were cultured in the presence of 25 or 50 μM Zn2+ was associated with an increased magnitude of GH-stimulated insulin biosynthesis. A close stoichiometric relationship between the level of receptor expression and the level of GH-stimulated insulin biosynthesis was observed. They conclude from these results that the hepatic GH receptor is able to mediate the effect of GH on insulin biosynthesis in RIN5-AH cells

  1. Structural and functional divergence of growth hormone-releasing hormone receptors in early sarcopterygians: lungfish and Xenopus.

    Directory of Open Access Journals (Sweden)

    Janice K V Tam

    Full Text Available The evolutionary trajectories of growth hormone-releasing hormone (GHRH receptor remain enigmatic since the discovery of physiologically functional GHRH-GHRH receptor (GHRHR in non-mammalian vertebrates in 2007. Interestingly, subsequent studies have described the identification of a GHRHR(2 in chicken in addition to the GHRHR and the closely related paralogous receptor, PACAP-related peptide (PRP receptor (PRPR. In this article, we provide information, for the first time, on the GHRHR in sarcopterygian fish and amphibians by the cloning and characterization of GHRHRs from lungfish (P. dolloi and X. laevis. Sequence alignment and phylogenetic analyses demonstrated structural resemblance of lungfish GHRHR to their mammalian orthologs, while the X. laevis GHRHR showed the highest homology to GHRHR(2 in zebrafish and chicken. Functionally, lungfish GHRHR displayed high affinity towards GHRH in triggering intracellular cAMP and calcium accumulation, while X. laevis GHRHR(2 was able to react with both endogenous GHRH and PRP. Tissue distribution analyses showed that both lungfish GHRHR and X. laevis GHRHR(2 had the highest expression in brain, and interestingly, X. laevis(GHRHR2 also had high abundance in the reproductive organs. These findings, together with previous reports, suggest that early in the Sarcopterygii lineage, GHRHR and PRPR have already established diverged and specific affinities towards their cognate ligands. GHRHR(2, which has only been found in xenopus, zebrafish and chicken hitherto, accommodates both GHRH and PRP.

  2. Perspectives of breast cancer etiology: synergistic interaction between smoking and exogenous hormone use

    Institute of Scientific and Technical Information of China (English)

    Hong-Hong Zhu; Cao-Hui Hu; Paul Strickland

    2011-01-01

    To explore breast cancer etiology, literature was searched using Medline. We explored the (1)plausibility of smoking in breast carcinogenesis; (2) physiological properties, susceptibility windows, and exposure timing of breast cells; (3) role of exogenous hormones in breast carcinogenesis; (4) biological mechanism of synergistic interactions between smoking and exogenous hormones in breast carcinogenesis; and (5) evidence from epidemiologic studies and the fitted secular trend between smoking rate, exogenous hormone use, and breast cancer incidence in past decades. We deduced that exogenous hormone use per se is not a significant cause and its association with breast cancer is distorted by chronic exposure to environmental carcinogens, especially smoking. We hypothesize that smoking is one of the causes of breast cancer and that this causality is strengthened by synergistic interaction between smoking and exogenous hormone use. Physicians should be cautious of prescribing exogenous hormones for those with chronic exposure to environmental carcinogens to prevent breast cancer.

  3. The origins of estrogen receptor alpha-positive and estrogen receptor alpha-negative human breast cancer

    International Nuclear Information System (INIS)

    Current hormonal therapies have benefited millions of patients with breast cancer. Their success, however, is often temporary and limited to a subset of patients whose tumors express estrogen receptor alpha (ER). The therapies are entirely ineffective in ER-negative disease. Recent studies suggest that there are many biological pathways and alterations involved in determining whether ER is expressed and how it is regulated during breast cancer evolution. Improving hormonal therapies, in addition to perfecting current strategies, will also target these newly discovered pathways and alterations, and others yet to be found. The present commentary will briefly highlight a few important observations and unanswered questions regarding ER status and growth regulation during breast cancer evolution, which hopefully will help to stimulate new thinking and progress in this important area of medial research

  4. Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1

    OpenAIRE

    Xiao, Jingbo; Huang, Zaohua; Chen, Catherine Z.; Agoulnik, Irina U; Southall, Noel; Hu, Xin; Jones, Raisa E.; Ferrer, Marc; Zheng, Wei; Agoulnik, Alexander I.; Marugan, Juan J

    2013-01-01

    The anti-fibrotic, vasodilatory, and pro-angiogenic therapeutic properties of recombinant relaxin peptide hormone have been investigated in several diseases and recent clinical trial data has shown benefit in treating acute heart failure. However, the remodeling capacity of these peptide hormones is difficult to study in chronic settings due to their short half-life and the need for intravenous administration. Here we present the first small-molecule series of human relaxin receptor 1 (RXFP1)...

  5. The glucocorticoid receptor hormone binding domain mediates transcriptional activation in vitro in the absence of ligand.

    OpenAIRE

    Schmitt, J.; Stunnenberg, H G

    1993-01-01

    We show that recombinant rat glucocorticoid receptor (vvGR) expressed using vaccinia virus is indistinguishable from authentic GR with respect to DNA and hormone binding. In the absence of hormone, vvGR is mainly found in the cytoplasm in a complex with heat shock protein 90. Upon incubation with ligand, vvGR is released from this complex and translocated to the nucleus. Thus, the ligand binding domain displays the known biochemical properties. However, in vitro, transcription from a syntheti...

  6. The role of melanin-concentrating hormone and its receptors in energy homeostasis

    OpenAIRE

    DouglasJMacNeil

    2013-01-01

    Extensive studies in rodents with melanin-concentrating hormone (MCH) have demonstrated that the neuropeptide hormone is a potent orexigen. Acutely, MCH causes an increase in food intake, while chronically it leads to increased weight gain, primarily as an increase in fat mass. Multiple knockout mice models have confirmed the importance of MCH in modulating energy homeostasis. Animals lacking MCH, MCH-containing neurons, or the MCH receptor all are resistant to diet-induced obesity. These gen...

  7. G-protein-coupled receptor controls steroid hormone signaling in cell membrane

    OpenAIRE

    Wang, Di; Zhao, Wen-Li; Cai, Mei-Juan; Wang, Jin-Xing; Zhao, Xiao-Fan

    2015-01-01

    G-protein-coupled receptors (GPCRs) are involved in animal steroid hormone signaling, but their mechanism is unclear. In this research, we report that a GPCR called ErGPCR-2 controls steroid hormone 20-hydroxyecdysone (20E) signaling in the cell membrane of the lepidopteran insect Helicoverpa armigera. ErGPCR-2 was highly expressed during molting and metamorphosis. 20E, via ErGPCR-2, regulated rapid intracellular calcium increase, protein phosphorylation, gene transcription, and insect metamo...

  8. Muscarinic receptor signaling and colon cancer progression

    Institute of Scientific and Technical Information of China (English)

    Guofeng Xie; Jean-Pierre Raufman

    2016-01-01

    Due to the lack of effective treatments, advanced colorectal cancer (CRC) remains a leading cause of cancer death in the United States. Emerging evidence supports the observation that muscarinic receptor (MR) signaling plays a critical role in growth and progression of CRC. MR activation by acetylcholine and bile acids results in transactivation of epidermal growth factor receptors (EGFR) and post-EGFR signal transduction that enhances cell proliferation, migration, and invasion. Here, the authors review recent progress in understanding the molecular mechanisms underlying MR-mediated CRC progression and its therapeutic implications.

  9. Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1.

    Science.gov (United States)

    Xiao, Jingbo; Huang, Zaohua; Chen, Catherine Z; Agoulnik, Irina U; Southall, Noel; Hu, Xin; Jones, Raisa E; Ferrer, Marc; Zheng, Wei; Agoulnik, Alexander I; Marugan, Juan J

    2013-01-01

    The anti-fibrotic, vasodilatory and pro-angiogenic therapeutic properties of recombinant relaxin peptide hormone have been investigated in several diseases, and recent clinical trial data has shown benefit in treating acute heart failure. However, the remodelling capacity of these peptide hormones is difficult to study in chronic settings because of their short half-life and the need for intravenous administration. Here we present the first small-molecule series of human relaxin/insulin-like family peptide receptor 1 agonists. These molecules display similar efficacy as the natural hormone in several functional assays. Mutagenesis studies indicate that the small molecules activate relaxin receptor through an allosteric site. These compounds have excellent physical and in vivo pharmacokinetic properties to support further investigation of relaxin biology and animal efficacy studies of the therapeutic benefits of relaxin/insulin-like family peptide receptor 1 activation. PMID:23764525

  10. 卡培他滨维持治疗在激素受体阴性晚期乳腺癌中的临床观察%Clinical observation of Capecitabine maintenance treatment in hormone receptor-negative metastatic breast cancer

    Institute of Scientific and Technical Information of China (English)

    吴凡; 刘健

    2014-01-01

    目的:观察卡培他滨维持治疗激素受体阴性转移性乳腺癌的近期、远期疗效及不良反应方法:对一线化疗疾病获得控制的晚期转移性乳腺癌予卡培他滨单药维持化疗直至疾病进展结果:卡培他滨维持化疗总有效率(CR+PR)为10.5%,肿瘤控制率(CR+PR+SD)为52.6%。中位疾病进展时间(mTTP)为13.4个月。主要不良反应为白细胞减少、手足综合征及口腔黏膜炎结论:卡培他滨维持治疗在转移性乳腺癌中疗效肯定,不良反应可耐受。%Objective: To explore the efficacy and adverse reactions of capecitabine in the maintenance treatment of hormone receptor-negative metastatic breast cancer. methods: Metastatic breast cancer patients who gain control by first-line chemotherapy was treated by capecitabine monotherapy maintenance regiment until disease progression. Results: Total effective rate (CR + PR) was 10.5%, the tumor control rate (CR + PR + SD) was 52.6% and median time to progression (mTTP) was 13.4 months in metastatic breast cancer patients treated by capecitabine maintenance chemotherapy. The main adverse events were hand-foot syndrome, leukopenia and mucositis Conclusion: Capecitabine maintenance therapy has a definite curative effect in metastatic breast cancer, which adverse reactions can be tolerated.

  11. 甲状腺乳头状癌TRβ1表达及其意义%Expression of thyroid hormone receptor β1 in thyroid papillary cancer and its significance

    Institute of Scientific and Technical Information of China (English)

    彭旭升; 石怀银

    2012-01-01

    Objective To study the clinical significance of thyroid hormone receptor β 1(TRβ 1) expression in thyroid papillary carcinoma and its adjacent and proliferating tissue. Methods TR p 1 protein expression in tissues of thyroid papillary carcinoma patients(201 with thyroid papillary carcinoma and 25 with benign proliferating thyroid papillary carcinoma) was detected by S-P immunohistochemistry. Results The positive TR β 1 expression rate was significantly lower in thyroid papillary carcinoma than in its adjacent and proliferating tissue(12.4% vs 99.5% and 92.0%, P<0.01). Conclusion TR β 1 expression rate is significantly lower in thyroid papillary carcinoma than in its adjacent and proliferating tissue, and can thus be used as a molecular marker for the diagnosis of benign and malignant thyroid papillary structure.%目的 比较甲状腺激素受体(TR)β 1在甲状腺乳头状癌、癌旁以及乳头状增生组织的表达差异,明确其临床意义.方法 采用免疫组化SP法检测226例甲状腺组织中的TRβ 1蛋白表达,其中甲状腺乳头状癌201例,良性增生25例.结果 甲状腺乳头状癌的阳性表达率为12.4%(25/201),癌旁组织表达率为99.5%(199/201),腺乳头状增生组织阳性表达率为92.0%(23/25),两组差异有统计学意义(P<0.01).结论 TRβ 1在甲状腺乳头状癌中的表达显著低于癌旁和乳头状增生,可作为判断甲状腺乳头结构良恶性的分子标志.

  12. Exogenous hormones in the aetiology of cancer in women.

    Science.gov (United States)

    Vessey, M P

    1984-07-01

    Both animal experimental work and epidemiological, clinical, and laboratory research on the effects of endogenous hormones in the human have made it clear that some influence of administered female sex hormones on the risk of certain cancers would be anticipated, and this has turned out to be the case. This review focuses on the administration of hormones during pregnancy, around the time of the menopause, and to prevent pregnancy. In the daughters who were exposed in utero to stilbestrol during the 1950s and 1960s, the most important effect is the development of clear cell adenocarcinoma of the vagina or cervix. Few cases of this disease have been reported before puberty, but the cumulative risk thereafter up to the age of 24 years is estimated to be between 1.4 and 4/10,000 exposed. Much less attention has been paid to the mothers who actually took the stilbestrol than to their daughters, but the published data fail to provide any convincing evidence of an increased risk of either breast or reporductive cancer among them. Regarding the administration of hormones around the time of menopause, it is well established that unopposed estrogen therapy in menopausal women can cause endometrial cancer. This has been demonstrated in a large number of case control studies reported since 1975. Most of these studies were conducted in the US and most concern the drup Premarin (conjugated equine estrogens). Some cohort studies also have been reported, and they largely support the results of the case control studies. There is now little doubt that combined oral contraceptives (OCs) protect against both epithelial ovarian cancer and endometrial cancer. Preliminary findings in the major cohort studies concerned with the longterm effects of OC use also are encouraging. A series of large case control studies conducted during the 1970s showed clearly that there is no general association between oral contraceptive use and breast cancer risk, but these large studies included few women

  13. Interactions between intakes of alcohol and postmenopausal hormones on risk of breast cancer

    DEFF Research Database (Denmark)

    Nielsen, Naja Rod; Grønbaek, Morten

    2008-01-01

    Alcohol and postmenopausal hormone use are well-established modifiable risk factors for breast cancer. Alcohol may decrease the metabolic clearance of estradiol, whereby the risk of breast cancer associated with hormone use may depend on blood alcohol levels. The objective is to determine whether...... alcohol interacts with hormone use on risk of breast cancer. The 5,035 postmenopausal women who participated in the Copenhagen City Heart Study were asked about their alcohol intake and hormone use at baseline in 1981-1983 and were followed until 2002 in the Danish cancer registry, with ... to follow-up. Proportional hazard models were used to analyze data. During follow-up, 267 women developed breast cancer. Alcohol consumption was associated with a small increased risk of breast cancer (hazard ratio = 1.11 per drink/day, 95% CI: 0.99-1.25). Women who used hormones also had a higher risk...

  14. Vaccine Therapy and Pembrolizumab in Treating Patients With Hormone-Resistant, Metastatic Prostate Cancer

    Science.gov (United States)

    2016-06-22

    Hormone-Resistant Prostate Cancer; Metastatic Malignant Neoplasm in the Bone; Metastatic Malignant Neoplasm in the Soft Tissues; Metastatic Prostate Carcinoma; Prostate Adenocarcinoma; Recurrent Prostate Carcinoma; Stage IV Prostate Cancer

  15. EFFICIENCY OF HORMONE THERAPY WITH LEIPRORELIN (LUCRIN DEPOT®) IN PATIENTS WITH PROSTATE CANCER

    OpenAIRE

    B. Ya. Alekseev; Kaprin, A. D.; K. M. Nyushko

    2014-01-01

    Prostate cancer (PC) is one of the most common cancers. Hormone therapy (HT) is the basic treatment for metastatic hormone-sensitive PC. HT with luteinizing-hormone-releasing hormone (LHRH) analogues is considered to be an effective method for hormone exposure as monotherapy and in combination with other drugs. Lucrin depot® is a potent and safe LHRH analogue whose efficacy has been proven by a number of clinical trials. This drug may be recommended as monotherapy or in combination with other...

  16. Anti-Müllerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer.

    Science.gov (United States)

    Beck, Tim N; Korobeynikov, Vladislav A; Kudinov, Alexander E; Georgopoulos, Rachel; Solanki, Nehal R; Andrews-Hoke, Magda; Kistner, Timothy M; Pépin, David; Donahoe, Patricia K; Nicolas, Emmanuelle; Einarson, Margret B; Zhou, Yan; Boumber, Yanis; Proia, David A; Serebriiskii, Ilya G; Golemis, Erica A

    2016-07-19

    Anti-Müllerian hormone (AMH) and its type II receptor AMHR2, both previously thought to primarily function in gonadal tissue, were unexpectedly identified as potent regulators of transforming growth factor (TGF-β)/bone morphogenetic protein (BMP) signaling and epithelial-mesenchymal transition (EMT) in lung cancer. AMH is a TGF-β/BMP superfamily member, and AMHR2 heterodimerizes with type I receptors (ALK2, ALK3) also used by the type II receptor for BMP (BMPR2). AMH signaling regulates expression of BMPR2, ALK2, and ALK3, supports protein kinase B-nuclear factor κB (AKT-NF-κB) and SMAD survival signaling, and influences BMP-dependent signaling in non-small cell lung cancer (NSCLC). AMH and AMHR2 are selectively expressed in epithelial versus mesenchymal cells, and loss of AMH/AMHR2 induces EMT. Independent induction of EMT reduces expression of AMH and AMHR2. Importantly, EMT associated with depletion of AMH or AMHR2 results in chemoresistance but sensitizes cells to the heat shock protein 90 (HSP90) inhibitor ganetespib. Recognition of this AMH/AMHR2 axis helps to further elucidate TGF-β/BMP resistance-associated signaling and suggests new strategies for therapeutic targeting of EMT. PMID:27396341

  17. Anti-Müllerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Tim N. Beck

    2016-07-01

    Full Text Available Anti-Müllerian hormone (AMH and its type II receptor AMHR2, both previously thought to primarily function in gonadal tissue, were unexpectedly identified as potent regulators of transforming growth factor (TGF-β/bone morphogenetic protein (BMP signaling and epithelial-mesenchymal transition (EMT in lung cancer. AMH is a TGF-β/BMP superfamily member, and AMHR2 heterodimerizes with type I receptors (ALK2, ALK3 also used by the type II receptor for BMP (BMPR2. AMH signaling regulates expression of BMPR2, ALK2, and ALK3, supports protein kinase B-nuclear factor κB (AKT-NF-κB and SMAD survival signaling, and influences BMP-dependent signaling in non-small cell lung cancer (NSCLC. AMH and AMHR2 are selectively expressed in epithelial versus mesenchymal cells, and loss of AMH/AMHR2 induces EMT. Independent induction of EMT reduces expression of AMH and AMHR2. Importantly, EMT associated with depletion of AMH or AMHR2 results in chemoresistance but sensitizes cells to the heat shock protein 90 (HSP90 inhibitor ganetespib. Recognition of this AMH/AMHR2 axis helps to further elucidate TGF-β/BMP resistance-associated signaling and suggests new strategies for therapeutic targeting of EMT.

  18. Expression of growth hormone and its receptor in chronic atrophic gastritis and its clinical significance

    Institute of Scientific and Technical Information of China (English)

    Jian-Min Si; Qian Cao; Min Gao

    2004-01-01

    AIM: To investigate the growth hormone (GH) and growth hormone receptor (GHR) expression of and its clinical significance in patients with chronic atrophic gastritis (CAG).METHODS:A total of 90 cases were enrolled in the study.Thirty were healthy controls,the other 60 patients were divided into two groups according to the endoscopical and histological diagnosis.Blood samples were drawn in the morning (menarche did not occur during the blood extraction in female patients),gastric mucosa was obtained by endoscopy.Serum GH and gastrice mucosal GHR levels were measured using radioimmunoassay (RIA) and En Vinsion technique.RESULTS:The average GH level was 1.021±0.132μ/L in CAG patients,in controls it was 2.869 0.512μ/L.There was a significant difference between these two groups(P<0.01).The positive rate of GHR in CAG patients was 10%,in controls the rate was 100%.There was a significant difference (P<0.01).There was no significant change of GH level (3.176±0.421μ/L) in patients with gastric carcinoma compared with controls (P>0.05).CONCLUSION:The study shows that levels of GH and GHR expression are low in CAG patients.CAG pathogenesis has a correlation with mucosal nutrient deficiency,decreased levels of GH and GHR have an adverse effect on the repair and regeneration of CAG.There is no significant change of GH in gastric carcinorma patients,GH dose not play a role in the pathogenesis of gastric cancer.

  19. EVALUATION OF STEROID HORMONES AND THEIR RECEPTORS IN DEVELOPMENT AND PROGRESSION OF RENAL CELL CARCINOMA

    Directory of Open Access Journals (Sweden)

    Nigel Bennett

    2014-06-01

    Full Text Available Steroid hormones and their receptors have important roles in normal kidney biology, and alterations in their expression and function help explain the differences in development of kidney diseases, such as nephrotic syndrome and chronic kidney disease. The distinct gender difference in incidence of renal cell carcinoma (RCC, with males having almost twice the incidence as females globally, also suggests a role for sex hormones or their receptors in RCC development and progression. There was a peak in interest in evaluating the roles of androgen and estrogen receptors in RCC pathogenesis in the late 20th century, with some positive outcomes for RCC therapy that targeted estrogen receptors, especially for metastatic disease. Since that time, however, there have been few studies that look at use of steroid hormone modulators for RCC, especially in the light of new therapies such as the tyrosine kinase inhibitors and new immune therapies, which are having some success for treatment of metastatic RCC. This review summarises past and current literature and attempts to stimulate renewed interest in research into the steroid hormones and their receptors, which might be used to effect, for example, in combination with the other newer targeted therapies for RCC.

  20. Estrogen receptor isoforms and progestin hormone dependence in a mouse mammary tumor model.

    Science.gov (United States)

    Actis, A M; Caruso, S P; Levin, E

    1994-09-01

    The close interaction between receptors and other transcription factors suggests that their corresponding transducing signals can trigger functional and structural changes in other related molecules. The effect of a progestinic agent, medroxyprogesterone acetate (MPA), on some of the estrogen-receptor (ER) parameters was studied in 2 murine mammary tumor sublines with different progestin hormone dependence for their respective growth. The relative binding affinity of estradiol and tamoxifen for the ER, the receptor content and the ER isoforms studied by HPLC were determined in the hormone-autonomous (HA) and the hormone-dependent (HD) tumor sublines. In the HA subline administration of MPA did not modify the tumor growth rate, whereas this was accelerated in the HD subline. The ER content was clearly increased in the HD tumor subline, but not in the HA subline, compared with the untreated controls. In contrast, the E2 and tamoxifen relative binding affinity for the ER and the isoform profiles were affected by MPA treatment in the HA, but not in the HD tumor subline. The functional change (decrease in relative binding affinity) can be attributed to the appearance of a lower-molecular-size ER isoform under the progestinic treatment. Modifications in one receptor molecule by the action of ligands corresponding to another type of receptor show the interconection between transcription factors and the necessity of broadening conventional concepts regarding hormone dependence in mammary tumorigenesis. PMID:8077051

  1. Hormones

    Science.gov (United States)

    Hormones are your body's chemical messengers. They travel in your bloodstream to tissues or organs. They work ... glands, which are special groups of cells, make hormones. The major endocrine glands are the pituitary, pineal, ...

  2. Mathematically modelling and controlling prostate cancer under intermittent hormone therapy

    Institute of Scientific and Technical Information of China (English)

    Yoshito Hirata; Gouhei Tanaka; Nicholas Bruchovsky; Kazuyuki Aihara

    2012-01-01

    In this review,we summarize our recently developed mathematical models that predict the effects of intermittent androgen suppression therapy on prostate cancer (PCa).Although hormone therapy for PCa shows remarkable results at the beginning of treatment,cancer cells frequently acquire the ability to grow without androgens during long-term therapy,resulting in an eventual relapse.To circumvent hormone resistance,intermittent androgen suppression was investigated as an alternative treatment option.However,at the present time,it is not possible to select an optimal schedule of on- and off-treatment cycles for any given patient.In addition,clinical trials have revealed that intermittent androgen suppression is effective for some patients but not for others.To resolve these two problems,we have developed mathematical models for PCa under intermittent androgen suppression.The mathematical models not only explain the mechanisms of intermittent androgen suppression but also provide an optimal treatment schedule for the on- and off-treatment periods.

  3. Molecular analysis of the koala reproductive hormones and their receptors: gonadotrophin-releasing hormone (GnRH), follicle-stimulating hormone β and luteinising hormone β with localisation of GnRH.

    Science.gov (United States)

    Busby, E R; Soeta, S; Sherwood, N M; Johnston, S D

    2014-12-01

    During evolution, reproductive hormones and their receptors in the brain-pituitary-gonadal axis have been altered by genetic mechanisms. To understand how the neuroendocrine control of reproduction evolved in mammals, it is important to examine marsupials, the closest group to placental mammals. We hypothesised that at least some of the hormones and receptors found in placental mammals would be present in koala, a marsupial. We examined the expression of koala mRNA for the reproductive molecules. Koala cDNAs were cloned from brain for gonadotrophin-releasing hormones (GnRH1 and GnRH2) or from pituitary for GnRH receptors, types I and II, follicle-stimulating hormone (FSH)β and luteinising hormone (LH)β, and from gonads for FSH and LH receptors. Deduced proteins were compared by sequence alignment and phylogenetic analysis with those of other vertebrates. In conclusion, the koala expressed mRNA for these eight putative reproductive molecules, whereas at least one of these molecules is missing in some species in the amniote lineage, including humans. In addition, GnRH1 and 2 are shown by immunohistochemistry to be expressed as proteins in the brain.

  4. Menopausal hormone therapy in relation to breast cancer characteristics and prognosis: a cohort study

    OpenAIRE

    Rosenberg, Lena U; Granath, Fredrik; Dickman, Paul W.; Einarsdóttir, Kristjana; Wedrén, Sara; Persson, Ingemar; Hall, Per

    2008-01-01

    Introduction Menopausal hormone therapy has been reported to increase the risk of certain subtypes of breast cancer and to be associated with a favorable survival. These associations could either be due to an increased mammographic surveillance or to a biological effect. We assessed these associations in a Swedish cohort of postmenopausal breast cancer patients holding information on mammographic examinations, menopausal hormone therapy use, other breast cancer risk factors, and cancer treatm...

  5. Selectively targeting estrogen receptors for cancer treatment

    NARCIS (Netherlands)

    Shanle, Erin K.; Xu, Wei

    2010-01-01

    Estrogens regulate growth and development through the action of two distinct estrogen receptors (ERs), ER alpha and ER beta, which mediate proliferation and differentiation of cells. For decades, ER alpha mediated estrogen signaling has been therapeutically targeted to treat breast cancer, most nota

  6. Death receptors: Targets for cancer therapy

    Energy Technology Data Exchange (ETDEWEB)

    Mahmood, Zafar [Proteomics Laboratory, Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Lucknow 226001 (India); Shukla, Yogeshwer, E-mail: yogeshwer_shukla@hotmail.com [Proteomics Laboratory, Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Lucknow 226001 (India)

    2010-04-01

    Apoptosis is the cell's intrinsic program to death, which plays an important role in physiologic growth control and homeostasis. Apoptosis can be triggered by death receptors (DRs), without any adverse effects. DRs are the members of tumor necrosis factor (TNF) receptor superfamily, known to be involved in apoptosis signaling, independent of p53 tumor-supressor gene. Selective triggering of DR-mediated apoptosis in cancer cells is a novel approach in cancer therapy. So far, the best characterized DRs are CD95 (Fas/Apo1), TNF-related apoptosis-inducing ligand receptor (TRAILR) and tumor necrosis factor receptor (TNFR). Among these, TRAILR is emerging as most promising agent for cancer therapy, because it induces apoptosis in a variety of tumor and transformed cells without any toxicity to normal cells. TRAIL treatment in combination with chemotherapy or radiotherapy enhances TRAIL sensitivity or reverses TRAIL resistance by regulating downstream effectors. This review covers the current knowledge about the DRs, summarizes main signaling in DRs and also summarizes the preclinical approaches of these DRs in cancer therapy.

  7. Growth Hormone (GH1) Gene Variation, the Growth Hormone Receptor (GHR) Exon 3 Deletion Polymorphism in a West-African Population

    OpenAIRE

    Millar, David S.; Lewis, Mark D.; Horan, Martin; Newsway, Vicky; Rees, D Aled; Easter, Tammy E.; Pepe, Guglielmina; Rickards, Olga; Norin, Martin; Scanlon, Maurice F.; Krawczak, Michael; Cooper, David N.

    2008-01-01

    Growth Hormone (GH1) Gene Variation, the Growth Hormone Receptor (GHR) Exon 3 Deletion Polymorphism in a West-African Population UNITED KINGDOM (Millar, David S.) UNITED KINGDOM Received: 2008-05-29 Revised: 2008-08-21 Accepted: 2008-09-22

  8. Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial

    OpenAIRE

    James, Nicholas D.; Sydes, Matthew R.; Mason, Malcolm D; Clarke, Noel W; Anderson, John; Dearnaley, David P; Dwyer, John; Jovic, Gordana; Ritchie, Alastair WS; Russell, J Martin; Sanders, Karen; Thalmann, George N; Bertelli, Gianfilippo; Birtle, Alison J; O'Sullivan, Joe M

    2012-01-01

    Summary Background Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE—an international, open-label, randomised controlled trial—uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the...

  9. FGF receptor genes and breast cancer susceptibility

    DEFF Research Database (Denmark)

    Agarwal, D; Pineda, S; Michailidou, K;

    2014-01-01

    Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying...... genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium.Methods:Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry......, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.Results:Little evidence of association with breast cancer risk...

  10. Circulating sex hormones and breast cancer risk factors in postmenopausal women : reanalysis of 13 studies

    NARCIS (Netherlands)

    Key, T. J.; Appleby, P. N.; Reeves, G. K.; Roddam, A. W.; Helzlsouer, K. J.; Alberg, A. J.; Rollison, D. E.; Dorgan, J. F.; Brinton, L. A.; Overvad, K.; Kaaks, R.; Trichopoulou, A.; Clavel-Chapelon, F.; Panico, S.; Duell, E. J.; Peeters, P. H. M.; Rinaldi, S.; Riboli, E.; Fentiman, I. S.; Dowsett, M.; Manjer, J.; Lenner, P.; Hallmans, G.; Baglietto, L.; English, D. R.; Giles, G. G.; Hopper, J. L.; Severi, G.; Morris, H. A.; Koenig, K.; Zeleniuch-Jacquotte, A.; Arslan, A. A.; Toniolo, P.; Shore, R. E.; Krogh, V.; Micheli, A.; Berrino, F.; Muti, P.; Barrett-Connor, E.; Laughlin, G. A.; Kabuto, M.; Akiba, S.; Stevens, R. G.; Neriishi, K.; Land, C. E.; Cauley, J. A.; Lui, Li Yung; Cummings, Steven R.; Gunter, M. J.; Rohan, T. E.; Strickler, H. D.

    2011-01-01

    BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concen

  11. Enzymatic Regulation of Steroidogenesis and Nuclear Receptor Activation : Special Focus on Vitamin D and Sex Hormones

    OpenAIRE

    LUNDQVIST, JOHAN

    2011-01-01

    Enzyme-catalyzed reactions are important to regulate steroidogenesis and nuclear receptor activation. The present investigation examines the role of steroid metabolism catalyzed by CYP7B1 for regulation of hormone receptor activation and the effects of vitamin D on enzymatic regulation of steroidogenesis. The study reports data indicating that CYP7B1 can regulate estrogenic signaling by converting estrogens into inactive or less active metabolites. Similar results were obtained for CYP7B1-med...

  12. Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice

    OpenAIRE

    Mavalli, Mahendra D.; DiGirolamo, Douglas J.; Fan, Yong; Riddle, Ryan C.; Campbell, Kenneth S.; van Groen, Thomas; Frank, Stuart J.; Sperling, Mark A.; Esser, Karyn A; Bamman, Marcas M; Clemens, Thomas L.

    2010-01-01

    Skeletal muscle development, nutrient uptake, and nutrient utilization is largely coordinated by growth hormone (GH) and its downstream effectors, in particular, IGF-1. However, it is not clear which effects of GH on skeletal muscle are direct and which are secondary to GH-induced IGF-1 expression. Thus, we generated mice lacking either GH receptor (GHR) or IGF-1 receptor (IGF-1R) specifically in skeletal muscle. Both exhibited impaired skeletal muscle development characterized by reductions ...

  13. NHERF1 Regulates Parathyroid Hormone Receptor Desensitization: Interference with β-Arrestin BindingS⃞

    OpenAIRE

    Wang, Bin; Yang, Yanmei; Abou-Samra, Abdul B.; Friedman, Peter A.

    2009-01-01

    Type 1 parathyroid hormone receptor (PTH1R) activation, desensitization, internalization, and recycling proceed in a cyclical manner. The Na+/H+ exchange regulatory factor 1 (NHERF1) is a cytoplasmic adapter protein that regulates trafficking and signaling of several G protein-coupled receptors (GPCRs) including the PTH1R. The mineral ion wasting and bone phenotype of NHERF1-null mice suggests that PTH1R may interact with NHERF1. The objective of this study was to exam...

  14. A new mutation in the thyroid hormone receptor gene of a Chinese family with resistance to thyroid hormone

    Institute of Scientific and Technical Information of China (English)

    DONG Qian; GONG Chun-xiu; GU Yi; SU Chang

    2011-01-01

    Background Resistance to thyroid hormone (RTH) is a dominant inherited syndrome of reduced tissue responsiveness to thyroid hormone. It is usually due to mutations located at the ligand-binding domain and adjacent hinge region of the thyroid hormone receptor β(TRβ). We report the clinical and laboratory characteristics and the genetic analysis of a patient with this rare disorder and his family members.Methods The clinical presentations and changes of thyroid function tests (TFTs) including magnetic resonance imaging (MRI) of pituitary and other laboratory tests were analysed. TFTs of his family's members were detected as well. Direct DNA sequencing of the TRβ gene was done for those with abnormal TFTs.Results The RTH child had goiter, irritability, aggressiveness, and sudoresis. His TFTs showed high levels of circulating free thyroid hormones (FT4 and FT3) and normal thyroid-stimulating hormone (TSH) concentrations. He felt worse when treated as hyperthyroidism (Grave disease) with thiamazole and his clinical presentations got improved obviously when treated as RTH with bromocriptine without obvious advert effect. We identified a novel missense mutation, A317D, located in exon 9 of the gene of this boy and his mother. His mother had not any clinical presentation, but having abnormal TFTs results.Conclusions This patient reported here was concordant with the criteria of RTH. The feature is dysfunction of hypothalamus-pituitary-thyroid axis. A novel mutation was found in the TRβ, A317D, of this family. This research verified the phenomena that there is a clinical heterogeneity within the same mutation of different RTH patients.

  15. Growth hormone receptor expression and function in pituitary adenomas

    DEFF Research Database (Denmark)

    Clausen, Lene R; Kristiansen, Mikkel T; Rasmussen, Lars M;

    2004-01-01

    OBJECTIVE AND DESIGN: Hypopituitarism, in particular GH deficiency, is prevalent in patients with clinically nonfunctioning pituitary adenomas (NFPAs) both before and after surgery. The factors regulating the growth of pituitary adenomas in general and residual tumour tissue in particular are not...... transcription 5) phosphorylation was measured by Western blot analysis as an index of GHR signalling; cell proliferation was evaluated by [H3]-thymidine incorporation and glycoprotein hormone production analysed by radioimmunoassay (RIA). RESULTS: All adenomas investigated expressed the GHR, but there was no...... detection of STAT5 phosphorylation. Overall, GH and IGF-I administration did not significantly stimulate cell proliferation in vitro, although some individual adenomas exhibited a proliferative response to various extents. GH also did not significantly influence glycoprotein hormone secretion in vitro...

  16. Vitamin D and androgen receptor-targeted therapy for triple-negative breast cancer.

    Science.gov (United States)

    Thakkar, A; Wang, B; Picon-Ruiz, M; Buchwald, P; Ince, Tan A

    2016-05-01

    Anti-estrogen and anti-HER2 treatments have been among the first and most successful examples of targeted therapy for breast cancer (BC). However, the treatment of triple-negative BC (TNBC) that lack estrogen receptor expression or HER2 amplification remains a major challenge. We previously discovered that approximately two-thirds of TNBCs express vitamin D receptor (VDR) and/or androgen receptor (AR) and hypothesized that TNBCs co-expressing AR and VDR (HR2-av TNBC) could be treated by targeting both of these hormone receptors. To evaluate the feasibility of VDR/AR-targeted therapy in TNBC, we characterized 15 different BC lines and identified 2 HR2-av TNBC lines and examined the changes in their phenotype, viability, and proliferation after VDR and AR-targeted treatment. Treatment of BC cell lines with VDR or AR agonists inhibited cell viability in a receptor-dependent manner, and their combination appeared to inhibit cell viability additively. Moreover, cell viability was further decreased when AR/VDR agonist hormones were combined with chemotherapeutic drugs. The mechanisms of inhibition by AR/VDR agonist hormones included cell cycle arrest and apoptosis in TNBC cell lines. In addition, AR/VDR agonist hormones induced differentiation and inhibited cancer stem cells (CSCs) measured by reduction in tumorsphere formation efficiency, high aldehyde dehydrogenase activity, and CSC markers. Surprisingly, we found that AR antagonists inhibited proliferation of most BC cell lines in an AR-independent manner, raising questions regarding their mechanism of action. In summary, AR/VDR-targeted agonist hormone therapy can inhibit HR2-av TNBC through multiple mechanisms in a receptor-dependent manner and can be combined with chemotherapy. PMID:27120467

  17. Investigations on hormone dependency of human mammary carcinomas transplanted into nude mice

    DEFF Research Database (Denmark)

    Brünner, N; Spang-Thomsen, M

    1981-01-01

    Since human mammary cancer can be transplanted into nude mice, this makes possible the in vivo study of relations between hormone dependency and the steroid hormone receptor content of the tumors. The macroscopic growth curve of the transplanted tumors during endocrine therapy will reflect...... the hormone dependency. The results can be compared with successive steroid hormone receptor determinations in the tumor tissue....

  18. Human metastatic melanoma cell lines express high levels of growth hormone receptor and respond to GH treatment

    International Nuclear Information System (INIS)

    Highlights: •Most cancer types of the NCI60 have sub-sets of cell lines with high GHR expression. •GHR is highly expressed in melanoma cell lines. •GHR is elevated in advanced stage IV metastatic tumors vs. stage III. •GH treatment of metastatic melanoma cell lines alters growth and cell signaling. -- Abstract: Accumulating evidence implicates the growth hormone receptor (GHR) in carcinogenesis. While multiple studies show evidence for expression of growth hormone (GH) and GHR mRNA in human cancer tissue, there is a lack of quantification and only a few cancer types have been investigated. The National Cancer Institute’s NCI60 panel includes 60 cancer cell lines from nine types of human cancer: breast, CNS, colon, leukemia, melanoma, non-small cell lung, ovarian, prostate and renal. We utilized this panel to quantify expression of GHR, GH, prolactin receptor (PRLR) and prolactin (PRL) mRNA with real-time RT qPCR. Both GHR and PRLR show a broad range of expression within and among most cancer types. Strikingly, GHR expression is nearly 50-fold higher in melanoma than in the panel as a whole. Analysis of human metastatic melanoma biopsies confirmed GHR gene expression in melanoma tissue. In these human biopsies, the level of GHR mRNA is elevated in advanced stage IV tumor samples compared to stage III. Due to the novel finding of high GHR in melanoma, we examined the effect of GH treatment on three NCI60 melanoma lines (MDA-MB-435, UACC-62 and SK-MEL-5). GH increased proliferation in two out of three cell lines tested. Further analysis revealed GH-induced activation of STAT5 and mTOR in a cell line dependent manner. In conclusion, we have identified cell lines and cancer types that are ideal to study the role of GH and PRL in cancer, yet have been largely overlooked. Furthermore, we found that human metastatic melanoma tumors express GHR and cell lines possess active GHRs that can modulate multiple signaling pathways and alter cell proliferation. Based on

  19. Human metastatic melanoma cell lines express high levels of growth hormone receptor and respond to GH treatment

    Energy Technology Data Exchange (ETDEWEB)

    Sustarsic, Elahu G. [Edison Biotechnology Institute, 1 Watertower Drive, Athens, OH (United States); Department of Biological Sciences, Ohio University, Athens, OH (United States); Junnila, Riia K. [Edison Biotechnology Institute, 1 Watertower Drive, Athens, OH (United States); Kopchick, John J., E-mail: kopchick@ohio.edu [Edison Biotechnology Institute, 1 Watertower Drive, Athens, OH (United States); Department of Biological Sciences, Ohio University, Athens, OH (United States); Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH (United States)

    2013-11-08

    Highlights: •Most cancer types of the NCI60 have sub-sets of cell lines with high GHR expression. •GHR is highly expressed in melanoma cell lines. •GHR is elevated in advanced stage IV metastatic tumors vs. stage III. •GH treatment of metastatic melanoma cell lines alters growth and cell signaling. -- Abstract: Accumulating evidence implicates the growth hormone receptor (GHR) in carcinogenesis. While multiple studies show evidence for expression of growth hormone (GH) and GHR mRNA in human cancer tissue, there is a lack of quantification and only a few cancer types have been investigated. The National Cancer Institute’s NCI60 panel includes 60 cancer cell lines from nine types of human cancer: breast, CNS, colon, leukemia, melanoma, non-small cell lung, ovarian, prostate and renal. We utilized this panel to quantify expression of GHR, GH, prolactin receptor (PRLR) and prolactin (PRL) mRNA with real-time RT qPCR. Both GHR and PRLR show a broad range of expression within and among most cancer types. Strikingly, GHR expression is nearly 50-fold higher in melanoma than in the panel as a whole. Analysis of human metastatic melanoma biopsies confirmed GHR gene expression in melanoma tissue. In these human biopsies, the level of GHR mRNA is elevated in advanced stage IV tumor samples compared to stage III. Due to the novel finding of high GHR in melanoma, we examined the effect of GH treatment on three NCI60 melanoma lines (MDA-MB-435, UACC-62 and SK-MEL-5). GH increased proliferation in two out of three cell lines tested. Further analysis revealed GH-induced activation of STAT5 and mTOR in a cell line dependent manner. In conclusion, we have identified cell lines and cancer types that are ideal to study the role of GH and PRL in cancer, yet have been largely overlooked. Furthermore, we found that human metastatic melanoma tumors express GHR and cell lines possess active GHRs that can modulate multiple signaling pathways and alter cell proliferation. Based on

  20. A role for the androgen receptor in the treatment of male breast cancer.

    Science.gov (United States)

    Zhu, Jason; Davis, Carter T; Silberman, Sandra; Spector, Neil; Zhang, Tian

    2016-02-01

    Male breast cancer (BC) is relatively rare, making up less than 1% of all breast cancer cases in the United States. Treatment guidelines for male BC are derived from studies on the treatment of female BC, and are based molecular and clinical characteristics, such as hormone receptor positivity. For female estrogen receptor positive (ER+) breast cancers, the standard of care includes three classes of endocrine therapies: selective estrogen receptor modulators, aromatase inhibitors, and pure anti-estrogens. In contrast to female ER+ breast cancers, there is less known about the optimal treatment for male ER+ BC. Furthermore, in contrast to ER, less is known about the role of the androgen receptor (AR) in male and female BC. We report here the treatment of a 28-year-old man with metastatic AR+, ER+ breast cancer otherwise refractory to chemotherapy, who has had a durable clinical response to hormonal suppression with the combination of aromatase inhibition (Letrozole) in conjunction with a GnRH agonist (Leuprolide).

  1. Desensitization, trafficking and resensitization of the pituitary thyrotropin-releasing hormone receptor

    Directory of Open Access Journals (Sweden)

    Patricia M Hinkle

    2012-12-01

    Full Text Available The pituitary receptor for thyrotropin-releasing hormone (TRH is a calcium-mobilizing G protein-coupled receptor (GPCR that signals through Gq/11, elevating calcium and activating protein kinase C. TRH receptor signaling is quickly desensitized as a consequence of receptor phosphorylation, arrestin binding and internalization. Following activation, TRH receptors are phosphorylated at multiple Ser/Thr residues in the cytoplasmic tail. Phosphorylation catalyzed by GPCR kinase 2 (GRK2 takes place rapidly, reaching a maximum within seconds. Arrestins bind to two phosphorylated regions, but only arrestin bound to the proximal region causes desensitization and internalization. Phosphorylation at Thr365 is critical for these responses. TRH receptors internalize in clathrin-coated vesicles with bound arrestin. Following endocytosis, vesicles containing phosphorylated TRH receptors soon merge with rab5-positive vesicles. Over approximately 20 minutes these form larger endosomes rich in rab4 and rab5, early sorting endosomes. After TRH is removed from the medium, dephosphorylated receptors start to accumulate in rab4-positive, rab5-negative recycling endosomes. The mechanisms responsible for sorting dephosphorylated receptors to recycling endosomes are unknown. TRH receptors from internal pools help repopulate the plasma membrane. Dephosphorylation of TRH receptors begins when TRH is removed from the medium regardless of receptor localization, although dephosphorylation is fastest when the receptor is on the plasma membrane. Protein phosphatase 1 is involved in dephosphorylation but the details of how the enzyme is targeted to the receptor remain obscure. It is likely that future studies will identify biased ligands for the TRH receptor, novel arrestin-dependent signaling pathways, mechanisms responsible for targeting kinases and phosphatases to the receptor, and principles governing receptor trafficking.

  2. Liver expression of steroid hormones and Apolipoprotein D receptors in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    FJ Vizoso; L Rodrigo; M Rodriguez; A Altadill; ML González-Diéguez; A Linares; LO González; S Junquera; F Fresno-Forcelledo; MD Corte

    2007-01-01

    AIM: To evaluate the tissular expression of Androgen (A), Estrogen (E) and Progesterone (Pg) receptors, and Apolipoprotein D (ApoD), in liver tumors from resected hepatocellular carcinoma (HCC) cases in order to assess their possible relationship to prognosis.METHODS We performed an immunohistochemical study using tissue microarrays (containing more than 260 cancer specimens, from 31 HCC patients and controls)to determine the presence of specific antibodies against AR, ER, PgR and ApoD, correlating their findings with several clinico-pathological and biological variables. The staining results were categorized using a semi-quantitive score based on their intensity, and the percentage of immunostained cells was measured.RESULTS: A total of 21 liver tumors (67.7%) were positive for AR; 16 (51.6%) for ER; 26 (83.9%) for PgR and 12 (38.7%) stained for ApoD. We have found a wide variability in the immunostaining score values for each protein, with a median (range) of 11.5 (11.5-229.5) for AR; 11.1 (8.5-65) for ER; 14.2 (4-61) for PgR; and 37.7 (13.8-81.1) for ApoD. A history of heavy ethanol consumption, correlated positively with AR and PgR and negatively with ER status. HCV chronic infection also correlated positively with AR and PgR status. However,the presence of ApoD immunostaining did not correlate with any of these variables. Tumors with a positive immuno-staining for PgR showed a better prognosis.CONCLUSION: Our results indicate a moderate clinical value of the steroid receptor status in HCC, emphasizing the need to perform further studies in order to evaluate the possible role of new hormonal-based therapies.

  3. Luteinizing hormone-releasing hormone targeted poly(methyl vinyl ether maleic acid) nanoparticles for doxorubicin delivery to MCF-7 breast cancer cells.

    Science.gov (United States)

    Varshosaz, Jaleh; Jahanian-Najafabadi, Ali; Ghazzavi, Jila

    2016-08-01

    The purpose of this study was to design a targeted anti-cancer drug delivery system for breast cancer. Therefore, doxorubicin (DOX) loaded poly(methyl vinyl ether maleic acid) nanoparticles (NPs) were prepared by ionic cross-linking method using Zn(2+) ions. To optimise the effect of DOX/polymer ratio, Zn/polymer ratio, and stirrer rate a full factorial design was used and their effects on particle size, zeta potential, loading efficiency (LE, %), and release efficiency in 72 h (RE72, %) were studied. Targeted NPs were prepared by chemical coating of tiptorelin/polyallylamin conjugate on the surface of NPs by using 1-ethyl-3-(3-dimethylaminopropyl) carboiimid HCl as cross-linking agent. Conjugation efficiency was measured by Bradford assay. Conjugated triptorelin and targeted NPs were studied by Fourier-transform infrared spectroscopy (FTIR). The cytotoxicity of DOX loaded in targeted NPs and non-targeted ones were studied on MCF-7 cells which overexpress luteinizing hormone-releasing hormone (LHRH) receptors and SKOV3 cells as negative LHRH receptors using Thiazolyl blue tetrazolium bromide assay. The best results obtained from NPs prepared by DOX/polymer ratio of 5%, Zn/polymer ratio of 50%, and stirrer rate of 960 rpm. FTIR spectrum confirmed successful conjugation of triptorelin to NPs. The conjugation efficiency was about 70%. The targeted NPs showed significantly less IC50 for MCF-7 cells compared to free DOX and non-targeted NPs. PMID:27463791

  4. Model of the complex of Parathyroid hormone-2 receptor and Tuberoinfundibular peptide of 39 residues

    Directory of Open Access Journals (Sweden)

    Persson Bengt

    2010-10-01

    Full Text Available Abstract Background We aim to propose interactions between the parathyroid hormone-2 receptor (PTH2R and its ligand the tuberoinfundibular peptide of 39 residues (TIP39 by constructing a homology model of their complex. The two related peptides parathyroid hormone (PTH and parathyroid hormone related protein (PTHrP are compared with the complex to examine their interactions. Findings In the model, the hydrophobic N-terminus of TIP39 is buried in a hydrophobic part of the central cavity between helices 3 and 7. Comparison of the peptide sequences indicates that the main discriminator between the agonistic peptides TIP39 and PTH and the inactive PTHrP is a tryptophan-phenylalanine replacement. The model indicates that the smaller phenylalanine in PTHrP does not completely occupy the binding site of the larger tryptophan residue in the other peptides. As only TIP39 causes internalisation of the receptor and the primary difference being an aspartic acid in position 7 of TIP39 that interacts with histidine 396 in the receptor, versus isoleucine/histidine residues in the related hormones, this might be a trigger interaction for the events that cause internalisation. Conclusions A model is constructed for the complex and a trigger interaction for full agonistic activation between aspartic acid 7 of TIP39 and histidine 396 in the receptor is proposed.

  5. Domains of the growth hormone receptor required for association and activation of JAK2 tyrosine kinase

    DEFF Research Database (Denmark)

    VanderKuur, J A; Wang, X; Zhang, L;

    1994-01-01

    Growth hormone (GH) has recently been shown to activate the GH receptor (GHR)-associated tyrosine kinase JAK2. In the present study, regions of the GHR required for JAK2 association with GHR were identified. GH-dependent JAK2 association with GHR was detected in Chinese hamster ovary (CHO) cells ...

  6. Growth Hormone Receptor Signaling Pathways and its Negative Regulation by SOCS2

    DEFF Research Database (Denmark)

    Fernández Pérez, Leandro; Flores-Morales, Amilcar; Guerra, Borja;

    Growth hormone (GH) is a critical regulator of linear body growth during childhood but continues to have important metabolic actions throughout life. The GH receptor (GHR) is ubiquitously expressed, and deficiency of GHR signaling causes a dramatic impact on normal physiology during somatic devel...

  7. Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: The Danish Breast Cancer Cooperative Group

    DEFF Research Database (Denmark)

    Kyndi, M.; Sorensen, F.B.; Overgaard, M.;

    2008-01-01

    present analysis included 1,000 of the 3,083 high-risk breast cancer patients randomly assigned to PMRT in the Danish Breast Cancer Cooperative Group (DBCG) protocol 82 trials b and c. Tissue microarray sections were stained for ER, PgR, and HER-2. Median follow-up time for patients alive was 17 years......+/HER-2+, Rec-/HER-2- (triple negative), and Rec-/HER-2+. Results A significantly improved overall survival after PMRT was seen only among patients characterized by good prognostic markers such as hormonal receptor-positive and HER-2- patients (including the two Rec+ subtypes). No significant overall...

  8. Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group

    DEFF Research Database (Denmark)

    Kyndi, Marianne; Sørensen, Flemming B; Knudsen, Helle;

    2008-01-01

    present analysis included 1,000 of the 3,083 high-risk breast cancer patients randomly assigned to PMRT in the Danish Breast Cancer Cooperative Group (DBCG) protocol 82 trials b and c. Tissue microarray sections were stained for ER, PgR, and HER-2. Median follow-up time for patients alive was 17 years......+/HER-2+, Rec-/HER-2-(triple negative), and Rec-/HER-2+. RESULTS: A significantly improved overall survival after PMRT was seen only among patients characterized by good prognostic markers such as hormonal receptor-positive and HER-2- patients (including the two Rec+ subtypes). No significant overall...

  9. Arsenic impacted the development, thyroid hormone and gene transcription of thyroid hormone receptors in bighead carp larvae (Hypophthalmichthys nobilis).

    Science.gov (United States)

    Sun, Hong-Jie; Xiang, Ping; Tang, Ming-Hu; Sun, Li; Ma, Lena Q

    2016-02-13

    Arsenic (As) contamination in aquatic environment adversely impacts aquatic organisms. The present study assessed the toxicity of different As species and concentrations on bighead carp (Hypophthalmichthys nobilis) at early life stage, a major fish in Yangtze River, China. We measured the changes in embryo and larvae survival rate, larvae aberration, concentrations of thyroid hormone thyroxine, and transcription levels of thyroid hormone receptors (TRs) in fish larvae after exposing to arsenite (AsIII) or arsenate (AsV) at 0, 10, 30, 50, 100, or 150 μg L(-1) for 78 h. As concentrations ≤ 150 μg L(-1) had limited effect on embryo survival rate (6-8% inhibition), but larvae survival rate decreased to 53-57% and larvae aberration rate increased to 20-24% after As exposure. Moreover, thyroxine levels elevated by 23% and 50% at 100 μg L(-1) AsIII and 150 μg L(-1) AsV. Besides, AsIII and AsV decreased the transcriptional levels of TRα by 72 and 53%, and TRβ by 91 and 81% at 150 μg L(-1) As. Our data showed that AsIII and AsV had limited effect on carp embryo survival, but they were both toxic to carp larvae, with AsIII showing more effect than AsV. As concentrations bighead carp larvae and disturbed their thyroid hormone homeostasis. PMID:26513566

  10. Expression of thyroid stimulating hormone receptor in differentiated thyroid carcinoma and its clinical significance

    Institute of Scientific and Technical Information of China (English)

    李清怀

    2013-01-01

    Objective To explore the expression of thyroid stimulating hormone (TSH) receptor in differentiated thyroid carcinoma and its clinical significance.Methods Seventy-four patients with differentiated thyroid carcinoma treated in our department from January 2009 to January 2011were selected as the observation group,and 28 patients with nodular goiter were selected as the control group.Expression of TSH receptor in the two groups were detected by immunohistochemistry.Results The positive rate of TSH receptor expression in the observation group was55.4 (41/74) ,significantly lower than that of the control

  11. Allosteric receptor activation by the plant peptide hormone phytosulfokine.

    Science.gov (United States)

    Wang, Jizong; Li, Hongju; Han, Zhifu; Zhang, Heqiao; Wang, Tong; Lin, Guangzhong; Chang, Junbiao; Yang, Weicai; Chai, Jijie

    2015-09-10

    Phytosulfokine (PSK) is a disulfated pentapeptide that has a ubiquitous role in plant growth and development. PSK is perceived by its receptor PSKR, a leucine-rich repeat receptor kinase (LRR-RK). The mechanisms underlying the recognition of PSK, the activation of PSKR and the identity of the components downstream of the initial binding remain elusive. Here we report the crystal structures of the extracellular LRR domain of PSKR in free, PSK- and co-receptor-bound forms. The structures reveal that PSK interacts mainly with a β-strand from the island domain of PSKR, forming an anti-β-sheet. The two sulfate moieties of PSK interact directly with PSKR, sensitizing PSKR recognition of PSK. Supported by biochemical, structural and genetic evidence, PSK binding enhances PSKR heterodimerization with the somatic embryogenesis receptor-like kinases (SERKs). However, PSK is not directly involved in PSKR-SERK interaction but stabilizes PSKR island domain for recruitment of a SERK. Our data reveal the structural basis for PSKR recognition of PSK and allosteric activation of PSKR by PSK, opening up new avenues for the design of PSKR-specific small molecules. PMID:26308901

  12. Hormone Receptor Expression Analyses in Neoplastic and Non-Neoplastic Canine Mammary Tissue by a Bead Based Multiplex Branched DNA Assay: A Gene Expression Study in Fresh Frozen and Formalin-Fixed, Paraffin-Embedded Samples.

    Science.gov (United States)

    Mohr, Annika; Lüder Ripoli, Florenza; Hammer, Susanne Conradine; Willenbrock, Saskia; Hewicker-Trautwein, Marion; Kiełbowicz, Zdzisław; Murua Escobar, Hugo; Nolte, Ingo

    2016-01-01

    Immunohistochemistry (IHC) is currently considered the method of choice for steroid hormone receptor status evaluation in human breast cancer and, therefore, it is commonly utilized for assessing canine mammary tumors. In case of low hormone receptor expression, IHC is limited and thus is complemented by molecular analyses. In the present study, a multiplex bDNA assay was evaluated as a method for hormone receptor gene expression detection in canine mammary tissues. Estrogen receptor (ESR1), progesterone receptor (PGR), prolactin receptor (PRLR) and growth hormone receptor (GHR) gene expressions were evaluated in neoplastic and non-neoplastic canine mammary tissues. A set of 119 fresh frozen and 180 formalin-fixed, paraffin-embedded (FFPE) was comparatively analyzed and used for assay evaluation. Furthermore, a possible association between the hormone receptor expression in different histological subtypes of canine malignant mammary tumors and the castration status, breed and invasive growth of the tumor were analyzed. The multiplex bDNA assay proved to be more sensitive for fresh frozen specimens. Hormone receptor expression found was significantly decreased in malignant mammary tumors in comparison to non-neoplastic tissue and benign mammary tumors. Among the histological subtypes the lowest gene expression levels of ESR1, PGR and PRLR were found in solid, anaplastic and ductal carcinomas. In summary, the evaluation showed that the measurement of hormone receptors with the multiplex bDNA assay represents a practicable method for obtaining detailed quantitative information about gene expression in canine mammary tissue for future studies. Still, comparison with IHC or quantitative real-time PCR is needed for further validation of the present method. PMID:27649560

  13. Epidermal dexamethasone receptors in dogs with confirmed hyperadrenocorticalism, hypothyroidism or undiagnosed hormonal alopecia.

    Science.gov (United States)

    van den Broek, A H; Stafford, W L

    1991-11-01

    Low capacity, high affinity [3H] dexamethasone binding receptors were identified in cytosolic preparations of the skin (mean number 42.0 +/- 25.2 fmol mg-1 protein, apparent dissociation constant (1 nM +/- 0.23) of clinically normal dogs. No [3H] dexamethasone binding was observed in the skin of nine out of 10 dogs with confirmed spontaneous hyperadrenocorticism or in the skin of three out of six dogs with undiagnosed hormonal alopecia. A reduction was detected in the number of [3H] dexamethasone binding receptors in the skin of one dog with confirmed hypothyroidism. This study provides evidence for the susceptibility of canine glucocorticoid receptors to down regulation by imbalances of endogenous hormones, particularly increased glucocorticoid concentrations. PMID:1780592

  14. Changes in parathyroid hormone receptor binding affinity during egg laying: implications for calcium homeostasis in chicken.

    Science.gov (United States)

    Yasuoka, T; Kawashima, M; Takahashi, T; Iwata, A; Oka, N; Tanaka, K

    1996-12-01

    Parathyroid hormone (PTH) receptor bindings were examined in the membrane fraction of the calvaria and the kidney of the hen by the use of [125I]PTH-related protein (PTHrP) binding assays. The binding specificity, reversibility, and saturation of the receptor were demonstrated. The equilibrium dissociation constant (Kd) and the maximum binding capacity (Bmax) were obtained by Scatchard analyses. In both calvaria and kidney, Kd and Bmax values decreased at 3 h before oviposition in egg-laying hens, but not in nonlaying hens. Administration of 17 beta-estradiol or progesterone in vivo caused a decrease in the Kd and Bmax values. Ionized calcium concentrations in the blood plasma showed a decrease at 13 h before oviposition. The results suggest that the PTH receptor binding in the calvaria and the kidney is affected by ovarian steroid hormones and may play a role in maintaining the calcium homeostasis in the egg-laying hen. PMID:8970893

  15. Targeting the Diuretic Hormone Receptor to Control the Cotton Leafworm, Spodoptera littoralis

    Science.gov (United States)

    Apone, Fabio; Ruggiero, Alessandra; Tortora, Assunta; Tito, Annalisa; Grimaldi, Maria Rosaria; Arciello, Stefania; Andrenacci, Davide; Lelio, Ilaria Di; Colucci, Gabriella

    2014-01-01

    The cotton leafworm, Spodoptera littoralis Boisduval (Lepidoptera: Noctuidae), is one of the most devastating pests of crops worldwide. Several types of treatments have been used against this pest, but many of them failed because of the rapid development of genetic resistance in the different insect populations. G protein coupled receptors have vital functions in most organisms, including insects; thus, they are appealing targets for species-specific pest control strategies. Among the insect G protein coupled receptors, the diuretic hormone receptors have several key roles in development and metabolism, but their importance in vivo and their potential role as targets of novel pest control strategies are largely unexplored. With the goal of using DHR genes as targets to control S. littoralis, we cloned a corticotropin-releasing factor-like binding receptor in this species and expressed the corresponding dsRNA in tobacco plants to knock down the receptor activity in vivo through RNA interference. We also expressed the receptor in mammalian cells to study its signaling pathways. The results indicate that this diuretic hormone receptor gene has vital roles in S. littoralis and represents an excellent molecular target to protect agriculturallyimportant plants from this pest. PMID:25368043

  16. Sex steroid induced apoptosis as a rational strategy to treat anti-hormone resistant breast and prostate cancer.

    Science.gov (United States)

    Jordan, V Craig; Fan, Ping; Abderrahman, Balkees; Maximov, Philipp Y; Hawsawi, Yousef M; Bhattacharya, Poulomi; Pokharel, Niranjana

    2016-05-01

    The combined incidence and the extended disease course of breast and prostate cancer is a major challenge for health care systems. The solution for society requires an economically viable treatment strategy to maintain individuals disease free and productive, so as to avoid the fracture of the family unit. Forty years ago, translational research using the antiestrogen tamoxifen was targeted to estrogen receptor (ER) positive micrometastatic tumor cells and established the long-term antihormone adjuvant treatment strategy used universally today. The antihormone strategy was the accepted structure of cancer biology. Sex steroid deprivation therapy remains the orthodox strategy for the treatment of both breast and prostate cancer. Despite major initial therapeutic success, the strategies of long term anti-hormone therapies with either tamoxifen or aromatase inhibitors (AI) or antiandrogens or abiraterone for breast and prostate cancer, respectively, eventually lead to a significant proportion of anti-hormone resistant or stimulated tumor growth. Remarkably, a general principle of anti-hormone resistance has emerged for both breast and prostate cancer based primarily on clinical and supportive laboratory data. Paradoxically, anti-hormone resistant cell populations emerge and grow but are vulnerable to the cytotoxicity of estrogen or androgen-induced apoptosis for both breast and prostate cancer, respectively. These consistent anticancer actions of sex steroids appear to recapitulate the more complex mechanism of bone remodeling in elderly men and women during sex steroid deprivation. Estrogen is the key hormone in both sexes because in men androgen is first converted to estrogen. Estrogen regulates and triggers apoptosis in osteoclasts that develop during estrogen deprivation and destroy bone to cause osteoporosis. Sex steroid deprived breast and prostate cancer has recruited a streamlined natural apoptotic program from the human genome, but this is suppressed in the

  17. A case–control study of reproductive factors, female hormone use, and risk of pancreatic cancer

    OpenAIRE

    Zhang, Yuqing; Coogan, Patricia F.; Palmer, Julie R; Strom, Brian L.; Rosenberg, Lynn

    2009-01-01

    Findings from several previous studies that have assessed the relation of reproductive factors and female hormone use to the risk of pancreatic cancer are inconclusive. The authors examined the association between reproductive factors and the use of oral contraceptives and postmenopausal hormone therapy to the risk of pancreatic cancer among 284 patients with pancreatic cancer and 1,096 controls using data from the hospital-based Case–Control Surveillance Study. Older age at first pregnancy a...

  18. High parity and hormonal contraception use as risk factors for cervical cancer in East Kalimantan

    Directory of Open Access Journals (Sweden)

    Swandari Paramita

    2010-11-01

    Full Text Available Aim: To find risk factors associated with cervical cancer.Methods: This a case-control study conducted in A.W. Sjahranie County General Hospital at Samarinda East Kalimantan from January until July 2009. There were 58 patients for each case and control group. Variables in this study were age, menarche, menopause, age of first marriage, parity, spouse’s smoking status, hormonal contraception use, type of hormonal contraception, duration of hormonal contraception, IUD (intra uterine device contraception use and duration of IUD contraception.Results: final data analysis shows that parity and duration of hormonal contraception use increased the risk of cervical cancer. Women who had 5-12 children than 0-4 children had 2.6-folds increased risk to be cervical cancer. Compared to women never use of hormonal contraception, those who ever had hormonal contraception for 1-4 years and 5-25 years had two time and 4.5 times increased risk to be cervical cancer respectively.Conclusion: Cervical cancer screening recommended to be focused on high-risk groups, among others, women with the number of children born more than fi ve people or women in particular users of hormonal contraception methods with a range of use more than fi ve years. (Med J Indones 2010; 19:268-72Keywords: Cervical cancer, hormonal contraception, menarche, parity

  19. Remarkable change in age-specific breast cancer incidence in the Swiss canton of Geneva and its possible relation with the use of hormone replacement therapy

    International Nuclear Information System (INIS)

    This article aims to explain the reasons for the remarkable change in age of breast cancer occurrence in the Swiss canton of Geneva. We used population-based data from the Geneva cancer registry, which collects information on method of detection, stage and tumour characteristics since 1975. For patients diagnosed between 1997–2003, we obtained additional information on use of hormone replacement therapy from a large prospective study on breast cancer. Using generalized log linear regression analysis, we compared age-specific incidence rates with respect to period, stage, oestrogen receptor status, method of detection and use of hormone replacement therapy. In the periods 1975–1979 and 1985–1989, breast cancer risk increased with age, showing the highest incidence rates among women aged ≥ 85 years. From 1997, the age-specific incidence curve changed completely (p < 0.0001), showing an incidence peak at 60–64 years and a reduced incidence among elderly women. This incidence peak concerned mainly early stage and oestrogen positive cancers and was exclusively observed among women who ever used hormone replacement therapy, regardless whether the tumour was screen-detected or not. The increasing prevalence of hormone replacement therapy use during the 1990s could explain the important change in age-specific breast cancer incidence, not only by increasing breast cancer risk, but also by revealing breast cancer at an earlier age

  20. Rational Design of Potent Antagonists to the Human Growth Hormone Receptor

    Science.gov (United States)

    Fuh, Germaine; Cunningham, Brian C.; Fukunaga, Rikiro; Nagata, Shigekazu; Goeddel, David V.; Wells, James A.

    1992-06-01

    A hybrid receptor was constructed that contained the extracellular binding domain of the human growth hormone (hGH) receptor linked to the transmembrane and intracellular domains of the murine granulocyte colony-stimulating factor receptor. Addition of hGH to a myeloid leukemia cell line (FDC-P1) that expressed the hybrid receptor caused proliferation of these cells. The mechanism for signal transduction of the hybrid receptor required dimerization because monoclonal antibodies to the hGH receptor were agonists whereas their monovalent fragments were not. Receptor dimerization occurs sequentially-a receptor binds to site 1 on hGH, and then a second receptor molecule binds to site 2 on hGH. On the basis of this sequential mechanism, which may occur in many other cytokine receptors, inactive hGH analogs were designed that were potent antagonists to hGH-induced cell proliferation. Such antagonists could be useful for treating clinical conditions of hGH excess, such as acromegaly.

  1. Development of GR/MR Chimeric Receptors and Their Response to Steroid Hormones

    Institute of Scientific and Technical Information of China (English)

    Huang Qiman; Yang Qunying; Elisabeth Martinez; Guo Sandui

    2000-01-01

    We have established an effective and reliable technique of developing GR/MR chimeric receptors by DNA homologous recombination. To develop the method we transformed several different E. coli strains with a linearized plasmid containing full length of mGR(mouse GR) and hormone binding domain(HBD) of rMR(rat MR), the linear DNA undergoes recombination due to the homology of the mGR and the rMR and recircularize , and propagation in E. coli. PCR was performed to screen correct construction in which fusion between GR and MR took place. The constructs were digested with appropriate restriction endonucleases to test probable fusion sites of GR and HBD of MR. Precise fusion sites of GR and MR for constructs AB1157 # 2 , AB1157 # 18, AB 1157 # 22, AB1157 # 32, CMK603 # 6 were verified by DNA sequencing. Trans fection of COS- 7 cells with the constructs and subsequent treatment of transfected COS-7 cells with steroid hormones were carried out, the results showed that the constructs gave response to tested hormones. The study suggested that the GR/MR chimeric receptors can give rise to fusion proteins and their interactive function between hormone and receptor.

  2. Androgen receptor expression as a prognostic and predictive marker in triple-negative breast cancer patients

    OpenAIRE

    Fatma Zakaria; Nehal El-Mashad; Dareen Mohamed

    2016-01-01

    Purpose: It is clear that triple-negative breast cancer (TNBC) tumors are heterogeneous group, but clinically important sub-sets have begun to emerge. We investigate the immunohistochemical expression of androgen receptor (AR) among those hormonal insensitive groups which have only the option of chemotherapy. Exploiting this knowledge for therapy has been challenging. Patients & methods: Seventy seven patients with TNBC subtype, treated from January 2009 until February 2011 were evaluated ...

  3. Estrogen and progesterone hormone receptor status in breast carcinoma: Comparison of immunocytochemistry and immunohistochemistry

    OpenAIRE

    K Radhika; A K Prayaga

    2010-01-01

    Context : Estrogen receptors (ER) and progesterone receptors (PR) play a significant role in the prognosis of breast cancer. For preoperative chemotherapy in locally advanced lesions, trucut biopsy is used to localize the ER and PR receptors by immunohistochemistry. Immunocytochemistry can be a better alternative to immunohistochemistry as it better fixes cells. AIMS : To evaluate the degree of correlation between immunocytochemical (ICC) and immunohistochemical (IHC) determination of ER an...

  4. Correlation between hormone dependency and the regulation of epidermal growth factor receptor by tumor promoters in human mammary carcinoma cells

    International Nuclear Information System (INIS)

    The effects of the tumor promoter phorbol 12-tetradecanoate 13-acetate (TPA) on the epidermal growth factor (EGF) receptor levels were investigated in hormone-dependent (MCF-7, T-47-D, and ZR-75-1) and hormone-independent (MDA-MB-231, HBL-100, and BT-20) human mammary carcinoma cell lines. In the absence of TPA, hormone-independent cell lines contained high concentrations of low-affinity EGF receptors, whereas hormone-dependent cell lines exhibited low concentrations of high-affinity receptors. TPA causes a change of the receptor from a high- to the low-affinity state in hormone-dependent cell lines, as well as in the hormone-independent HBL-100, whereas the affinity remained unchanged in MDA-MB-231 and BT-20 cells. Tumor promoters such as TPA or teleocidin inhibited the proliferation of these cell lines at concentrations above 10 μM with the exception of the T-47-D cells. Evaluation of different TPA analogs indicated a positive correlation between the growth-inhibitory effects and their ability to stimulate the subcellular redistribution of protein kinase C activity in MCF-7 cells. These data suggest a protein kinase C-mediated down-regulation of the progesterone receptor concentration and of the EGF receptor affinity, which is supposed to mediate the mitogenic response. Furthermore, these results support the hypothesis that the tumor-derived growth factors induced by estradiol act via the EGF receptor in hormone-dependent mammary carcinoma cells

  5. Gonadotropin-inhibitory hormone receptor signaling and its impact on reproduction in chickens.

    Science.gov (United States)

    Bédécarrats, Grégoy Y; McFarlane, Heather; Maddineni, Sreenivasa R; Ramachandran, Ramesh

    2009-09-01

    In birds, as in other vertebrates, reproduction is controlled by the hypothalamo-pituitary-gonadal axis with each component secreting specific neuropeptides or hormones. Until recently, it was believed this axis is exclusively under the stimulatory control of hypothalamic gonadotropin-releasing hormone I (GnRH-I) which in turn, stimulates luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion from the pituitary gland. However, the discovery of a novel inhibitory hypothalamic peptide able to reduce LH secretion (gonadotropin-inhibitory hormone: GnIH) challenged this dogma. Furthermore, with the characterization of its specific receptor (GnIHR), progress has been made to clarify the physiological relevance of GnIH in birds. This short review discusses the recent advances in GnIHR signaling at the level of the pituitary gland and the gonads. GnIHR is a member of the G-protein coupled receptor (GPCR) family which couples to G(alphai) and, upon activation inhibits adenylyl cyclase (AC) activity, thus reducing intracellular cAMP levels. This implies that GnIH interferes with signaling of any GPCR coupled to G(alphas), including GnRH, LH and FSH receptors. In the chicken pituitary gland, the GnRHR-II/GnIHR ratio changes during sexual maturation in favor of GnRHR-II that appears to result in hypothalamic control of gonadotropin secretion shifting from inhibitory to stimulatory, with corresponding changes in GnRH-induced cAMP levels. Within the gonads, GnIH and its receptor may act in an autocrine/paracrine manner and may interfere with LH and FSH signaling to influence ovarian follicular maturation and recruitment, as well as spermatogenesis. PMID:19332068

  6. Polymorphism of growth hormone receptor (GHR gene in Holstein Friesian dairy cattle

    Directory of Open Access Journals (Sweden)

    Restu Misrianti

    2011-12-01

    Full Text Available Growth hormone gene have a critical role in the regulation of lactation, mammary gland development and growth process through its interaction with a specific receptor. Growth hormone (GH is an anabolic hormone which is synthesized and secreted by somatotrop cell in pituitary anterior lobe, and interacts with a specific receptor on the surface of the target cells. Growth hormone receptor (GHR has been suggested as candidate gene for traits related to milk production in Bovidae. The purpose of this study was to identify genetic polymorphism of the Growth Hormone Receptor (GHR genes in Holstein Friesian (HF cattle. Total of 353 blood samples were collected from five populations belonging to Cikole Dairy Cattle Breeding Station (BPPT-SP Cikole (88 samples, Pasir Kemis (95 samples, Cilumber (98 samples, Cipelang Livestock Embryo Center (BET Cipelang (40 samples, Singosari National Artificial Insemination Centre (BBIB Singosari (32 samples and 17 frozen semen samples from Lembang Artificial Insemination Center (BIB Lembang. Genomic DNAs were extracted by a standard phenol-chloroform protocol and amplified by a polymerase chain reaction (PCR techniques then PCR products were genotyped by the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP methods. There were two allele dan three genotypes were found namely: allele A and G, Genotype AA, AG and GG repectively. Allele A frequency (0.70-0.82 relatively higher than allele G frequency (0.18-0.30. Chi square test show that on group of BET Cipelang, BIB Lembang and BBIB Singosari population were not significantly different (0.00-0.93, while on group of BET Cipelang, BIB Lembang dan BBIB Singosari population were significantly different (6.02-11.13. Degree of observed heterozygosity (Ho ranged from 0.13-0.42 and expected heterozygosity (He ranged from 0.29-0.42.

  7. Disruption of parathyroid hormone and parathyroid hormone-related peptide receptor phosphorylation prolongs ERK1/2 MAPK activation and enhances c-fos expression

    OpenAIRE

    Tawfeek, Hesham A.; Abou-Samra, Abdul B.

    2012-01-01

    Previous studies have demonstrated that parathyroid hormone (PTH) binding to the PTH/PTH-related peptide receptor (PPR) stimulates G protein coupling, receptor phosphorylation, β-arrestin translocation, and internalization of the ligand/receptor complex. The extracellular signal-regulated mitogen-activated protein kinases 1/2 (ERK1/2 MAPK) are downstream effectors of PPR. In the current study, we investigated the role of PPR phosphorylation in the PTH regulation of the ERK1/2 MAPK pathway. Sh...

  8. Potential applications for sigma receptor ligands in cancer diagnosis and therapy.

    Science.gov (United States)

    van Waarde, Aren; Rybczynska, Anna A; Ramakrishnan, Nisha K; Ishiwata, Kiichi; Elsinga, Philip H; Dierckx, Rudi A J O

    2015-10-01

    Sigma receptors (sigma-1 and sigma-2) represent two independent classes of proteins. Their endogenous ligands may include the hallucinogen N,N-dimethyltryptamine (DMT) and sphingolipid-derived amines which interact with sigma-1 receptors, besides steroid hormones (e.g., progesterone) which bind to both sigma receptor subpopulations. The sigma-1 receptor is a ligand-regulated molecular chaperone with various ion channels and G-protein-coupled membrane receptors as clients. The sigma-2 receptor was identified as the progesterone receptor membrane component 1 (PGRMC1). Although sigma receptors are over-expressed in tumors and up-regulated in rapidly dividing normal tissue, their ligands induce significant cell death only in tumor tissue. Sigma ligands may therefore be used to selectively eradicate tumors. Multiple mechanisms appear to underlie cell killing after administration of sigma ligands, and the signaling pathways are dependent both on the type of ligand and the type of tumor cell. Recent evidence suggests that the sigma-2 receptor is a potential tumor and serum biomarker for human lung cancer and an important target for inhibiting tumor invasion and cancer progression. Current radiochemical efforts are focused on the development of subtype-selective radioligands for positron emission tomography (PET) imaging. Right now, the mostpromising tracers are [18F]fluspidine and [18F]FTC-146 for sigma-1 receptors and [11C]RHM-1 and [18F]ISO-1 for the sigma-2 subtype. Nanoparticles coupled to sigma ligands have shown considerable potential for targeted delivery of antitumor drugs in animal models of cancer, but clinical studies exploring this strategy in cancer patients have not yet been reported. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID:25173780

  9. Current applications of PET imaging of sex hormone receptors with a fluorinated analogue of estradiol or of testosterone

    International Nuclear Information System (INIS)

    Currently, the most frequent approach in the oncologic applications of positron emission tomography (PET) is detecting the hypermetabolic activity of the cancer tissue. A more specific approach, which may be complementary, is detecting the overexpression of receptors. In this review article, we aim to evaluate the results that are currently available for PET imaging of the sex hormone receptors in clinical oncology. The indication of PET and now PET/CT has been more disputed in breast carcinoma than in many other primary cancers (e.g., lung, head and neck, colorectal, lymphoma). 18F-fluorodeoxyglucose (FDG), the glucose analogue for PET imaging, has a limited sensitivity to detect the primary breast tumors in case of lobular or in situ forms or small sized tumors localised on systematic mammography, and to identify minimal node invasion in the axilla. Using 16α-(18F]fluoro-17β-estradiol (FES), a fluorinated estradiol analogue, PET is able to detect the over-expression of the oestrogen receptor (ER) in lesions, at a whole-body level. FES and FDG appear complementary for a better diagnostic performance in staging locally advanced breast cancer or restaging recurrent or metastatic breast cancer. Another potential indication is predicting the response to starting or resuming hormone therapy in patients with metastatic breast cancer, in relation with the ER status of all lesions revealed by FES PET. In two retrospective studies, FDG PET was also able to predict the response to hormone therapy, on basis of a metabolic flare, observed either after 7-10 days of treatment or during an estradiol challenge. A prospective comparison of those approaches is warranted. One study reported predicting response to neoadjuvant chemotherapy thanks to a low value of FES SUVmax or FES/FDG SUV max ratio. The presence of ER in uterine tumors, including the benign ones, in ovarian cancers or even in meningiomas, may have therapeutic consequences and FES PET could have a clinical utility

  10. HORMONE THERAPY IN ADVANCED ER+/HER2- NEGATIVE BREAST CANCER WITH PI3K INHIBITORS: A REVIEW OF THE LITERATURE

    Directory of Open Access Journals (Sweden)

    Ivan Inkov

    2016-08-01

    Full Text Available Breast cancer is a heterogenous disease, showing as several different clinical and histologic types. Most of breast cancers express hormone receptors for estrogen and progesterone, which are considered as estrogen receptor-positive and progesterone-receptor-positive, respectively. Endocrine therapy was the first class of target-directed therapy approved for treating breast cancer and is still very important for the treatment of HR+ breast cancer because of its effectiveness and good toxicity profile. It targets receptor-mediated signaling pathways implicated in cell survival and proliferation, such as those mediated by hormone receptors. Although these approaches have improved the management of advanced breast cancer, many patients either fail to respond to initial therapy (primary or de novo resistance or eventually become resistant to treatment (secondary or acquired resistance. To expand the use of existing endocrine treatments and their efficiency, new methods are needed. Such new approaches would boost the benefit of existing endocrine therapy by extending time to disease progression, avoiding or overcoming resistance to endocrine treatment, and delaying the use of chemotherapy. This article will review the central role of the PI3K inhibitors in driving ER+/HER2- breast tumors. Also, schemes to combine pathway inhibitors with endocrine therapy for better patient outcome, and approaches to identify patient populations that would benefit most from inhibition of the PI3K/AKT/mTOR pathway will be assessed.

  11. Hormones and breast cancer: can we use them in ways that could reduce the risk?

    Directory of Open Access Journals (Sweden)

    Khalid Mahmud

    2011-12-01

    Full Text Available Many hormones promote or inhibit breast cancer in different ways. These effects and the mechanisms involved are reviewed in order to suggest a potentially safer use of hormones. Natural estrogens, administered transdermally, and natural progesterone may be the safest combination of female hormones. Increased intake of cruciferous vegetables could provide additional safety by improving 2-hydoxyestrone and diminishing 16 alphahydroxyestrone. Testosterone and dehydroepiandrosterone (DHEA may directly inhibit breast cancer, but could potentially stimulate it by being aromatized into estrogen in the breast. Modest doses with blood level monitoring appear logical. Melatonin and oxytocin are inhibitory to breast and other cancers. Insulin is a growth factor for breast cancer. Managing insulin resistance before the onset of diabetes could reduce the risk. Tri-iodothyronine (T3 has multiple anti-breast cancer effects. Synthroid may not increase T3 levels adequately. Human growth hormone does not appear to increase risk; but it should not be given for performance enhancement.

  12. Requirement of tyrosine residues 333 and 338 of the growth hormone (GH) receptor for selected GH-stimulated function

    DEFF Research Database (Denmark)

    Lobie, P E; Allevato, G; Norstedt, G;

    1995-01-01

    We have examined the involvement of tyrosine residues 333 and 338 of the growth hormone (GH) receptor in the cellular response to GH. Stable Chinese hamster ovary (CHO) cell clones expressing a receptor with tyrosine residues at position 333 and 338 of the receptor substituted for phenylalanine...

  13. Presence of CCK-A, B receptors and effect of gastrin and cholecystokinin on growth of pancreatobiliary cancer cell lines

    Institute of Scientific and Technical Information of China (English)

    Jin-Young Jang; Sun-Whe Kim; Ja-Lok Ku; Yong-Hyun Park; Jae-Gahb Park

    2005-01-01

    AIM: To investigate the effects of gastrin and cholecystokinin (CCK) and their specific antagonists on the growth of pancreatic and biliary tract cancer cell lines.METHODS: Five pancreatic and 6 biliary cancer cell lines with 2 conrtol cells were used in this study. Cell proliferation study was done using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) test and direct cell count method. Reverse transcription-polymerase chain reaction (RT-PCR) and slot blot hybridization were performed to examine and quantify the expression of hormonal receptors in these cell lines.RESULTS: SNU-308 showed a growth stimulating effect by gastrin-17, as did SNU-478 by both gastrin-17 and CCK-8. The trophic effect of these two hormones was completely blocked by specific antagonists (L-365, 260for gastrin and L-364, 718 for CCK). Other cell lines did not respond to gastrin or CCK. In RT-PCR, the presence of CCK-A receptor and CCK-B/gastrin receptor mRNA was detected in all biliary and pancreatic cancer cell lines. In slot blot hybridization, compared to the cell lines which did not respond to hormones, those that responded to hormones showed high expression of receptor mRNA.CONCLUSION: Gastrin and CCK exert a trophic action on some of the biliary tract cancers.

  14. Fulvestrant radiosensitizes human estrogen receptor-positive breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jing, E-mail: wangstella5@163.com [Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road 107, Shandong Province (China); Department of Oncology, Affiliated Hospital of Qingdao University Medical College, Shandong Province (China); Yang, Qifeng, E-mail: qifengy@gmail.com [Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road 107, Shandong Province (China); Haffty, Bruce G., E-mail: hafftybg@umdnj.edu [Department of Radiation Oncology, UMDNJ-Robert Wood Johnson School of Medicine, Cancer Institute of New Jersey, NB (United States); Li, Xiaoyan, E-mail: xiaoyanli1219@gmail.com [Department of Oncology, Affiliated Hospital of Qingdao University Medical College, Shandong Province (China); Moran, Meena S., E-mail: meena.moran@yale.edu [Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT (United States)

    2013-02-08

    Highlights: ► Fulvestrant radiosensitizes MCF-7 cells. ► Fulvestrant increases G1 arrest and decreases S phase in MCF-7 cells. ► Fulvestrant down-regulates DNA-PKcs and RAD51 in MCF-7 cells. -- Abstract: The optimal sequencing for hormonal therapy and radiation are yet to be determined. We utilized fulvestrant, which is showing promise as an alternative to other agents in the clinical setting of hormonal therapy, to assess the cellular effects of concomitant anti-estrogen therapy (fulvestrant) with radiation (F + RT). This study was conducted to assess the effects of fulvestrant alone vs. F + RT on hormone-receptor positive breast cancer to determine if any positive or negative combined effects exist. The effects of F + RT on human breast cancer cells were assessed using MCF-7 clonogenic and tetrazolium salt colorimetric (MTT) assays. The assays were irradiated with a dose of 0, 2, 4, 6 Gy ± fulvestrant. The effects of F + RT vs. single adjuvant treatment alone on cell-cycle distribution were assessed using flow cytometry; relative expression of repair proteins (Ku70, Ku80, DNA-PKcs, Rad51) was assessed using Western Blot analysis. Cell growth for radiation alone vs. F + RT was 0.885 ± 0.013 vs. 0.622 ± 0.029 @2 Gy, 0.599 ± 0.045 vs. 0.475 ± 0.054 @4 Gy, and 0.472 ± 0.021 vs. 0.380 ± 0.018 @6 Gy RT (p = 0.003). While irradiation alone induced G2/M cell cycle arrest, the combination of F + RT induced cell redistribution in the G1 phase and produced a significant decrease in the proportion of cells in G2 phase arrest and in the S phase in breast cancer cells (p < 0.01). Furthermore, levels of repair proteins DNA-PKcs and Rad51 were significantly decreased in the cells treated with F + RT compared with irradiation alone. F + RT leads to a decrease in the surviving fraction, increased cell cycle arrest, down regulating of nonhomologous repair protein DNA-PKcs and homologous recombination repair protein RAD51. Thus, our findings suggest that F + RT

  15. G Protein-Coupled Receptors in Cancer

    Science.gov (United States)

    Bar-Shavit, Rachel; Maoz, Myriam; Kancharla, Arun; Nag, Jeetendra Kumar; Agranovich, Daniel; Grisaru-Granovsky, Sorina; Uziely, Beatrice

    2016-01-01

    Despite the fact that G protein-coupled receptors (GPCRs) are the largest signal-conveying receptor family and mediate many physiological processes, their role in tumor biology is underappreciated. Numerous lines of evidence now associate GPCRs and their downstream signaling targets in cancer growth and development. Indeed, GPCRs control many features of tumorigenesis, including immune cell-mediated functions, proliferation, invasion and survival at the secondary site. Technological advances have further substantiated GPCR modifications in human tumors. Among these are point mutations, gene overexpression, GPCR silencing by promoter methylation and the number of gene copies. At this point, it is imperative to elucidate specific signaling pathways of “cancer driver” GPCRs. Emerging data on GPCR biology point to functional selectivity and “biased agonism”; hence, there is a diminishing enthusiasm for the concept of “one drug per GPCR target” and increasing interest in the identification of several drug options. Therefore, determining the appropriate context-dependent conformation of a functional GPCR as well as the contribution of GPCR alterations to cancer development remain significant challenges for the discovery of dominant cancer genes and the development of targeted therapeutics. PMID:27529230

  16. G Protein-Coupled Receptors in Cancer.

    Science.gov (United States)

    Bar-Shavit, Rachel; Maoz, Myriam; Kancharla, Arun; Nag, Jeetendra Kumar; Agranovich, Daniel; Grisaru-Granovsky, Sorina; Uziely, Beatrice

    2016-01-01

    Despite the fact that G protein-coupled receptors (GPCRs) are the largest signal-conveying receptor family and mediate many physiological processes, their role in tumor biology is underappreciated. Numerous lines of evidence now associate GPCRs and their downstream signaling targets in cancer growth and development. Indeed, GPCRs control many features of tumorigenesis, including immune cell-mediated functions, proliferation, invasion and survival at the secondary site. Technological advances have further substantiated GPCR modifications in human tumors. Among these are point mutations, gene overexpression, GPCR silencing by promoter methylation and the number of gene copies. At this point, it is imperative to elucidate specific signaling pathways of "cancer driver" GPCRs. Emerging data on GPCR biology point to functional selectivity and "biased agonism"; hence, there is a diminishing enthusiasm for the concept of "one drug per GPCR target" and increasing interest in the identification of several drug options. Therefore, determining the appropriate context-dependent conformation of a functional GPCR as well as the contribution of GPCR alterations to cancer development remain significant challenges for the discovery of dominant cancer genes and the development of targeted therapeutics. PMID:27529230

  17. High expression of follicle stimulating hormone receptor in testicular tissue of idiopathic azoospermic patients with severe spermatogenic defects

    Institute of Scientific and Technical Information of China (English)

    Wang Liquan; Huang Hefeng; Jin Fan; Zhou Caiyun; Qian Yuli; Chen Jianhua

    2014-01-01

    Background Follicle stimulating hormone is necessary for normal reproduction in men.The biochemical actions of follicle stimulating hormone result from binding to the follicle stimulating hormone receptor in the plasma membrane of Sertoli cells.Here,we investigated the expression of the follicle stimulating hormone receptor in different testicular histological phenotypes of patients with idiopathic azoospermia.Methods Fifty-seven cases of idiopathic azoospermia were classified into three groups according to the results of testicular biopsy:patients with hypospermatogenesis,patients with maturation arrest,and patients with Sertoli cell-only syndrome.Thirteen azoospermic patients identified by testicular biopsy as being capable of completing spermatogenesis acted as the control group.Immunohistochemistry and real-time quantitative reverse-transcriptase polymerase chain reaction were performed in each case,and the serum hormone level was also measured in all patients.Results The serum follicle stimulating hormone level in patients with Sertoli cell-only syndrome was significantly higher than in patients with hypospermatogenesis,maturation arrest,and complete spermatogenesis (P<0.01).The serum follicle stimulating hormone level in patients with maturation arrest was significantly higher than in patients with hypospermatogenesis and complete spermatogenesis (P<0.05).There was no difference in serum follicle stimulating hormone levels in patients with hypospermatogenesis and complete spermatogenesis.The follicle stimulating hormone receptor expression level of testicular samples with Sertoli cell-only syndrome was significantly higher than in those with hypospermatogenesis,maturation arrest,and complete spermatogenesis (P<0.05),but no significant difference was observed among hypospermatogenesis,maturation arrest,and complete spermatogenesis testicular samples.Conclusions Different serum follicle stimulating hormone levels and follicle stimulating hormone receptor

  18. EGFR Targeting in Hormone-Refractory Prostate Cancer: Current Appraisal and Prospects for Treatment

    Directory of Open Access Journals (Sweden)

    Gerard Milano

    2010-07-01

    Full Text Available The incidence of prostate cancer increases with age and because of its high prevalence this disease has become a major public health concern. Despite advances in our understanding of the biological mechanisms responsible for the development of this cancer, the transition to the hormone refractory stage (HRPC and metastatic progression pose real problems of clinical management. Currently, docetaxel chemotherapy has been shown to have a slight but significant impact on survival, though the gain in median survival is still less than three months. Research is therefore continuing to improve treatment outcomes. The progression of prostate cancer is accompanied by the overexpression of EGFR (epidermal growth factor receptor in a very large majority of cases, suggesting that this may play a mechanistic role. Unfortunately, although preclinical findings seem to be promising for therapies targeting the EGFR in HRPC, current clinical results are disappointing. These results should however encourage us to look for different ways of using anti-EGFR agents or combining them with other targeted therapies.

  19. Semen quality and reproductive hormones before orchiectomy in men with testicular cancer

    DEFF Research Database (Denmark)

    Petersen, P M; Skakkebaek, N E; Vistisen, K;

    1999-01-01

    cancer (TGCC) investigated before orchiectomy, semen analysis was carried out in 63 patients and hormonal investigations, including measurement of follicle-stimulating hormone, luteinizing hormone (LH), testosterone, estradiol, sex hormone-binding globulin (SHBG), inhibin B, and human chorionic...... gonadotropin (hCG), in 71 patients. Hormone levels in patients with elevated hCG (n = 41) were analyzed separately. To discriminate between general cancer effects and specific effects associated with TGCC, the same analyses were carried out in a group of 45 consecutive male patients with malignant lymphoma...... (group 2). Group 3 comprised 141 men employed in a Danish company who served as controls in the comparison of semen parameters. As a control group in hormone investigations, 193 men were selected randomly from the Danish National Personal Register to make up group 4. RESULTS: We found significantly lower...

  20. Long chain fatty Acyl-CoA synthetase 4 is a biomarker for and mediator of hormone resistance in human breast cancer.

    Directory of Open Access Journals (Sweden)

    Xinyu Wu

    Full Text Available The purpose of this study was to determine the role of long-chain fatty acyl-CoA synthetase 4 (ACSL4 in breast cancer. Public databases were utilized to analyze the relationship between ACSL4 mRNA expression and the presence of steroid hormone and human epidermal growth factor receptor 2 (HER2 in both breast cancer cell lines and tissue samples. In addition, cell lines were utilized to assess the consequences of either increased or decreased levels of ACSL4 expression. Proliferation, migration, anchorage-independent growth and apoptosis were used as biological end points. Effects on mRNA expression and signal transduction pathways were also monitored. A meta-analysis of public gene expression databases indicated that ACSL4 expression is positively correlated with a unique subtype of triple negative breast cancer (TNBC, characterized by the absence of androgen receptor (AR and therefore referred to as quadruple negative breast cancer (QNBC. Results of experiments in breast cancer cell lines suggest that simultaneous expression of ACSL4 and a receptor is associated with hormone resistance. Forced expression of ACSL4 in ACSL4-negative, estrogen receptor α (ER-positive MCF-7 cells resulted in increased growth, invasion and anchorage independent growth, as well as a loss of dependence on estrogen that was accompanied by a reduction in the levels of steroid hormone receptors. Sensitivity to tamoxifen, triacsin C and etoposide was also attenuated. Similarly, when HER2-positive, ACSL4-negative, SKBr3 breast cancer cells were induced to express ACSL4, the proliferation rate increased and the apoptotic effect of lapatinib was reduced. The growth stimulatory effect of ACSL4 expression was also observed in vivo in nude mice when MCF-7 control and ACSL4-expressing cells were utilized to induce tumors. Our data strongly suggest that ACSL4 can serve as both a biomarker for, and mediator of, an aggressive breast cancer phenotype.

  1. Effect of small molecules modulating androgen receptor (SARMs in human prostate cancer models.

    Directory of Open Access Journals (Sweden)

    Anna Tesei

    Full Text Available The management of hormone-refractory prostate cancer represents a major challenge in the therapy of this tumor, and identification of novel androgen receptor antagonists is needed to render treatment more effective. We analyzed the activity of two novel androgen receptor antagonists, (S-11 and (R-9, in in vitro and in vivo experimental models of hormone-sensitive or castration-resistant prostate cancer (CRPC. In vitro experiments were performed on LNCaP, LNCaP-AR, LNCaP-Rbic and VCaP human prostate cancer cells. Cytotoxic activity was assessed by SRB and BrdU uptake, AR transactivation by luciferase reporter assay and PSA levels by Real Time RT-PCR and ELISA assays. Cell cycle progression-related markers were evaluated by western blot. In vivo experiments were performed on SCID mice xenografted with cells with different sensitivity to hormonal treatment. In hormone-sensitive LNCaP and LNCaP-AR cells, the latter expressing high androgen receptor levels, (R-9 and (S-11 exhibited a higher cytotoxic effect compared to that of the reference compound ((R-bicalutamide, also in the presence of the synthetic androgen R1881. Furthermore, the cytotoxic effect produced by (R-9 was higher than that of (S-11 in the two hormone-resistant LNCaP-AR and VCaP cells. A significant reduction in PSA levels was observed after exposure to both molecules. Moreover, (S-11 and (R-9 inhibited DNA synthesis by blocking the androgen-induced increase in cyclin D1 protein levels. In vivo studies on the toxicological profile of (R-9 did not reveal the presence of adverse events. Furthermore, (R-9 inhibited tumor growth in various in vivo models, especially LNCaP-Rbic xenografts, representative of recurrent disease. Our in vitro results highlight the antitumor activity of the two novel molecules (R-9 and (S-11, making them a potentially attractive option for the treatment of CRPC.

  2. European Code against Cancer 4th Edition: Medical exposures, including hormone therapy, and cancer.

    Science.gov (United States)

    Friis, Søren; Kesminiene, Ausrele; Espina, Carolina; Auvinen, Anssi; Straif, Kurt; Schüz, Joachim

    2015-12-01

    The 4th edition of the European Code against Cancer recommends limiting - or avoiding when possible - the use of hormone replacement therapy (HRT) because of the increased risk of cancer, nevertheless acknowledging that prescription of HRT may be indicated under certain medical conditions. Current evidence shows that HRT, generally prescribed as menopausal hormone therapy, is associated with an increased risk of cancers of the breast, endometrium, and ovary, with the risk pattern depending on factors such as the type of therapy (oestrogen-only or combined oestrogen-progestogen), duration of treatment, and initiation according to the time of menopause. Carcinogenicity has also been established for anti-neoplastic agents used in cancer therapy, immunosuppressants, oestrogen-progestogen contraceptives, and tamoxifen. Medical use of ionising radiation, an established carcinogen, can provide major health benefits; however, prudent practices need to be in place, with procedures and techniques providing the needed diagnostic information or therapeutic gain with the lowest possible radiation exposure. For pharmaceutical drugs and medical radiation exposure with convincing evidence on their carcinogenicity, health benefits have to be balanced against the risks; potential increases in long-term cancer risk should be considered in the context of the often substantial and immediate health benefits from diagnosis and/or treatment. Thus, apart from HRT, no general recommendations on reducing cancer risk were given for carcinogenic drugs and medical radiation in the 4th edition of European Code against Cancer. It is crucial that the application of these measures relies on medical expertise and thorough benefit-risk evaluation. This also pertains to cancer-preventive drugs, and self-medication with aspirin or other potential chemopreventive drugs is strongly discouraged because of the possibility of serious, potentially lethal, adverse events.

  3. Identification of intracellular domains in the growth hormone receptor involved in signal transduction

    Energy Technology Data Exchange (ETDEWEB)

    Billestrup, N.; Allevato, G.; Moldrup, A. [Hagedorn Research Lab., Gentofte (Denmark)] [and others

    1994-12-31

    The growth hormone (GH) receptor belongs to the GH/prolactin/cytokine super-family of receptors. The signal transduction mechanism utilized by this class of receptors remains largely unknown. In order to identify functional domains in the intracellular region of the GH receptor we generated a number of GH receptor mutants and analyzed their function after transfection into various cell lines. A truncated GH receptor missing 184 amino acids at the C-terminus was unable to medite GH effects on transcription of the Spi 2.1 and insulin genes. However, this mutant was fully active in mediating GH-stimulated metabolic effects such as protein synthesis and lipolysis. Furthermore, this mutant GH receptor internalized rapidly following GH binding. Another truncated GH receptor lacking all but five amino acids of the cytoplasmic domain could not mediate any effects of GH nor did it internalize. Deletion of the proline-rich region or changing the four prolines to alanines also resulted in a GH receptor deficient in signaling. Mutation of phenylalanine 346 to alanine resulted in a GH receptor which did not internalize rapidly; however, this mutant GH receptor was capable of mediating GH-stimulated transcription as well as metabolic effects. These results indicate that the intracellular part of the GH receptor can be divided into at least three functional domains: (1) for transcriptional activity, two domains are involved, one located in the C-terminal 184 amino acids and the other in the proline-rich domain; (2) for metabolic effects, a domain located in or near the proline-rich region is of importance; and (3) for internalization, phenylalanine 346 is necessary. 28 refs., 1 fig.

  4. Expression of the growth hormone receptor gene in insulin producing cells

    DEFF Research Database (Denmark)

    Møldrup, Annette; Billestrup, N; Nielsen, Jens Høiriis

    1990-01-01

    Growth hormone (GH) plays a dual role in glucose homeostasis. On the one hand, it exerts an insulin antagonistic effect on the peripheral tissue, on the other hand, it stimulates insulin biosynthesis and beta-cell proliferation. The expression of GH-receptors on the rat insulinoma cell line RIN-5AH......-T2-clone B was studied. The binding characteristics with regard to specificity for the native 22 kDa hGH, and the 20 kDa variant were similar to that reported on rat adipocytes. Normal rat islet cells showed a similar affinity for hGH. The RIN cells express GH receptors similar to the cloned liver...... receptor. It is hypothesized that defects in the receptor expression on the beta-cells may contribute to the susceptibility to develop diabetes....

  5. ELABELA: a hormone essential for heart development signals via the apelin receptor.

    Science.gov (United States)

    Chng, Serene C; Ho, Lena; Tian, Jing; Reversade, Bruno

    2013-12-23

    We report here the discovery and characterization of a gene, ELABELA (ELA), encoding a conserved hormone of 32 amino acids. Present in human embryonic stem cells, ELA is expressed at the onset of zebrafish zygotic transcription and is ubiquitous in the naive ectodermal cells of the embryo. Using zinc-finger-nuclease-mediated gene inactivation in zebrafish, we created an allelic series of ela mutants. ela null embryos have impaired endoderm differentiation potential marked by reduced gata5 and sox17 expression. Loss of Ela causes embryos to develop with a rudimentary heart or no heart at all, surprisingly phenocopying the loss of the apelin receptor (aplnr), which we show serves as Ela's cognate G protein-coupled receptor. Our results reveal the existence of a peptide hormone, ELA, which, together with APLNR, forms an essential signaling axis for early cardiovascular development.

  6. Osteopontin deficiency enhances parathyroid hormone/ parathyroid hormone related peptide receptor (PPR) signaling-induced alteration in tooth formation and odontoblastic morphology

    OpenAIRE

    Morishita, Maki; Ono, Noriaki; Miyai, Kentano; Nakagawa, Tomomi; Hanyu, Ryo; Nagao, Masashi; Kamolratanakul, Paksinee; Notomi, Takuya; Rittling, Susan R; Denhardt, David T.; Kronenberg, Henry M.; Ezura, Yoichi; Hayata, Tadayoshi; Nakamoto, Tetsuya; Noda, Masaki

    2011-01-01

    Parathyroid hormone/parathyroid hormone-related protein receptor (PPR) signaling is known to be involved in tooth development. In bone, extracellular matrix protein osteopontin (OPN) is a negative regulator of PPR signaling in bone formation. However, the role of OPN in modulation of PPR action in tooth development is not understood. Therefore, we examined the tooth in double mutant mice. Constitutively active PPR was expressed specifically in the odontoblasts and osteoblasts (caPPR-tg) in th...

  7. Receptors of Hypothalamic-Pituitary-Ovarian-Axis Hormone in Uterine Myomas

    Directory of Open Access Journals (Sweden)

    Danuta Plewka

    2014-01-01

    Full Text Available In this study the expression of GnRH, FSH, LH, ER-α, ER-β, and PR receptors was examined in uterine myomas of women in reproductive and perimenopausal age. In cases of GnRH and tropic hormones a membranous and cytoplasmic immunohistochemical reaction was detected, in cases of ER-α and PR the reaction was located in cell nucleus, and in the case of ER-β it manifested also a cytoplasmic location. In some of the examined cases the expression was detected in endometrium, myocytes, and endothelium of blood vessels, in uterine glands and myoma cells. In myometrium the level of GnRH and LH receptors increases with age, whereas the level of progesterone and both estrogen receptors decreases. In myomas of women in reproductive age, independently of their size, expression of GnRH, FSH, and LH receptors was more pronounced than in myometrium. In women of perimenopausal age, independently of myoma size, expression of LH and estrogen α receptors was higher while expression of GnRH receptors was lower than in myometrium. FSH receptor expression was not observed. Expression of estrogen receptor β was not affected by age of the woman or size of myoma. Analysis of obtained results indicates on existing in small myomas local feedback axis between GnRH-LH-progesterone.

  8. Study of change of sex hormone receptors in diabetic impotent patients

    International Nuclear Information System (INIS)

    To study the relationship between diabetic impotence and sex hormones as well as sex hormone receptors. 32 diabetic impotent patients, 32 diabetic patients with normal sex function, 32 impotent patients without diabetes, and 40 healthy men were enrolled. The plasma sex hormone levels were examined by radioimmunoassay, and sex hormone receptors in white blood cells by radioreceptor assay. Compared with healthy men and impotent patients without diabetes, PRL levels in both diabetic impotent patients and diabetic patients with normal sex function increased markedly, T and AR levels decreased, and the ratio of E2/T and ER/AR increased. Compared with diabetic patients with normal sex function, while there was no significant difference in PRL, T and E2/T ratio, the AR level of diabetic impotent patients further decreased, and the ER/AR ratio further increased. Negative correlation was found between age and AR as well as T. The decline of AR and the increase of ER/AR ratio might be one main cause of diabetic impotence. And the decline of T and AR might be an important cause of the increase of diabetic impotence incidence with age

  9. A gate-latch-lock mechanism for hormone signalling by abscisic acid receptors

    KAUST Repository

    Melcher, Karsten

    2009-12-03

    Abscisic acid (ABA) is a ubiquitous hormone that regulates plant growth, development and responses to environmental stresses. Its action is mediated by the PYR/PYL/RCAR family of START proteins, but it remains unclear how these receptors bind ABA and, in turn, how hormone binding leads to inhibition of the downstream type 2C protein phosphatase (PP2C) effectors. Here we report crystal structures of apo and ABA-bound receptors as well as a ternary PYL2-ABA-PP2C complex. The apo receptors contain an open ligand-binding pocket flanked by a gate that closes in response to ABA by way of conformational changes in two highly conserved ?-loops that serve as a gate and latch. Moreover, ABA-induced closure of the gate creates a surface that enables the receptor to dock into and competitively inhibit the PP2C active site. A conserved tryptophan in the PP2C inserts directly between the gate and latch, which functions to further lock the receptor in a closed conformation. Together, our results identify a conserved gate-latch-lock mechanism underlying ABA signalling. © 2009 Macmillan Publishers Limited. All rights reserved.

  10. Expression of anti-Mullerian hormone receptor on the appendix testis in connection with urological disorders

    Institute of Scientific and Technical Information of China (English)

    Kornél Kistamás; Olga Ruzsnavszky; Andrea Telek; Lívia Kosztka; Ilona Kovács; Beatrix Dienes; László Csernoch

    2013-01-01

    The female internal sex organs develop from the paramesonephric (Mullerian) duct.In male embryos,the regression of the Mullerian duct is caused by the anti-Mullerian hormone (AMH),which plays an important role in the process of testicular descent.The physiological remnant of the Mullerian duct in males is the appendix testis (AT).In our previous study,we presented evidence for the decreased incidence of AT in cryptorchidism with intraoperative surgery.In this report,the expression of the anti-Mullerian hormone receptor type 2 (AMHR2),the specific receptor of AMH,on the AT was investigated in connection with different urological disorders,such as hernia inguinalis,torsion of AT,cysta epididymis,varicocele,hydrocele testis and various forms of undescended testis.The correlation between the age of the patients and the expression of the AMHR2 was also examined.Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry were used to detect the receptor's mRNA and protein levels,respectively.We demonstrate that AMHR2 is expressed in the ATs.Additionally,the presence of this receptor was proven at the mRNA and protein levels.The expression pattern of the receptor correlated with neither the examined urological disorders nor the age of the patients;therefore,the function of the AT remains obscure.

  11. A gate-latch-lock mechanism for hormone signalling by abscisic acid receptors

    Energy Technology Data Exchange (ETDEWEB)

    Melcher, Karsten; Ng, Ley-Moy; Zhou, X Edward; Soon, Fen-Fen; Xu, Yong; Suino-Powell, Kelly M; Park, Sang-Youl; Weiner, Joshua J; Fujii, Hiroaki; Chinnusamy, Viswanathan; Kovach, Amanda; Li, Jun; Wang, Yonghong; Li, Jiayang; Peterson, Francis C; Jensen, Davin R; Yong, Eu-Leong; Volkman, Brian F; Cutler, Sean R; Zhu, Jian-Kang; Xu, H Eric; (NU Sinapore); (Van Andel); (MCW); (UCR); (Chinese Aca. Sci.)

    2010-01-12

    Abscisic acid (ABA) is a ubiquitous hormone that regulates plant growth, development and responses to environmental stresses. Its action is mediated by the PYR/PYL/RCAR family of START proteins, but it remains unclear how these receptors bind ABA and, in turn, how hormone binding leads to inhibition of the downstream type 2C protein phosphatase (PP2C) effectors. Here we report crystal structures of apo and ABA-bound receptors as well as a ternary PYL2-ABA-PP2C complex. The apo receptors contain an open ligand-binding pocket flanked by a gate that closes in response to ABA by way of conformational changes in two highly conserved β-loops that serve as a gate and latch. Moreover, ABA-induced closure of the gate creates a surface that enables the receptor to dock into and competitively inhibit the PP2C active site. A conserved tryptophan in the PP2C inserts directly between the gate and latch, which functions to further lock the receptor in a closed conformation. Together, our results identify a conserved gate-latch-lock mechanism underlying ABA signalling.

  12. Menopausal hormone use and ovarian cancer risk : individual participant meta-analysis of 52 epidemiological studies

    NARCIS (Netherlands)

    Gapstur, S. M.; Patel, A. V.; Banks, E.; Dal Maso, L.; Talamini, R.; Chetrit, A.; Hirsh-Yechezkel, G.; Lubin, F.; Sadetzki, S.; Beral, V.; Bull, D.; Cairns, B.; Crossley, B.; Gaitskell, K.; Goodill, A.; Green, J.; Hermon, C.; Key, T.; Moser, K.; Reeves, G.; Sitas, F.; Collins, R.; Peto, R.; Gonzalez, C. A.; Lee, N.; Marchbanks, P.; Ory, H. W.; Peterson, H. B.; Wingo, P. A.; Martin, N.; Silpisornkosol, S.; Theetranont, C.; Boosiri, B.; Chutivongse, S.; Jimakorn, P.; Virutamasen, P.; Wongsrichanalai, C.; Goodman, M. T.; Lidegaard, O.; Kjaer, S. K.; Morch, L. S.; Kjaer, S. K.; Tjonneland, A.; Byers, T.; Rohan, T.; Mosgaard, B.; Vessey, M.; Yeates, D.; Freudenheim, J. L.; Titus, L. J.; Chang-Claude, J.; Kaaks, R.; Anderson, K. E.; Lazovich, D.; Robien, K.; Hampton, J.; Newcomb, P. A.; Rossing, M. A.; Thomas, D. B.; Weiss, N. S.; Lokkegaard, E.; Riboli, E.; Clavel-Chapelon, F.; Cramer, D.; Hankinson, S. E.; Tamimi, R. M.; Tworoger, S. S.; Franceschi, S.; La Vecchia, C.; Negri, E.; Adami, H. O.; Magnusson, C.; Riman, T.; Weiderpass, E.; Wolk, A.; Schouten, L. J.; van den Brandt, P. A.; Chantarakul, N.; Koetsawang, S.; Rachawat, D.; Palli, D.; Black, A.; Brinton, L. A.; Freedman, D. M.; Hartge, P.; Hsing, A. W.; Jnr, J. V. Lacey; Lissowska, J.; Hoover, R. N.; Schairer, C.; Babb, C.; Urban, M.; Graff-Iversen, S.; Selmer, R.; Bain, C. J.; Green, A. C.; Purdie, D. M.; Siskind, V.; Webb, P. M.; Moysich, K.; McCann, S. E.; Hannaford, P.; Kay, C.; Binns, C. W.; Lee, A. H.; Zhang, M.; Ness, R. B.; Nasca, P.; Coogan, P. F.; Palmer, J. R.; Rosenberg, L.; Whittemore, A.; Katsouyanni, K.; Trichopoulou, A.; Trichopoulos, D.; Tzonou, A.; Dabancens, A.; Martinez, L.; Molina, R.; Salas, O.; Lurie, G.; Carney, M. E.; Wilkens, L. R.; Hartman, L.; Manjer, J.; Olsson, H.; Kumle, M.; Grisso, J. A.; Morgan, M.; Wheeler, J. E.; Edwards, R. P.; Kelley, J. L.; Modugno, F.; Onland-Moret, N. C.; Peeters, P. H. M.; Casagrande, J.; Pike, M. C.; Wu, A. H.; Canfell, K.; Miller, A. B.; Gram, I. T.; Lund, E.; McGowan, L.; Shu, X. O.; Zheng, W.; Farley, T. M. M.; Holck, S.; Meirik, O.; Risch, H. A.

    2015-01-01

    Background Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on

  13. Atypical chemokine receptors in cancer: friends or foes?

    Science.gov (United States)

    Massara, Matteo; Bonavita, Ornella; Mantovani, Alberto; Locati, Massimo; Bonecchi, Raffaella

    2016-06-01

    The chemokine system is a fundamental component of cancer-related inflammation involved in all stages of cancer development. It controls not only leukocyte infiltration in primary tumors but also angiogenesis, cancer cell proliferation, and migration to metastatic sites. Atypical chemokine receptors are a new, emerging class of regulators of the chemokine system. They control chemokine bioavailability by scavenging, transporting, or storing chemokines. They can also regulate the activity of canonical chemokine receptors with which they share the ligands by forming heterodimers or by modulating their expression levels or signaling activity. Here, we summarize recent results about the role of these receptors (atypical chemokine receptor 1/Duffy antigen receptor for chemokine, atypical chemokine receptor 2/D6, atypical chemokine receptor 3/CXC-chemokine receptor 7, and atypical chemokine receptor 4/CC-chemokine receptor-like 1) on the tumorigenesis process, indicating that their effects are strictly dependent on the cell type on which they are expressed and on their coexpression with other chemokine receptors. Indeed, atypical chemokine receptors inhibit tumor growth and progression through their activity as negative regulators of chemokine bioavailability, whereas, on the contrary, they can promote tumorigenesis when they regulate the signaling of other chemokine receptors, such as CXC-chemokine receptor 4. Thus, atypical chemokine receptors are key components of the regulatory network of inflammation and immunity in cancer and may have a major effect on anti-inflammatory and immunotherapeutic strategies. PMID:26908826

  14. Modulation of interleukin 2 receptor expression on normal human lymphocytes by thymic hormones.

    OpenAIRE

    Sztein, M B; Serrate, S A; Goldstein, A. L.

    1986-01-01

    The expression of interleukin 2 receptors (IL-2R) is a critical step leading to normal lymphocyte proliferation. Since thymosin fraction 5 (TF5), a thymic hormone preparation, enhances lymphoproliferative responses of human cells, we examined the effects of TF5 on the expression of IL-2R on mitogen-stimulated human lymphocytes. TF5 significantly increased the percentage and antigen density of cells expressing IL-2R after stimulation with an optimal concentration of phytohemagglutinin (PHA) wh...

  15. Prostate-specific antigen and hormone receptor expression in male and female breast carcinoma

    Directory of Open Access Journals (Sweden)

    Cohen Cynthia

    2010-09-01

    Full Text Available Abstract Background Prostate carcinoma is among the most common solid tumors to secondarily involve the male breast. Prostate specific antigen (PSA and prostate-specific acid phosphatase (PSAP are expressed in benign and malignant prostatic tissue, and immunohistochemical staining for these markers is often used to confirm the prostatic origin of metastatic carcinoma. PSA expression has been reported in male and female breast carcinoma and in gynecomastia, raising concerns about the utility of PSA for differentiating prostate carcinoma metastasis to the male breast from primary breast carcinoma. This study examined the frequency of PSA, PSAP, and hormone receptor expression in male breast carcinoma (MBC, female breast carcinoma (FBC, and gynecomastia. Methods Immunohistochemical staining for PSA, PSAP, AR, ER, and PR was performed on tissue microarrays representing six cases of gynecomastia, thirty MBC, and fifty-six FBC. Results PSA was positive in two of fifty-six FBC (3.7%, focally positive in one of thirty MBC (3.3%, and negative in the five examined cases of gynecomastia. PSAP expression was absent in MBC, FBC, and gynecomastia. Hormone receptor expression was similar in males and females (AR 74.1% in MBC vs. 67.9% in FBC, p = 0.62; ER 85.2% vs. 68.5%, p = 0.18; and PR 51.9% vs. 48.2%, p = 0.82. Conclusions PSA and PSAP are useful markers to distinguish primary breast carcinoma from prostate carcinoma metastatic to the male breast. Although PSA expression appeared to correlate with hormone receptor expression, the incidence of PSA expression in our population was too low to draw significant conclusions about an association between PSA expression and hormone receptor status in breast lesions.

  16. Key Regulators of Mitochondrial Biogenesis are Increased in Kidneys of Growth Hormone Receptor Knockout (GHRKO) Mice

    OpenAIRE

    Gesing, Adam; Bartke, Andrzej; Wang, Feiya; Karbownik-Lewinska, Malgorzata; Masternak, Michal M.

    2011-01-01

    The growth hormone (GH) receptor knockout mice (GHRKO) are remarkably long-lived and highly insulin sensitive. Alterations in mitochondrial biogenesis are associated with aging and various metabolic derangements. We have previously demonstrated increased gene expression of key regulators of mitochondriogenesis in kidneys, hearts and skeletal muscles of GHRKO mice. The aim of the present study was to quantify the protein levels of the following regulators of mitochondriogenesis: peroxisome pro...

  17. 506 Basal T Cell Subpopulations of Normal Humans Vary by Stress Hormone Receptor Polymorphisms

    OpenAIRE

    Rehm, Kristina; Xiang, Lianbin; Marshall, Gailen

    2012-01-01

    Background Psychological stress has been correlated with allergy and asthma activity although there are clearly individual differences in the responses to the same stressor. These individual differences could be influenced by stress hormone receptor binding affinity, which could be altered by single nucleotide polymorphisms (SNPs). Methods We categorized differences in immunoregulatory profiles from peripheral blood mononuclear cells (PBMC) of 207 normal volunteers according to various glucoc...

  18. Melanin concentrating hormone receptor 1 (MCHR1) antagonists - Still a viable approach for obesity treatment?

    DEFF Research Database (Denmark)

    Högberg, T.; Frimurer, T.M.; Sasmal, P.K.

    2012-01-01

    Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the melanin concentrating hormone (MCH) and its receptor 1. The development of MCHR1 antagonists are described with a specific perspective on different chemotypes inve...... and recent X-ray structures of GPCRs invoked in selectivity issues indicate a way to support future drug design. © 2012 Elsevier Ltd. All rights reserved....

  19. UV filters induce transcriptional changes of different hormonal receptors in Chironomus riparius embryos and larvae.

    Science.gov (United States)

    Ozáez, Irene; Aquilino, Mónica; Morcillo, Gloria; Martínez-Guitarte, José-Luis

    2016-07-01

    Organic ultraviolet (UV) filters are emerging contaminants that are ubiquitous in fresh and marine aquatic systems due to their extensive use in cosmetics, plastics, paints, textiles, and many other industrial products. The estrogenic effects of organic UV filters have been long demonstrated in vertebrates, and other hormonal activities may be altered, according to more recent reports. The impact of UV filters on the endocrine system of invertebrates is largely unknown. We have previously reported that some UV filters may affect ecdysone-related genes in the aquatic insect Chironomus riparius, an ecotoxicologically important model organism. To further analyze other possible effects on endocrine pathways, we first characterized four pivotal genes related with hormonal pathways in insects; thereafter, these genes were assessed for alterations in transcriptional activity after exposure to 4-methylbenzylidene camphor (4MBC) or benzophenone-3 (BP-3), two extensively used sunscreens. We found that both chemicals disturbed the expression of all four genes analyzed: hormonal receptor 38 (HR38), methoprene-tolerant (Met), membrane-associate progesterone receptor (MAPR) and insulin-like receptor (INSR), measured by changes in mRNA levels by real-time PCR. An upregulatory effect at the genomic level was detected in different developmental stages. Interestingly, embryos appeared to be more sensitive to the action of the UV filters than larvae. Our results suggest that the risk of disruption through different endocrine routes is not negligible, considering the significant effects of UV filters on key hormonal receptor and regulatory genes. Further effort is needed to develop environmental risk assessment studies on these pollutants, particularly for aquatic invertebrate model organisms. PMID:27089421

  20. The Relationship Between Gene Polymorphism of Leptin and Leptin Receptor and Growth Hormone Deficiency

    OpenAIRE

    He, Jinshui; Fang, Yanling; Lin, Xinfu; Zhou, Huowang; ZHU, SHAOBO; Zhang, Yugui; Yang, Huicong; Ye, Xiaoling

    2016-01-01

    Backgrounds Growth hormone deficiency (GHD) is a major cause of congenital short stature. GHD patients have significantly decreased serum leptin levels, which are regulated by gene polymorphism of leptin and leptin receptor. This study thus investigated the relationship between gene polymorphism and susceptibility to GHD. Material/Methods A case-control study was performed using 180 GHD children in addition to 160 healthy controls. After the extraction of whole genomic DNA, the genotypes of l...

  1. Outcomes of Estrogen Receptor Negative and Progesterone Receptor Positive Breast Cancer

    Science.gov (United States)

    Chan, Melissa; Chang, Martin C.; González, Rosa; Lategan, Belinda; del Barco, Elvira; Vera-Badillo, Francisco; Quesada, Paula; Goldstein, Robyn; Cruz, Ignacio; Ocana, Alberto; Cruz, Juan J.; Amir, Eitan

    2015-01-01

    Purpose To describe the clinical features and outcomes of estrogen receptor negative (ER-) and progesterone receptor positive (PgR+) breast cancer. Methods We retrospectively reviewed a well-characterized database of sequential patients diagnosed with early stage invasive breast carcinoma. Outcomes of interest were time to relapse (TTR) and overall survival (OS). Multivariable Cox proportional hazards analysis was conducted to assess the association of ER-/PgR+ with TTR and OS in comparison to ER+ and to ER- and PgR negative (ER-/PgR-) tumors irrespective of HER2 status. ER and PgR expression was conservatively defined as 10% or greater staining of cancer cells. Results 815 patients were followed for a median of 40.5 months; 56 patients (7%) had ER-/PgR+, 624 (77%) had ER+ and 136 (17%) had ER-/PgR- phenotypes. Compared with ER+ tumors, ER-/PgR+ tumors were associated with younger age (50 versus 59 years, p=0.03), high grade (50% versus 24%, p<0.001) and more frequent HER2 overexpression/amplification (43% versus 14%, p<0.001). TTR for ER-/PgR+ was intermediate between ER+ and ER-/PgR- tumors, but was not significantly different from ER+ tumors. Recurrences in the ER-/PgR+ and ER-/PgR- groups occurred early in follow-up while in ER+ tumors recurrences continued to occur over the duration of follow-up. OS of ER-/PgR+ was similar to ER+ tumors and better than that of ER-/PgR- tumors. Conclusions The ER-/PgR+ phenotype is associated with higher grade with HER2 overexpression/amplification and occurs more commonly in younger women. Risk of relapse and death more closely resembles ER+ than ER-/PgR- tumors suggesting this phenotype represents a group of more aggressive hormone receptor positive tumors. PMID:26161666

  2. The Metabolism, Analysis, and Targeting of Steroid Hormones in Breast and Prostate Cancer.

    Science.gov (United States)

    Capper, Cameron P; Rae, James M; Auchus, Richard J

    2016-06-01

    Breast and prostate cancers are malignancies in which steroid hormones drive cellular proliferation. Over the past century, this understanding has led to successful treatment strategies aimed to inhibit hormone-mediated tumor growth. Nonetheless, disease relapse and progression still pose significant clinical problems, with recurrent and metastatic tumors often exhibiting resistance to current drug therapies. The central role of androgens and estrogens in prostate and breast cancer etiology explains not only why endocrine therapies are often initially successful but also why many tumors ultimately become resistant. It is hypothesized that reducing the concentration of active hormones in the systemic circulation may be insufficient to block cancer progression, as this action selects for tumor cells that can generate active steroids from circulating precursors. This review aims to highlight the currently known differences of steroid biosynthesis in normal physiology versus hormone-dependent cancers, modern approaches to the assessment and targeting of these pathways, and priorities for future research. PMID:26969590

  3. Long-term Efficacy and Safety of Enzalutamide Monotherapy in Hormone-naïve Prostate Cancer

    DEFF Research Database (Denmark)

    Tombal, Bertrand; Borre, Michael; Rathenborg, Per;

    2015-01-01

    patients with metastases at baseline, 13 (50%) had a complete and four (15.4%) had a partial response as best overall tumor response up to 97 wk on treatment. There was overall maintenance of total-body bone mineral density (BMD) and moderate changes in lean and fat body mass at 49 and 97 wk. The most...... cancer, enzalutamide maintained long-term reductions in prostate-specific antigen, with a minimal impact on total-body bone mineral density. TRIAL REGISTRATION: NCT01302041.......BACKGROUND: Enzalutamide is an androgen receptor inhibitor with a demonstrated overall survival benefit in metastatic castration-resistant prostate cancer. A phase 2 study of enzalutamide monotherapy in patients with hormone-naïve prostate cancer (HNPC) showed a high response rate...

  4. Growth hormone (GH)-independent dimerization of GH receptor by a leucine zipper results in constitutive activation

    DEFF Research Database (Denmark)

    Behncken, S N; Billestrup, Nils; Brown, R;

    2000-01-01

    Growth hormone initiates signaling by inducing homodimerization of two GH receptors. Here, we have sought to determine whether constitutively active receptor can be created in the absence of the extracellular domain by substituting it with high affinity leucine zippers to create dimers of the gro......Growth hormone initiates signaling by inducing homodimerization of two GH receptors. Here, we have sought to determine whether constitutively active receptor can be created in the absence of the extracellular domain by substituting it with high affinity leucine zippers to create dimers...

  5. The Thyroid Hormone Receptors Inhibit Hepatic Interleukin-6 Signaling During Endotoxemia

    Science.gov (United States)

    Contreras-Jurado, Constanza; Alonso-Merino, Elvira; Saiz-Ladera, Cristina; Valiño, Arturo José; Regadera, Javier; Alemany, Susana; Aranda, Ana

    2016-01-01

    Decreased thyroidal hormone production is found during lipopolysaccharide (LPS)-induced endotoxic shock in animals as well as in critically ill patients. Here we studied the role of the thyroid hormone receptors (TRs) in activation of STAT3, NF-κB and ERK, which play a key role in the response to inflammatory cytokines during sepsis. TR knockout mice showed down-regulation of hepatic inflammatory mediators, including interleukin 6 (IL-6) in response to LPS. Paradoxically, STAT3 and ERK activity were higher, suggesting that TRs could act as endogenous repressors of these pathways. Furthermore, hyperthyroidism increased cytokine production and mortality in response to LPS, despite decreasing hepatic STAT3 and ERK activity. This suggested that TRs could directly repress the response of the cells to inflammatory mediators. Indeed, we found that the thyroid hormone T3 suppresses IL-6 signalling in macrophages and hepatocarcinoma cells, inhibiting STAT3 activation. Consequently, the hormone strongly antagonizes IL-6-stimulated gene transcription, reducing STAT3 recruitment and histone acetylation at IL-6 target promoters. In conclusion, TRs are potent regulators of inflammatory responses and immune homeostasis during sepsis. Reduced responses to IL-6 should serve as a negative feedback mechanism for preventing deleterious effects of excessive hormone signaling during infections. PMID:27484112

  6. From Bittner to Barr: a viral, diet and hormone breast cancer aetiology hypothesis

    OpenAIRE

    Lawson, James S; Tran, Dinh; Rawlinson, William D.

    2000-01-01

    It is hypothesized that the human homologue of the mouse mammary tumour virus (HHMMTV) and other viruses, such as human papillomavirus (HPV) and Epstein-Barr virus (EBV), act as cofactors with diet, oestrogens and other hormones in the initiation and promotion of some types of breast cancer in genetically susceptible women. It is further hypothesized that diet influences the risk of breast cancer, through its influence on oestrogen metabolism and that of other hormones, in combination with ge...

  7. Reproductive Factors, Exogenous Hormones, and Pancreatic Cancer Risk in the CTS

    OpenAIRE

    Lee, Eunjung; Horn-Ross, Pamela L.; Rull, Rudolph P.; Neuhausen, Susan L; Anton-Culver, Hoda; Ursin, Giske; Henderson, Katherine D.; Bernstein, Leslie

    2013-01-01

    Female steroid hormones are hypothesized to play a protective role in pancreatic cancer risk. However, results from epidemiologic studies that examined hormone-related exposures have been inconsistent. The California Teachers Study is a cohort study of female public school professionals that was established in 1995–1996. Of the 118,164 eligible study participants, 323 women were diagnosed with incident invasive pancreatic cancer through December 31, 2009. Multivariable Cox proportional hazard...

  8. Dietary acrylamide intake and estrogen and progesterone receptor-defined postmenopausal breast cancer risk

    DEFF Research Database (Denmark)

    Pedersen, Grete S; Hogervorst, Janneke G F; Schouten, Leo J;

    2010-01-01

    Acrylamide, a potential human carcinogen, has been discovered in a variety of heat-treated carbohydrate-rich food products. Previously, dietary acrylamide intake was shown to be associated with endocrine-related cancers in humans. We assessed the association between dietary acrylamide intake...... breast cancer cases were ascertained, with hormone receptor status information for 43%. Cox proportional hazards analysis was applied to determine hazard ratios in quintiles of dietary acrylamide intake stratifying on estrogen receptor (ER) and progesterone receptor (PR) and smoking status...... ratios were 1.31 (95% CI: 0.87-1.97, P (trend) = 0.26) for ER+, 1.47 (0.86-2.51, P (trend) = 0.14) for PR+, and 1.43 (0.83-2.46, P (trend) = 0.16) for ER+PR+, when comparing women in the highest quintile of acrylamide intake (median 36.8 microg/day) to women in the lowest (median 9.5 microg...

  9. Expression of growth hormone receptor and its mRNA in hepatic cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Hong-Tao Wang; Shuang Chen; Jie Wang; Qing-Jia Ou; Chao Liu; Shu-Sen Zheng; Mei-Hai Deng; Xiao-Ping Liu

    2003-01-01

    AIM: To investigate the expression of growth hormone receptor (GHR) and mRNA of GHR in cirrhotic livers of rats with the intension to find the basis for application of recombinant human growth hormone (rhGH) to patients with liver cirrhosis.METHODS: Hepatic cirrhosis was induced in SpragueDawley rats by administration of thioacetamide intraperitoneally for 9-12 weeks. Collagenase Ⅳ was perfused in situ for isolation of hepatocytes. The expression of GHR and its mRNA in cirrhotic livers was studied with radio-ligand binding assay, RT-PCR and digital image analysis.RESULTS: One class of specific growth hormone-binding site, GHR, was detected in hepatocytes and hepatic tissue of cirrhotic livers. The binding capacity of GHR (RT, fmol/mg protein) in rat cirrhotic liver tissue (30.8±1.9) was significantly lower than that in normal control (74.9±3.9) at the time point of the ninth week after initiation of induction of cirrhosis (n=10, P<0.05), and it decreased gradually along with the accumulation of collagen in the process of formation and development of liver cirrhosis (P<0.05). The number of binding sites (×10 4/cell) of GHR on rat cirrhotic hepatocytes (0.86±0.16) was significantly lower than that (1.28±0.24)in control (n= 10, P<0.05). The binding affinity of GHR among liver tissue, hepatocytes of various groups had no significant difference (P>0.05). The expression of GHR mRNA (riOD,pixel) in rat cirrhotic hepatic tissues (23.3±3.1) was also significantly lower than that (29.3±3.4) in normal control (n=10, P<0.05).CONCLUSION: The growth hormone receptor was expressed in a reduced level in liver tissue of cirrhotic rats,and lesser expression of growth hormone receptors was found in a later stage of cirrhosis. The reduced expression of growth hormone receptor was partly due to its decreased expression on cirrhotic hepatocytes and the reduced expression of its mRNA in cirrhotic liver tissue.

  10. Transcriptional network of androgen receptor in prostate cancer progression.

    Science.gov (United States)

    Takayama, Ken-ichi; Inoue, Satoshi

    2013-08-01

    The androgen receptor belongs to the nuclear receptor superfamily and functions as a ligand-dependent transcription factor. It binds to the androgen responsive element and recruits coregulatory factors to modulate gene transcription. In addition, the androgen receptor interacts with other transcription factors, such as forkhead box A1, and other oncogenic signaling pathway molecules that bind deoxyribonucleic acid and regulate transcription. Androgen receptor signaling plays an important role in the development of prostate cancer. Prostate cancer cells proliferate in an androgen-dependent manner, and androgen receptor blockade is effective in prostate cancer therapy. However, patients often progress to castration-resistant prostate cancer with elevated androgen receptor expression and hypersensitivity to androgen. Recently, comprehensive analysis tools, such as complementary DNA microarray, chromatin immunoprecipitation-on-chip and chromatin immunoprecipitation-sequence, have described the androgen-mediated diverse transcriptional program and gene networks in prostate cancer. Furthermore, functional and clinical studies have shown that some of the androgen receptor-regulated genes could be prognostic markers and potential therapeutic targets for the treatment of prostate cancer, particularly castration-resistant prostate cancer. Thus, identifying androgen receptor downstream signaling events and investigating the regulation of androgen receptor activity is critical for understanding the mechanism of carcinogenesis and progression to castration-resistant prostate cancer.

  11. Female Hormonal Factors and the Risk of Endometrial Cancer in Lynch Syndrome

    Science.gov (United States)

    Dashti, Seyedeh Ghazaleh; Chau, Rowena; Ouakrim, Driss Ait; Buchanan, Daniel D.; Clendenning, Mark; Young, Joanne P.; Winship, Ingrid M.; Arnold, Julie; Ahnen, Dennis J.; Haile, Robert W.; Casey, Graham; Gallinger, Steven; Thibodeau, Stephen N.; Lindor, Noralane M.; Le Marchand, Loïc; Newcomb, Polly A.; Potter, John D.; Baron, John A.; Hopper, John L.; Jenkins, Mark A.; Win, Aung Ko

    2015-01-01

    Importance Apart from hysterectomy, there is no consensus recommendation for reducing endometrial cancer risk for women with a mismatch repair (MMR) gene mutation (Lynch syndrome). Objective To investigate the association between hormonal factors and endometrial cancer risk in Lynch syndrome. Design, Setting, and Participants A retrospective cohort study including 1,128 women with a MMR gene mutation identified from the Colon Cancer Family Registry was conducted. Data were analyzed using a weighted cohort approach. Participants were recruited between 1997 and 2012, from centers across the United States, Australia, Canada, and New Zealand. Exposures Age at menarche, first and last live birth, and menopause, number of live births, hormonal contraceptive use, and postmenopausal hormone use. Main Outcome and Measures Self-reported diagnosis of endometrial cancer. Results Endometrial cancer was diagnosed in 133 women (incidence per 100 person-years, 0.29; 95% confidence interval [CI], 0.24 to 0.34). A lower risk of endometrial cancer was associated with later age at menarche (hazard ratio [HR] per year, 0.85 [95%CI, 0.73 to 0.99]; P=.04), parity (parous vs nulliparous: HR, 0.21 [95%CI, 0.10 to 0.42]; P<.001), and hormonal contraceptive use (≥1 year vs <1 year: HR, 0.39 [95%CI, 0.23 to 0.64]; P<.001). There was no statistically significant association between endometrial cancer and age at first and last live birth, age at menopause, and postmenopausal hormone use. Conclusions and Relevance For women with a MMR gene mutation, some endogenous and exogenous hormonal factors were associated with a lower risk of endometrial cancer. These directions and strengths of associations were similar to those for the general population. If replicated, these findings suggest that women with a MMR gene mutation may be counseled like the general population in regard to hormonal influences on endometrial cancer risk. PMID:26151267

  12. Suppression of Ovarian Function With Either Tamoxifen or Exemestane Compared With Tamoxifen Alone in Treating Premenopausal Women With Hormone-Responsive Breast Cancer

    Science.gov (United States)

    2016-07-29

    Estrogen Receptor Positive Breast Cancer; Progesterone Receptor Positive Tumor; Recurrent Breast Carcinoma; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer

  13. Association between polymorphisms in the aryl hydrocarbon receptor repressor gene and disseminated testicular germ cell cancer

    DEFF Research Database (Denmark)

    Brokken, Leon J S; Lundberg-Giwercman, Yvonne; Rajpert-De Meyts, Ewa;

    2013-01-01

    In the Western world, testicular germ cell cancer (TGCC) is the most common malignancy of young men. The malignant transformation of germ cells is thought to be caused by developmental and hormonal disturbances, probably related to environmental and lifestyle factors because of rapidly increasing...... receptor (AHR). AHR signaling pathway is known to interfere with reproductive hormone signaling, which is supposed to play a role in the pathogenesis and invasive progression of TGCC. The aim of the present study was to identify whether AHR-related polymorphisms were associated with risk as well...... supports the hypothesis that compounds acting through AHR may play a role in the invasive progression of TGCC, either directly or through modification of reproductive hormone action....

  14. ERG Cooperates with Androgen Receptor in Regulating Trefoil Factor 3 in Prostate Cancer Disease Progression

    Directory of Open Access Journals (Sweden)

    David S. Rickman

    2010-12-01

    Full Text Available To elucidate the role of ETS gene fusions in castration-resistant prostate cancer (CRPC, we characterized the transcriptome of 54 CRPC tumor samples from men with locally advanced or metastatic disease. Trefoil factor 3 (TFF3 emerged as the most highly differentially regulated gene with respect to ERG rearrangement status and resistance to hormone ablation therapy. Conventional chromatin immunoprecipitation (ChIP-polymerase chain reaction and ChIP followed by DNA sequencing (ChIP-seq revealed direct binding of ERG to ETS binding sites in the TFF3 promoter in ERG-rearranged prostate cancer cell lines. These results were confirmed in ERG-rearranged hormone-naive prostate cancer (HNPC and CRPC tissue samples. Functional studies demonstrated that ERG has an inhibitory effect on TFF3 expression in hormone-naive cancer but not in the castration-resistant state. In addition, we provide evidence suggesting an effect of androgen receptor signaling on ERG-regulated TFF3 expression. Furthermore, TFF3 overexpression enhances ERG-mediated cell invasion in CRPC prostate cancer cells. Taken together, our findings reveal a novel mechanism for enhanced tumor cell aggressiveness resulting from ERG rearrangement in the castration-resistant setting through TFF3 gene expression.

  15. ERG cooperates with androgen receptor in regulating trefoil factor 3 in prostate cancer disease progression.

    Science.gov (United States)

    Rickman, David S; Chen, Ying-Bei; Banerjee, Samprit; Pan, Yihang; Yu, Jindan; Vuong, Terry; Perner, Sven; Lafargue, Christopher J; Mertz, Kirsten D; Setlur, Sunita R; Sircar, Kanishka; Chinnaiyan, Arul M; Bismar, Tarek A; Rubin, Mark A; Demichelis, Francesca

    2010-12-01

    To elucidate the role of ETS gene fusions in castration-resistant prostate cancer (CRPC), we characterized the transcriptome of 54 CRPC tumor samples from men with locally advanced or metastatic disease. Trefoil factor 3 (TFF3) emerged as the most highly differentially regulated gene with respect to ERG rearrangement status and resistance to hormone ablation therapy. Conventional chromatin immunoprecipitation (ChIP)-polymerase chain reaction and ChIP followed by DNA sequencing (ChIP-seq) revealed direct binding of ERG to ETS binding sites in the TFF3 promoter in ERG-rearranged prostate cancer cell lines. These results were confirmed in ERG-rearranged hormone-naive prostate cancer (HNPC) and CRPC tissue samples. Functional studies demonstrated that ERG has an inhibitory effect on TFF3 expression in hormone-naive cancer but not in the castration-resistant state. In addition, we provide evidence suggesting an effect of androgen receptor signaling on ERG-regulated TFF3 expression. Furthermore, TFF3 overexpression enhances ERG-mediated cell invasion in CRPC prostate cancer cells. Taken together, our findings reveal a novel mechanism for enhanced tumor cell aggressiveness resulting from ERG rearrangement in the castration-resistant setting through TFF3 gene expression.

  16. Prospective studies of hormonal and life-style related factors and risk of cancer

    OpenAIRE

    Wirén, Sara

    2014-01-01

    Background: Androgens are important in prostate cancer development but how circulating levels of androgens affect risk of prostate cancer of different aggressiveness is not clear. Being childless has been associated with a lower risk of prostate cancer, but it is not clear if this association is causal or a result of residual confounding. Fathering of dizygotic twins, a marker of high fertility, has not been studied in relation to risk of prostate cancer. Another marker of life-long hormonal ...

  17. Upregulation of Leukotriene Receptors in Gastric Cancer

    Directory of Open Access Journals (Sweden)

    Daniel Schubert

    2011-08-01

    Full Text Available Background: Leukotrienes (LT mediate allergic and inflammatory processes. Previously, we identified significant changes in the expression pattern of LT receptors in the gastric mucosa after eradication of Helicobacter pylori infection. The aim of the present study was to evaluate the expression of 5-lipoxygenase (5-LOX and LT receptors in gastric cancer (GC. Methods: The expression of 5-LOX and receptors for LTB4 (BLT-1, BLT-2 and cysteinyl-LT (CysLT-1, CysLT-2 were analyzed by immunohistochemistry (IHC in GC samples of 35 consecutive patients who underwent gastrectomy and in 29 tumor-free tissue specimens from gastric mucosa. Results: Male-to-female ratio was 24:11. The median age was 70 years (range 34–91. Twenty-two patients had GC of intestinal, six of diffuse, six of mixed and one of undifferentiated type. The IHC analysis showed a nearly ubiquitous expression of studied proteins in GC (88–97% and in tumor-free specimens as well (89–100%. An increase in the immunoreactive score of both BLT receptors and CysLT-1 was observed in GC compared to tumor-free gastric mucosa (p < 0.001 for BLT-1; p < 0.01 for BLT-2 and CysLT-1, Mann-Whitney U-test. No differences in the IHC expression of 5-LOX and CsyLT-2 were observed between GC and tumor-free mucosa. The expression of BLT-2, CysLT-1 and CysLT-2 was increased in GC of intestinal type when compared to the diffuse type (p < 0.05; Mann-Whitney U-test. Conclusions: LTB4 receptors and CysLT-1 are up-regulated in GC tissue implying a role in gastric carcinogenesis.

  18. Upregulation of Leukotriene Receptors in Gastric Cancer

    International Nuclear Information System (INIS)

    Leukotrienes (LT) mediate allergic and inflammatory processes. Previously, we identified significant changes in the expression pattern of LT receptors in the gastric mucosa after eradication of Helicobacter pylori infection. The aim of the present study was to evaluate the expression of 5-lipoxygenase (5-LOX) and LT receptors in gastric cancer (GC). The expression of 5-LOX and receptors for LTB4 (BLT-1, BLT-2) and cysteinyl-LT (CysLT-1, CysLT-2) were analyzed by immunohistochemistry (IHC) in GC samples of 35 consecutive patients who underwent gastrectomy and in 29 tumor-free tissue specimens from gastric mucosa. Male-to-female ratio was 24:11. The median age was 70 years (range 34–91). Twenty-two patients had GC of intestinal, six of diffuse, six of mixed and one of undifferentiated type. The IHC analysis showed a nearly ubiquitous expression of studied proteins in GC (88–97%) and in tumor-free specimens as well (89–100%). An increase in the immunoreactive score of both BLT receptors and CysLT-1 was observed in GC compared to tumor-free gastric mucosa (p < 0.001 for BLT-1; p < 0.01 for BLT-2 and CysLT-1, Mann-Whitney U-test). No differences in the IHC expression of 5-LOX and CsyLT-2 were observed between GC and tumor-free mucosa. The expression of BLT-2, CysLT-1 and CysLT-2 was increased in GC of intestinal type when compared to the diffuse type (p < 0.05; Mann-Whitney U-test). LTB4 receptors and CysLT-1 are up-regulated in GC tissue implying a role in gastric carcinogenesis

  19. Upregulation of Leukotriene Receptors in Gastric Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Venerito, Marino [Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg 39120 (Germany); Kuester, Doerthe [Institute of Pathology, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg 39120 (Germany); Harms, Caroline [Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg 39120 (Germany); Schubert, Daniel [Department of General, Visceral and Vascular Surgery, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, Magdeburg 39120 (Germany); Wex, Thomas, E-mail: thomas.wex@med.ovgu.de; Malfertheiner, Peter [Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg 39120 (Germany)

    2011-08-08

    Leukotrienes (LT) mediate allergic and inflammatory processes. Previously, we identified significant changes in the expression pattern of LT receptors in the gastric mucosa after eradication of Helicobacter pylori infection. The aim of the present study was to evaluate the expression of 5-lipoxygenase (5-LOX) and LT receptors in gastric cancer (GC). The expression of 5-LOX and receptors for LTB4 (BLT-1, BLT-2) and cysteinyl-LT (CysLT-1, CysLT-2) were analyzed by immunohistochemistry (IHC) in GC samples of 35 consecutive patients who underwent gastrectomy and in 29 tumor-free tissue specimens from gastric mucosa. Male-to-female ratio was 24:11. The median age was 70 years (range 34–91). Twenty-two patients had GC of intestinal, six of diffuse, six of mixed and one of undifferentiated type. The IHC analysis showed a nearly ubiquitous expression of studied proteins in GC (88–97%) and in tumor-free specimens as well (89–100%). An increase in the immunoreactive score of both BLT receptors and CysLT-1 was observed in GC compared to tumor-free gastric mucosa (p < 0.001 for BLT-1; p < 0.01 for BLT-2 and CysLT-1, Mann-Whitney U-test). No differences in the IHC expression of 5-LOX and CsyLT-2 were observed between GC and tumor-free mucosa. The expression of BLT-2, CysLT-1 and CysLT-2 was increased in GC of intestinal type when compared to the diffuse type (p < 0.05; Mann-Whitney U-test). LTB4 receptors and CysLT-1 are up-regulated in GC tissue implying a role in gastric carcinogenesis.

  20. Altered metabolism of growth hormone receptor mutant mice: a combined NMR metabonomics and microarray study.

    Directory of Open Access Journals (Sweden)

    Horst Joachim Schirra

    Full Text Available BACKGROUND: Growth hormone is an important regulator of post-natal growth and metabolism. We have investigated the metabolic consequences of altered growth hormone signalling in mutant mice that have truncations at position 569 and 391 of the intracellular domain of the growth hormone receptor, and thus exhibit either low (around 30% maximum or no growth hormone-dependent STAT5 signalling respectively. These mutations result in altered liver metabolism, obesity and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: The analysis of metabolic changes was performed using microarray analysis of liver tissue and NMR metabonomics of urine and liver tissue. Data were analyzed using multivariate statistics and Gene Ontology tools. The metabolic profiles characteristic for each of the two mutant groups and wild-type mice were identified with NMR metabonomics. We found decreased urinary levels of taurine, citrate and 2-oxoglutarate, and increased levels of trimethylamine, creatine and creatinine when compared to wild-type mice. These results indicate significant changes in lipid and choline metabolism, and were coupled with increased fat deposition, leading to obesity. The microarray analysis identified changes in expression of metabolic enzymes correlating with alterations in metabolite concentration both in urine and liver. Similarity of mutant 569 to the wild-type was seen in young mice, but the pattern of metabolites shifted to that of the 391 mutant as the 569 mice became obese after six months age. CONCLUSIONS/SIGNIFICANCE: The metabonomic observations were consistent with the parallel analysis of gene expression and pathway mapping using microarray data, identifying metabolites and gene transcripts involved in hepatic metabolism, especially for taurine, choline and creatinine metabolism. The systems biology approach applied in this study provides a coherent picture of metabolic changes resulting from impaired STAT5 signalling by the growth hormone

  1. Adipokinetic hormones and their G protein-coupled receptors emerged in Lophotrochozoa.

    Science.gov (United States)

    Li, Shizhong; Hauser, Frank; Skadborg, Signe K; Nielsen, Stine V; Kirketerp-Møller, Nikolaj; Grimmelikhuijzen, Cornelis J P

    2016-01-01

    Most multicellular animals belong to two evolutionary lineages, the Proto- and Deuterostomia, which diverged 640-760 million years (MYR) ago. Neuropeptide signaling is abundant in animals belonging to both lineages, but it is often unclear whether there exist evolutionary relationships between the neuropeptide systems used by proto- or deuterostomes. An exception, however, are members of the gonadotropin-releasing hormone (GnRH) receptor superfamily, which occur in both evolutionary lineages, where GnRHs are the ligands in Deuterostomia and GnRH-like peptides, adipokinetic hormone (AKH), corazonin, and AKH/corazonin-related peptide (ACP) are the ligands in Protostomia. AKH is a well-studied insect neuropeptide that mobilizes lipids and carbohydrates from the insect fat body during flight. In our present paper, we show that AKH is not only widespread in insects, but also in other Ecdysozoa and in Lophotrochozoa. Furthermore, we have cloned and deorphanized two G protein-coupled receptors (GPCRs) from the oyster Crassostrea gigas (Mollusca) that are activated by low nanomolar concentrations of oyster AKH (pQVSFSTNWGSamide). Our discovery of functional AKH receptors in molluscs is especially significant, because it traces the emergence of AKH signaling back to about 550 MYR ago and brings us closer to a more complete understanding of the evolutionary origins of the GnRH receptor superfamily. PMID:27628442

  2. Gonadal steroid hormone receptors and sex differences in the hypothalamo-pituitary-adrenal axis.

    Science.gov (United States)

    Handa, R J; Burgess, L H; Kerr, J E; O'Keefe, J A

    1994-12-01

    The rapid activation of stress-responsive neuroendocrine systems is a basic reaction of animals to perturbations in their environment. One well-established response is that of the hypothalamo-pituitary-adrenal (HPA) axis. In rats, corticosterone is the major adrenal steroid secreted and is released in direct response to adrenocorticotropin (ACTH) secreted from the anterior pituitary gland. ACTH in turn is regulated by the hypothalamic factor, corticotropin-releasing hormone. A sex difference exists in the response of the HPA axis to stress, with females reacting more robustly than males. It has been demonstrated that in both sexes, products of the HPA axis inhibit reproductive function. Conversely, the sex differences in HPA function are in part due to differences in the circulating gonadal steroid hormone milieu. It appears that testosterone can act to inhibit HPA function, whereas estrogen can enhance HPA function. One mechanism by which androgens and estrogens modulate stress responses is through the binding to their cognate receptors in the central nervous system. The distribution and regulation of androgen and estrogen receptors within the CNS suggest possible sites and mechanisms by which gonadal steroid hormones can influence stress responses. In the case of androgens, data suggest that the control of the hypothalamic paraventricular nucleus is mediated trans-synaptically. For estrogen, modulation of the HPA axis may be due to changes in glucocorticoid receptor-mediated negative feedback mechanisms. The results of a variety of studies suggest that gonadal steroid hormones, particularly testosterone, modulate HPA activity in an attempt to prevent the deleterious effects of HPA activation on reproductive function. PMID:7729815

  3. Current medical treatment of estrogen receptor-positive breast cancer

    Institute of Scientific and Technical Information of China (English)

    Franco; Lumachi; Davide; A; Santeufemia; Stefano; MM; Basso

    2015-01-01

    Approximately 80% of breast cancers(BC) are estrogen receptor(ER)-positive and thus endocrine therapy(ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adrenalectomy and hypophysectomy in women with advanced BC have been demonstrated many years ago, and currently ET consist of(1) ovarian function suppression(OFS), usually obtained using gonadotropinreleasing hormone agonists(Gn RHa);(2) selective estrogen receptor modulators or down-regulators(SERMs or SERDs); and(3) aromatase inhibitors(AIs), or a combination of two or more drugs. For patients aged less than 50 years and ER+ BC, there is no conclusive evidence that the combination of OFS and SERMs(i.e., tamoxifen) or chemotherapy is superior to OFS alone. Tamoxifen users exhibit a reduced risk of BC, both invasive and in situ, especially during the first 5 years of therapy, and extending the treatment to 10 years further reduced the risk of recurrences. SERDs(i.e., fulvestrant) are especially useful in the neoadjuvant treatment of advanced BC, alone or in combination with either cytotoxic agents or AIs. There are two types of AIs: type Ⅰ are permanent steroidal inhibitors of aromatase, while type Ⅱ are reversible nonsteroidal inhibitors. Several studies demonstrated the superiority of the third-generation AIs(i.e., anastrozole and letrozole) compared with tamoxifen, and adjuvant therapy with AIs reduces the recurrence risk especially in patients with advanced BC. Unfortunately, some cancers are or became ET-resistant, and thus other drugs have been suggested in combination with SERMs or AIs, including cyclin-dependent kinase 4/6 inhibitors(palbociclib) and mammalian target of rapamycin(m TOR) inhibitors, such as everolimus. Further studies are required to confirm their real usefulness.

  4. Gonadotropin-releasing hormone agonist use in men without a cancer registry diagnosis of prostate cancer

    Directory of Open Access Journals (Sweden)

    Kuo Yong-fang

    2008-07-01

    Full Text Available Abstract Background Use of gonadotropin-releasing hormone (GnRH agonists has become popular for virtually all stages of prostate cancer. We hypothesized that some men receive these agents after only a limited work-up for their cancer. Such cases may be missed by tumor registries, leading to underestimates of the total extent of GnRH agonist use. Methods We used linked Surveillance, Epidemiology and End-Results (SEER-Medicare data from 1993 through 2001 to identify GnRH agonist use in men with either a diagnosis of prostate cancer registered in SEER, or with a diagnosis of prostate cancer based only on Medicare claims (from the 5% control sample of Medicare beneficiaries residing in SEER areas without a registered diagnosis of cancer. The proportion of incident GnRH agonist users without a registry diagnosis of prostate cancer was calculated. Factors associated with lack of a registry diagnosis were examined in multivariable analyses. Results Of incident GnRH agonist users, 8.9% had no diagnosis of prostate cancer registered in SEER. In a multivariable logistic regression model, lack of a registry diagnosis of prostate cancer in GnRH agonist users was significantly more likely with increasing comorbidity, whereas it was less likely in men who had undergone either inpatient admission or procedures such as radical prostatectomy, prostate biopsy, or transurethral resection of the prostate. Conclusion Reliance solely on tumor registry data may underestimate the rate of GnRH agonist use in men with prostate cancer.

  5. Systemic cancer immunotherapy with Toll-like receptor 7 agonists

    Science.gov (United States)

    Hotz, Christian; Bourquin, Carole

    2012-01-01

    Toll-like receptor (TLR) 7 agonists represent a promising strategy for the immunotherapy of cancer. We have recently investigated the influence of TLR tolerance on the efficacy of systemic tumor treatment with TLR7 ligands. We propose that considering the kinetics of receptor sensitivity highly improves the outcome of cancer immunotherapy. PMID:22720251

  6. Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans.

    Directory of Open Access Journals (Sweden)

    Marc R Van Gilst

    2005-02-01

    Full Text Available Mammalian nuclear hormone receptors (NHRs, such as liver X receptor, farnesoid X receptor, and peroxisome proliferator-activated receptors (PPARs, precisely control energy metabolism. Consequently, these receptors are important targets for the treatment of metabolic diseases, including diabetes and obesity. A thorough understanding of NHR fat regulatory networks has been limited, however, by a lack of genetically tractable experimental systems. Here we show that deletion of the Caenorhabditis elegans NHR gene nhr-49 yielded worms with elevated fat content and shortened life span. Employing a quantitative RT-PCR screen, we found that nhr-49 influenced the expression of 13 genes involved in energy metabolism. Indeed, nhr-49 served as a key regulator of fat usage, modulating pathways that control the consumption of fat and maintain a normal balance of fatty acid saturation. We found that the two phenotypes of the nhr-49 knockout were linked to distinct pathways and were separable: The high-fat phenotype was due to reduced expression of enzymes in fatty acid beta-oxidation, and the shortened adult life span resulted from impaired expression of a stearoyl-CoA desaturase. Despite its sequence relationship with the mammalian hepatocyte nuclear factor 4 receptor, the biological activities of nhr-49 were most similar to those of the mammalian PPARs, implying an evolutionarily conserved role for NHRs in modulating fat consumption and composition. Our findings in C. elegans provide novel insights into how NHR regulatory networks are coordinated to govern fat metabolism.

  7. 甲状腺素及受体与心肌缺血%The relationship among thyroid hormone, thyroid hormone receptor and myocardial ischemia

    Institute of Scientific and Technical Information of China (English)

    晏浩; 李文林; 徐建军

    2010-01-01

    Sub-clinical hypothyroidism is associated with both high risk of coronary heart disease and increased mortality from cardiovascular causes. This review summarizes the protective effects of thyroid hormone on myocardial ischemia, and possible mechanisms of thyroid hormone and thyroid hormone receptors.%亚临床甲状腺功能减退被认为与冠心病发病率和心脏疾病死亡密切相关,新近研究发现甲状腺素(tlhryroid hormone,TH)对缺血心肌有保护作用,现从甲状腺素及其受体角度阐述其机制.

  8. Hormonal therapy and chemotherapy in patients with hormone-sensitive prostate cancer

    Directory of Open Access Journals (Sweden)

    R. A. Gafanov

    2016-01-01

    Full Text Available Prostate cancer is the most common men`s cancer in men in developed world and the second cause of death in this population. This review focuses on management of advanced castration resistant prostate cancer (CRPC has been rapidly changing and is still evolving. In the last years, there has been an increasing knowledge of prostate cancer biology. New therapeutic agents and approaches have been evaluated demonstrating benefits in survival and quality of life in patients with metastatic prostate cancer.

  9. Docetaxel treatment in the elderly patient with hormone refractory prostate cancer

    Directory of Open Access Journals (Sweden)

    Victoria J Sinibaldi

    2008-01-01

    Full Text Available Victoria J SinibaldiSidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MA, USAAbstract: Docetaxel is an anti-microtubular agent in the family of the taxanes, now FDA approved as first line chemotherapy for the treatment of hormone refractory metastatic prostate cancer. Recent data from two large randomized Phase III trials showed a survival advantage in hormone refractory prostate cancer patients treated with docetaxel. This discovery changed the perceptions about utilization of chemotherapy for this devastating disease and introduced a new paradigm/standard of care treatment for this patient population. The management of elderly patients with metastatic prostate cancer is an important issue because according to data from the Surveillance, Epidemiology, and End Results (SEER program, the American Cancer Society, and the United Nations, the incidence of prostate cancer in elderly men is expected to increase since people are living longer. In this paper we will review the results of trials evaluating docetaxel in hormone refractory prostate cancer and the implications of these trials as they relate to diagnosis and management of this disease in the elderly man.Keywords: docetaxel, hormone refractory prostate cancer, elderly patient

  10. Breast cancer incidence and use of hormone therapy in Denmark 1978-2007

    DEFF Research Database (Denmark)

    von Euler-Chelpin, My

    2011-01-01

    Internationally, there have recently been reports of declining incidence rates for breast cancer. Decreased use of hormone therapy and decreased use of mammography has been put forward as possible reasons for this decline. The aim of this study was to analyse breast cancer incidence trends in Den...

  11. Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers:

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Rookus, Matti; Andrieu, Nadine;

    2009-01-01

    BACKGROUND: Several reproductive and hormonal factors are known to be associated with ovarian cancer risk in the general population, including parity and oral contraceptive (OC) use. However, their effect on ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has only been investigated in a...

  12. Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers

    NARCIS (Netherlands)

    A. Eisen (Andrea); J. Lubinski (Jan); J. Gronwald (Jacek); P. Moller (Pal); H. Lynch (Henry); J. Klijn (Jan); C. Kim-Sing (Charmaine); S.L. Neuhausen (Susan); L. Gilbert (Lucy); P. Ghadirian (Parviz); S. Manoukian (Siranoush); G. Rennert (Gad); E. Friedman (Eitan); C. Isaacs (Claudine); B. Rosen (Barry); M.J. Daly (Mark); P. Sun (Ping); S. Narod (Steven); O.I. Olopade (Olofunmilayo); S. Cummings (Shelly); N. Tung (Nadine); F.J. Couch (Fergus); W.D. Foulkes (William); S.M. Domchek (Susan); D. Stoppa-Lyonnet (Dominique); R. Gershoni-Baruch (Ruth); D. Horsman (David); H. Saal (Howard); E. Warner (Ellen); W. Meschino (Wendy); K. Offit (Kenneth); A. Trivedi (Amber); M. Robson (Mark); M. Osborne (Michael); D. Gilchrist (Dawna); J.N. Weitzel (Jeffrey); W. McKinnon (Wendy); M. Wood (Marie); C. Maugard (Christine); B. Pasini (Barbara); T. Wagner (Teresa); K. Sweet; B. Pasche (Boris); T. Fallen (Taya); B.Y. Karlan (Beth); C. Eng (Charis); R.N. Kurz; S. Armel (Susan); A. Tulman (Anna); P.J. Ainsworth (Peter); E. Lemire (Edmond); J. McLennan; G. Evans (Gareth); T. Byrski (Tomas); T. Huzarski (Tomas); L. Shulman (Lee)

    2008-01-01

    textabstractBackground: Hormone therapy (HT) is commonly given to women to alleviate the climacteric symptoms associated with menopause. There is concern that this treatment may increase the risk of breast cancer. The potential association of HT and breast cancer risk is of particular interest to wo

  13. Increased risk of breast cancer following different regimens of hormone replacement therapy frequently used in Europe

    DEFF Research Database (Denmark)

    Stahlberg, Claudia; Pedersen, Anette Tønnes; Lynge, Elsebeth;

    2004-01-01

    Epidemiologic studies have shown an increased risk of breast cancer following hormone replacement therapy (HRT). The aim of this study was to investigate whether different treatment regimens or the androgenecity of progestins influence the risk of breast cancer differently. The Danish Nurse Cohort...

  14. Postmenopausal hormone therapy and breast cancer: a clinician's message for patients.

    Science.gov (United States)

    Speroff, Leon

    2004-08-01

    The Women's Health Initiative agrees with some but not all case-control and cohort studies that current use of postmenopausal estrogen-progestin therapy is associated with a small increase in the risk of breast cancer. It is not known whether this is because of new tumor growth or an effect of hormonal therapy on preexisting tumors. Many studies indicate that women who develop breast cancer while using postmenopausal hormone therapy have a reduced risk of dying from breast cancer; this is consistent with an effect on preexisting tumors so that tumors appear at a less virulent and aggressive stage.

  15. The Arabidopsis NPR1 Protein Is a Receptor for the Plant Defense Hormone Salicylic Acid

    Directory of Open Access Journals (Sweden)

    Yue Wu

    2012-06-01

    Full Text Available Salicylic acid (SA is an essential hormone in plant immunity, but its receptor has remained elusive for decades. The transcriptional coregulator NPR1 is central to the activation of SA-dependent defense genes, and we previously found that Cys521 and Cys529 of Arabidopsis NPR1's transactivation domain are critical for coactivator function. Here, we demonstrate that NPR1 directly binds SA, but not inactive structural analogs, with an affinity similar to that of other hormone-receptor interactions and consistent with in vivo Arabidopsis SA concentrations. Binding of SA occurs through Cys521/529 via the transition metal copper. Mechanistically, our results suggest that binding of SA causes a conformational change in NPR1 that is accompanied by the release of the C-terminal transactivation domain from the N-terminal autoinhibitory BTB/POZ domain. While NPR1 is already known as a link between the SA signaling molecule and defense-gene activation, we now show that NPR1 is the receptor for SA.

  16. The Role of Estrogen Receptor β in Prostate Cancer

    OpenAIRE

    Christoforou, Paraskevi; Christopoulos, Panagiotis F; Koutsilieris, Michael

    2014-01-01

    Although androgen receptor (AR) signaling is the main molecular tool regulating growth and function of the prostate gland, estrogen receptor β (ERβ) is involved in the differentiation of prostatic epithelial cells and numerous antiproliferative actions on prostate cancer cells. However, ERβ splice variants have been associated with prostate cancer initiation and progression mechanisms. ERβ is promising as an anticancer therapy and in the prevention of prostate cancer. Herein, we review the re...

  17. The role of Estrogen Receptor Beta in Prostate Cancer.

    OpenAIRE

    Christoforou, Paraskevi; Christopoulos, Panagiotis F; Koutsilieris, Michael

    2014-01-01

    Although androgen receptor (AR) signaling is the main molecular tool regulating growth and function of prostate gland, estrogen receptor beta (ERβ) is involved contributive in the differentiation of prostatic epithelial cells and numerous antiproliferative actions on prostate cancer cells. However, ERβ splice variants have been associated with prostate cancer initiation and progression mechanisms. Nowadays, ERß is a promising target as an anticancer therapy and prevention for prostate cancer....

  18. Salt Bridges Overlapping the Gonadotropin-Releasing Hormone Receptor Agonist Binding Site Reveal a Coincidence Detector for G Protein-Coupled Receptor Activation

    OpenAIRE

    Janovick, Jo Ann; Pogozheva, Irina D.; Mosberg, Henry I.; Conn, P. Michael

    2011-01-01

    G protein-coupled receptors (GPCRs) play central roles in most physiological functions, and mutations in them cause heritable diseases. Whereas crystal structures provide details about the structure of GPCRs, there is little information that identifies structural features that permit receptors to pass the cellular quality control system or are involved in transition from the ground state to the ligand-activated state. The gonadotropin-releasing hormone receptor (GnRHR), because of its small s...

  19. Thyroid hormone exerts negative feedback on hypothalamic type 4 melanocortin receptor expression.

    Science.gov (United States)

    Decherf, Stéphanie; Seugnet, Isabelle; Kouidhi, Soumaya; Lopez-Juarez, Alejandra; Clerget-Froidevaux, Marie-Stéphanie; Demeneix, Barbara A

    2010-03-01

    The type 4 melanocortin receptor MC4R, a key relay in leptin signaling, links central energy control to peripheral reserve status. MC4R activation in different brain areas reduces food intake and increases energy expenditure. Mice lacking Mc4r are obese. Mc4r is expressed by hypothalamic paraventricular Thyrotropin-releasing hormone (TRH) neurons and increases energy usage through activation of Trh and production of the thyroid hormone tri-iodothyronine (T(3)). These facts led us to test the hypothesis that energy homeostasis should require negative feedback by T(3) on Mc4r expression. Quantitative PCR and in situ hybridization showed hyperthyroidism reduces Mc4r mRNA levels in the paraventricular nucleus. Comparative in silico analysis of Mc4r regulatory regions revealed two evolutionarily conserved potential negative thyroid hormone-response elements (nTREs). In vivo ChIP assays on mouse hypothalamus demonstrated association of thyroid hormone receptors (TRs) with a region spanning one nTRE. Further, in vivo gene reporter assays revealed dose-dependent T(3) repression of transcription from the Mc4r promoter in mouse hypothalamus, in parallel with T(3)-dependent Trh repression. Mutagenesis of the nTREs in the Mc4r promoter demonstrated direct regulation by T(3), consolidating the ChIP results. In vivo shRNA knockdown, TR over-expression approaches and use of mutant mice lacking specific TRs showed that both TRalpha and TRbeta contribute to Mc4r regulation. T(3) repression of Mc4r transcription ensures that the energy-saving effects of T(3) feedback on Trh are not overridden by MC4R activation of Trh. Thus parallel repression by T(3) on hypothalamic Mc4r and Trh contributes to energy homeostasis.

  20. 3,5-T2 is an alternative ligand for the thyroid hormone receptor β1.

    Science.gov (United States)

    Mendoza, A; Navarrete-Ramírez, P; Hernández-Puga, G; Villalobos, P; Holzer, G; Renaud, J P; Laudet, V; Orozco, A

    2013-08-01

    Several liganded nuclear receptors have alternative ligands acting in a tissue-specific fashion and playing important biological roles. We present evidence that 3,5-diiodothyronine (T(2)), a naturally occurring iodothyronine that results from T(3) outer-ring deiodination, is an alternative ligand for thyroid hormone receptor β1 (TRβ1). In tilapia, 2 TRβ isoforms differing by 9 amino acids in the ligand-binding domain were cloned. Binding and transactivation studies showed that T(2) activates the human and the long tilapia TRβ1 isoform, but not the short one. A chimeric human TRβ1 (hTRβ1) that contained the 9-amino-acid insert showed no response to T(2), suggesting that the conformation of the hTRβ1 naturally allows T(2) binding and that other regions of the receptor are implicated in TR activation by T(2). Indeed, further analysis showed that the N terminus is essential for T(2)-mediated transactivation but not for that by T(3) in the long and hTRβ1, suggesting a functional interaction between the N-terminal domain and the insertion in the ligand-binding domain. To establish the functional relevance of T(2)-mediated TRβ1 binding and activation, mRNA expression and its regulation by T(2) and T(3) was evaluated for both isoforms. Our data show that long TRβ1expression is 10(6)-fold higher than that of the short isoform, and T(3) and T(2) differentially regulate the expression of these 2 TRβ1 isoforms in vivo. Taken together, our results prompted a reevaluation of the role and mechanism of action of thyroid hormone metabolites previously believed to be inactive. More generally, we propose that classical liganded receptors are only partially locked to very specific ligands and that alternative ligands may play a role in the tissue-specific action of receptors. PMID:23736295

  1. Morphological and Hormonal Identiifcation of Porcine Atretic Follicles and Relationship Analysis of Hormone Receptor Levels During Granulosa Cell Apoptosis In vivo

    Institute of Scientific and Technical Information of China (English)

    YU De-bing; YU Min-li; LIN Fei; JIANG Bao-chun; YANG Li-na; WANG Si-yu; ZHAO Ying; WNAG Zheng-chao

    2014-01-01

    Recent reports have demonstrated that follicular atresia is initiated or caused by granulosa cell apoptosis followed by theca cell degeneration in mammalian ovaries, but the mechanism of follicular atresia is still to be elucidated. Therefore, our present study was designed to examine our hypothesis that the changes of follicular microenvironment induce the granulosa cell apoptosis during pocrine follicular atresia in vivo. We ifrstly isolated intact porcine antral follicles and identiifed them into three groups, healthy follicles (HF), early atretic follicles (EAF) and progressed atretic follicles (PAF) through morphology and histology. To further conifrm their status, we detected hormone levels in follicular lfuids and the expression level of apoptosis gene Bax in granulosa cells. The rate of progesterone (P) and estradiol (E2) was increased with the expression of Bax, indicating hormone can be used as a marker of granulosa cell apoptosis or follicular atresia. Finally, we analyzed the expression level of hormone receptor genes in granulosa cells and their relationship with follicular atresia. In PAF, the expression of Progesterone receptor (PGR) was increased signiifcantly while estradiol receptor (ER) had no notable changes, which suggesting the increased-PGR accelerated the effect of P-stimulated granulosa cell apoptosis. The dramatic increasing of androgen receptor (AR) expression in PAF and the obvious increase of tumor necrosis factor-αreceptor (TNFR) in EAF indicated that there are different pathways regulating granulosa cell apoptosis during follicular atresia. Together, our results suggested that different pathways of granulosa cell apoptosis was induced by changing the follicular microenvironment during follicular atresia.

  2. The Function of Steroid Receptor Coactivator-1 in Normal Tissues and Cancer

    Directory of Open Access Journals (Sweden)

    Claire A. Walsh, Li Qin, Jean Ching-Yi Tien, Leonie S. Young, Jianming Xu

    2012-01-01

    Full Text Available In 1995, the steroid receptor coactivator-1 (SRC-1 was identified as the first authentic steroid receptor coactivator. Since then, the SRC proteins have remained at the epicenter of coregulator biology, molecular endocrinology and endocrine-related cancer. Cumulative works on SRC-1 have shown that it is primarily a nuclear receptor coregulator and functions to construct highly specific enzymatic protein complexes which can execute efficient and successful transcriptional activation of designated target genes. The versatile nature of SRC-1 enables it to respond to steroid dependent and steroid independent stimulation, allowing it to bind across many families of transcription factors to orchestrate and regulate complex physiological reactions. This review highlights the multiple functions of SRC-1 in the development and maintenance of normal tissue functions as well as its major role in mediating hormone receptor responsiveness. Insights from genetically manipulated mouse models and clinical data suggest SRC-1 is significantly overexpressed in many cancers, in particular, cancers of the reproductive tissues. SRC-1 has been associated with cellular proliferation and tumor growth but its major tumorigenic contributions are promotion and execution of breast cancer metastasis and mediation of resistance to endocrine therapies. The ability of SRC-1 to coordinate multiple signaling pathways makes it an important player in tumor cells' escape of targeted therapy.

  3. Receptors and effects of gut hormones in three osteoblastic cell lines

    Directory of Open Access Journals (Sweden)

    Wilson Peter JM

    2011-07-01

    Full Text Available Abstract Background In recent years the interest on the relationship of gut hormones to bone processes has increased and represents one of the most interesting aspects in skeletal research. The proportion of bone mass to soft tissue is a relationship that seems to be controlled by delicate and subtle regulations that imply "cross-talks" between the nutrient intake and tissues like fat. Thus, recognition of the mechanisms that integrate a gastrointestinal-fat-bone axis and its application to several aspects of human health is vital for improving treatments related to bone diseases. This work analysed the effects of gut hormones in cell cultures of three osteoblastic cell lines which represent different stages in osteoblastic development. Also, this is the first time that there is a report on the direct effects of glucagon-like peptide 2, and obestatin on osteoblast-like cells. Methods mRNA expression levels of five gut hormone receptors (glucose-dependent insulinotropic peptide [GIP], glucagon-like peptide 1 [GLP-1], glucagon-like peptide 2 [GLP-2], ghrelin [GHR] and obestatin [OB] were analysed in three osteoblastic cell lines (Saos-2, TE-85 and MG-63 showing different stages of osteoblast development using reverse transcription and real time polymerase chain reaction. The responses to the gut peptides were studied using assays for cell viability, and biochemical bone markers: alkaline phosphatase (ALP, procollagen type 1 amino-terminal propeptides (P1NP, and osteocalcin production. Results The gut hormone receptor mRNA displayed the highest levels for GIP in Saos-2 and the lowest levels in MG-63, whereas GHR and GPR39 (the putative obestatin receptor expression was higher in TE-85 and MG-63 and lower in Saos-2. GLP-1 and GLP-2 were expressed only in MG-63 and TE-85. Treatment of gut hormones to cell lines showed differential responses: higher levels in cell viability in Saos-2 after GIP, in TE-85 and MG-63 after GLP-1, GLP-2, ghrelin and

  4. Diversification and coevolution of the ghrelin/growth hormone secretagogue receptor system in vertebrates.

    Science.gov (United States)

    Tine, Mbaye; Kuhl, Heiner; Teske, Peter R; Tschöp, Matthias H; Jastroch, Martin

    2016-04-01

    The gut hormone ghrelin is involved in numerous metabolic functions, such as the stimulation of growth hormone secretion, gastric motility, and food intake. Ghrelin is modified by ghrelin O-acyltransferase (GOAT) or membrane-bound O-acyltransferase domain-containing 4 (MBOAT4) enabling action through the growth hormone secretagogue receptors (GHS-R). During the course of evolution, initially strong ligand/receptor specificities can be disrupted by genomic changes, potentially modifying physiological roles of the ligand/receptor system. Here, we investigated the coevolution of ghrelin, GOAT, and GHS-R in vertebrates. We combined similarity search, conserved synteny analyses, phylogenetic reconstructions, and protein structure comparisons to reconstruct the evolutionary history of the ghrelin system. Ghrelin remained a single-gene locus in all vertebrate species, and accordingly, a single GHS-R isoform was identified in all tetrapods. Similar patterns of the nonsynonymous (dN) and synonymous (dS) ratio (dN/dS) in the vertebrate lineage strongly suggest coevolution of the ghrelin and GHS-R genes, supporting specific functional interactions and common physiological pathways. The selection profiles do not allow confirmation as to whether ghrelin binds specifically to GOAT, but the ghrelin dN/dS patterns are more similar to those of GOAT compared to MBOAT1 and MBOAT2 isoforms. Four GHS-R isoforms were identified in teleost genomes. This diversification of GHS-R resulted from successive rounds of duplications, some of which remained specific to the teleost lineage. Coevolution signals are lost in teleosts, presumably due to the diversification of GHS-R but not the ghrelin gene. The identification of the GHS-R diversity in teleosts provides a molecular basis for comparative studies on ghrelin's physiological roles and regulation, while the comparative sequence and structure analyses will assist translational medicine to determine structure-function relationships of the

  5. Clinical relevance of "withdrawal therapy" as a form of hormonal manipulation for breast cancer

    Directory of Open Access Journals (Sweden)

    Robertson John FR

    2011-09-01

    Full Text Available Abstract Background It has been shown in in-vitro experiments that "withdrawal" of tamoxifen inhibits growth of tumor cells. However, evidence is scarce when this is extrapolated into clinical context. We report our experience to verify the clinical relevance of "withdrawal therapy". Methods Breast cancer patients since 1998 who fulfilled the following criteria were selected from the departmental database and the case-notes were retrospectively reviewed: (1 estrogen receptor positive, operable primary breast cancer in elderly (age > 70 years, locally advanced or metastatic breast cancer; (2 disease deemed suitable for treatment by hormonal manipulation; (3 disease assessable by UICC criteria; (4 received "withdrawal" from a prior endocrine agent as a form of therapy; (5 on "withdrawal therapy" for ≥ 6 months unless they progressed prior. Results Seventeen patients with median age of 84.3 (53.7-92.5 had "withdrawal therapy" as second to tenth line of treatment following prior endocrine therapy using tamoxifen (n = 10, an aromatase inhibitor (n = 5, megestrol acetate (n = 1 or fulvestrant (n = 1. Ten patients (58.8% had clinical benefit (CB (complete response/partial response/stable disease ≥ 6 months with a median duration of Clinical Benefit (DoCB of 10+ (7-27 months. Two patients remain on "withdrawal therapy" at the time of analysis. Conclusion "Withdrawal therapy" appears to produce sustained CB in a significant proportion of patients. This applies not only to "withdrawal" from tamoxifen, but also from other categories of endocrine agents. "Withdrawal" from endocrine therapy is, therefore, a viable intercalating option between endocrine agents to minimise resistance and provide additional line of therapy. It should be considered as part of the sequencing of endocrine therapy.

  6. [The correlations between polymorphism of growth hormone receptor gene and butcher traits in rabbit].

    Science.gov (United States)

    Deng, Xiao-Song; Wan, Jie; Chen, Shi-Yi; Wang, Yan; Lai, Song-Jia; Jiang, Mei-Shan; Xu, Min

    2008-11-01

    Five rabbit populations (Belgian hare, Tianfu black rabbit, Great line of Zika rabbit, Harbin white rabbit, and California rabbit) were used to analyze the polymorphism of growth hormone receptor (GHR) gene by PCR-SSCP. Results indicated that there were two mutation sites (C705T and C810T) in the 5 populations. The least square analyses showed that the live weight, visceraste weight, and slaughter percentage of AA and MM genotypes were significantly lower than BB and NN genotypes (P0.05). It suggested that GHR gene may be a candidate gene responsible for butcher trait in rabbit.

  7. A single arginine residue determines species specificity of the human growth hormone receptor.

    OpenAIRE

    Souza, S C; Frick, G P; X Wang; Kopchick, J J; Lobo, R B; Goodman, H M

    1995-01-01

    Although growth hormone (GH) receptors (GHRs) in many species bind human (h) GH as well as their own GH, the hGHR only binds primate GH. Arg43 in hGHR interacts with Asp171 of hGH. Nonprimates have a His in the position equivalent to residue 171 of primate GH and a Leu in position 43 of primate GHR. To determine whether Arg43 accounts for the species specificity of the hGHR, point mutations that changed Leu43 to Arg were introduced into the cDNAs encoding the bovine (b) GHR or the rat GH bind...

  8. Hormonal therapy and chemotherapy in patients with hormone-sensitive prostate cancer

    OpenAIRE

    R. A. Gafanov

    2016-01-01

    Prostate cancer is the most common men`s cancer in men in developed world and the second cause of death in this population. This review focuses on management of advanced castration resistant prostate cancer (CRPC) has been rapidly changing and is still evolving. In the last years, there has been an increasing knowledge of prostate cancer biology. New therapeutic agents and approaches have been evaluated demonstrating benefits in survival and quality of life in patients with metastatic prostat...

  9. Hormone Replacement Therapy and Risk of Breast Cancer in Korean Women: A Quantitative Systematic Review

    OpenAIRE

    Bae, Jong-Myon; Kim, Eun Hee

    2015-01-01

    Objectives: The epidemiological characteristics of breast cancer incidence by age group in Korean women are unique. This systematic review aimed to investigate the association between hormone replacement therapy (HRT) and breast cancer risk in Korean women. Methods: We searched electronic databases such as KoreaMed, KMbase, KISS, and RISS4U as well as PubMed for publications on Korean breast cancer patients. We also conducted manual searching based on references and citations in potential pap...

  10. Factors associated to persistence with hormonal therapy in women with breast cancer

    OpenAIRE

    Brito, Cláudia; Portela, Margareth Crisóstomo; Vasconcellos, Mauricio Teixeira Leite de

    2014-01-01

    OBJECTIVE To analyze factors associated with persistence to breast cancer hormone therapy in order to contribute to the quality of care improvement. METHODS Retrospective longitudinal study, based on secondary data. A cohort of 5,861 women with breast cancer registered in different datasets of the Brazilian National Cancer Institute and the Brazilian Unified Health System were analyzed. All women were treated at this hospital, which provides free medication, and the follow-up period was from ...

  11. Aromatase inhibitors with or without gonadotropin-releasing hormone analogue in metastatic male breast cancer: a case series

    Science.gov (United States)

    Zagouri, F; Sergentanis, T N; Koutoulidis, V; Sparber, C; Steger, G G; Dubsky, P; Zografos, G C; Psaltopoulou, T; Gnant, M; Dimopoulos, M-A; Bartsch, R

    2013-01-01

    Background: Data regarding the safety and effectiveness of aromatase inhibitors (AIs) as monotherapy or combined with gonadotropin-releasing hormone (GnRH) analogue in male breast cancer are scarce. Methods: In this retrospective chart review, cases of male breast cancer patients treated with AIs with or without a GnRH analogue were evaluated. Results: Twenty-three men were included into this case series. Aromatase inhibitors in combination with or without a GnRH analogue were given as first-line therapy in 60.9% and as second-line therapy in 39.1% of patients, respectively. All patients had visceral metastases, whereas in five of them bone lesions coexisted. In all cases AIs were tolerated well, and no case of grade 3 and 4 adverse events was reported. A partial response was observed in 26.1% of patients and stable disease in 56.5%. Median overall survival (OS) was 39 months and median progression-free survival (PFS) was 13 months. Regarding OS and PFS, no significant effects of GnRH analogue co-administration or type of AI were noted. Conclusion: Our study shows that AIs with or without GnRH analogues may represent an effective and safe treatment option for hormone-receptor positive, pretreated, metastatic, male breast cancer patients. PMID:23722469

  12. A novel unidirectional cross-talk from the insulin-like growth factor-I receptor to leptin receptor in human breast cancer cells.

    Science.gov (United States)

    Ozbay, Tuba; Nahta, Rita

    2008-06-01

    Obesity is a major risk factor for the development and progression of breast cancer. Increased circulating levels of the obesity-associated hormones leptin and insulin-like growth factor-I (IGF-I) and overexpression of the leptin receptor (Ob-R) and IGF-I receptor (IGF-IR) have been detected in a majority of breast cancer cases and during obesity. Due to correlations between increased leptin, Ob-R, IGF-I, and IGF-IR in breast cancer, we hypothesized that molecular interactions may exist between these two signaling pathways. Coimmunoprecipitation and immunoblotting showed that IGF-IR and Ob-R interact in the breast cancer cell lines MDA-MB-231, MCF7, BT474, and SKBR3. Stimulation of cells with IGF-I promoted Ob-R phosphorylation, which was blocked by IGF-IR kinase inhibition. In addition, IGF-I activated downstream signaling molecules in the leptin receptor and IGF-IR pathways. In contrast to IGF-I, leptin did not induce phosphorylation of IGF-IR, indicating that receptor cross-signaling is unidirectional, occurring from IGF-IR to Ob-R. Our results show, for the first time, a novel interaction and cross-talk between the IGF-I and leptin receptors in human breast cancer cells.

  13. A nested case-control study of adjuvant hormonal therapy persistence and compliance, and early breast cancer recurrence in women with stage I-III breast cancer

    OpenAIRE

    Bennett, Kathleen

    2013-01-01

    PUBLISHED Background: Non-persistence and non-compliance are common in women prescribed hormonal therapy for breast cancer, but little is known about their influence on recurrence. Methods: A nested case–control study of associations between hormonal therapy non-persistence and non-compliance and the risk of early recurrence in women with stage I–III breast cancer was undertaken. Cases, defined as women with a breast cancer recurrence within 4 years of hormonal therapy initiati...

  14. A nested case–control study of adjuvant hormonal therapy persistence and compliance, and early breast cancer recurrence in women with stage I–III breast cancer

    OpenAIRE

    Barron, T I; Cahir, C; Sharp, L.; Bennett, K.

    2013-01-01

    Background: Non-persistence and non-compliance are common in women prescribed hormonal therapy for breast cancer, but little is known about their influence on recurrence. Methods: A nested case–control study of associations between hormonal therapy non-persistence and non-compliance and the risk of early recurrence in women with stage I–III breast cancer was undertaken. Cases, defined as women with a breast cancer recurrence within 4 years of hormonal therapy initiation, were matched to contr...

  15. Quality of life impact of primary treatments for localized prostate cancer patients without hormonal treatment

    OpenAIRE

    Pardo, Y.; Guedea Edo, Ferran; Aguiló, F.; Fernández, P.; Macías, V.; Mariño, A.; Hervás, A; Herruzo, A.; Ortiz, M.J.; Ponce de León, J.; Craven-Bratle, J.; Suárez, J.F.; Boladeras, A.; Pont, A.; Ayala, A

    2010-01-01

    Purpose Earlier studies evaluating the effect on quality of life (QoL) of localized prostate cancer interventions included patients receiving adjuvant hormone therapy, which could have affected their outcomes. Our objective was to compare the QoL impact of the three most common primary treatments on patients who were not receiving adjuvant hormonal treatment. PATIENTS AND METHODS: This was a prospective study of 435 patients treated with radical prostatectomy, external-beam radiotherapy, or b...

  16. Postmenopausal hormone therapy and the risk of breast cancer. A clinician's view.

    Science.gov (United States)

    Speroff, Leon

    2004-09-24

    Reports from the Women's Health Initiative (WHI) and the Million Women Study have indicated that postmenopausal hormone therapy increases the risk of breast cancer. At this point in time, it is not certain whether these data reflect a small increase in risk or an impact of hormone therapy on pre-existing tumors. The purpose of this review is to provide an analysis of the epidemiologic data that can help the clinician inform patients and assist patients in their decision-making.

  17. Multi-nutrient supplement improves hormone ratio associated with cancer risk

    OpenAIRE

    Bazzan, Anthony J.; Zabrecky, George P; Newberg, Andrew B

    2013-01-01

    Background Gynecological cancers are among the most common in women and are directly related to a variety of hormonal factors. One potential risk factor associated with developing a gynecological malignancy is the ratio of two hormone metabolites, 2-Hydroxyestrone (2-HE) and 16alpha-Hydroxyestrone (16alpha-HE). A number of botanical constituents such as indoles, flavonoids, and resveratrol have been shown to have a favorable effect on the metabolic pathways that affect this ratio. The present...

  18. The role of kinin receptors in cancer and therapeutic opportunities.

    Science.gov (United States)

    da Costa, Patrícia L N; Sirois, Pierre; Tannock, Ian F; Chammas, Roger

    2014-04-01

    Kinins are generated within inflammatory tissue microenvironments, where they exert diverse functions, including cell proliferation, leukocyte activation, cell migration, endothelial cell activation and nociception. These pleiotropic functions depend on signaling through two cross talking receptors, the constitutively expressed kinin receptor 2 (B2R) and the inducible kinin receptor 1 (B1R). We have reviewed evidence, which supports the concept that kinin receptors, especially kinin receptor 1, are promising targets for cancer therapy, since (1) many tumor cells express aberrantly high levels of these receptors; (2) some cancers produce kinins and use them as autocrine factors to stimulate their growth; (3) activation of kinin receptors leads to activation of macrophages, dendritic cells and other cells from the tumor microenvironment; (4) kinins have pro-angiogenic properties; (5) kinin receptors have been implicated in cancer migration, invasion and metastasis; and (6) selective antagonists for either B1R or B2R have shown anti-proliferative, anti-inflammatory, anti-angiogenic and anti-migratory properties. The multiple cross talks between kinin receptors and renin-angiotensin system (RAS) as well as its implications for targeting KKS or RAS for the treatment of malignancies are also discussed. It is expected that B1R antagonists would interfere less with housekeeping functions and therefore would be attractive compounds to treat selected types of cancer. Reliable clinical studies are needed to establish the translatability of these data to human settings and the usefulness of kinin receptor antagonists. PMID:24333733

  19. The expression of the pituitary growth hormone-releasing hormone receptor and its splice variants in normal and neoplastic human tissues

    OpenAIRE

    Havt, Alexandre; Andrew V. Schally; Varga József L.; Toller Gábor L.; Horváth Judit E. (New Orleans); Szepesházi Károly; Köster, Frank; Kovitz, Kevin; Groot, Kate; Zarándi Márta; Kanashiro, Celia A.; Halmos Gábor (1962-) (gyógyszerész, receptorfarmakológus, experimentális onkológus)

    2005-01-01

    Various attempts to detect human pituitary growth hormone-releasing hormone receptor (pGHRH-R) in neoplastic extrapituitary tissues have thus far failed. Recently, four splice variants (SVs) of GHRH-R have been described, of which SV1 has the highest structural homology to pGHRH-R and likely plays a role in tumor growth. The aim of this study was to reinvestigate whether human tumors and normal human extrapituitary tissues express the pGHRH-R and to corroborate our previous findings on its SV...

  20. Circulating thyroxine, thyroid-stimulating hormone, and hypothyroid status and the risk of prostate cancer.

    Directory of Open Access Journals (Sweden)

    Alison M Mondul

    Full Text Available BACKGROUND: Thyroid hormones may influence risk of cancer through their role in cell differentiation, growth, and metabolism. One study of circulating thyroid hormones supports this hypothesis with respect to prostate cancer. We undertook a prospective analysis of thyroid hormones and prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC Study. METHODS: Within the ATBC Study, a randomized controlled trial of α-tocopherol and β-carotene supplements and cancer incidence in male smokers, 402 prostate cancer cases were sampled. Controls were matched 2:1 to cases on age and date of blood collection. Odds ratios (OR and 95% confidence intervals (CI of prostate cancer were estimated for quintiles of serum total and free thyroxine (T4, thyroid-stimulating hormone (TSH, thyroid-binding globulin (TBG, and by categories of thyroid status. RESULTS: Men with serum higher TSH had a decreased risk of prostate cancer compared to men with lower TSH (Q5 vs. Q1-4: OR = 0.70, 95% CI: 0.51-0.97, p = 0.03. When the T4 and TSH measurements were combined to define men as hypothyroid, euthyroid or hyperthyroid, hypothyroid men had a lower risk of prostate cancer compared to euthyroid men (OR = 0.48, 95% CI = 0.28-0.81, p = 0.006. We observed no association between hyperthyroid status and risk, although the number of hyperthyroid men with prostate cancer was small (n = 9. CONCLUSIONS: In this prospective study of smokers, men with elevated TSH and those classified as being in a hypothyroid state were at decreased risk of prostate cancer. Future studies should examine the association in other populations, particularly non-smokers and other racial/ethnic groups.

  1. HORMONAL THERAPY WITH LEUPRORELIN (LUCRIN-DEPOT® IN PATIENTS WITH PROSTATE CANCER

    Directory of Open Access Journals (Sweden)

    I. G. Rusakov

    2014-08-01

    Full Text Available Leuproprelin acetate (Lucrin-depot is an efficacious and safe luteinizing hormone-releasing hormone analogue, the efficiency of which has been proven in a number of large clinical studies. The agent exhibits a sustained release, is easy-to-use and well-tolerated, and causes minimal side effects. Lucrin-depot may be recommended for use as alone and in combination with other hormonal agents in patients with prostate cancer if androgenic deprivation is indicated.

  2. P2X receptors: New players in cancer pain

    Institute of Scientific and Technical Information of China (English)

    Alessia; Franceschini; Elena; Adinolfi

    2014-01-01

    Pain is unfortunately a quite common symptom for cancer patients. Normally pain starts as an episodic experience at early cancer phases to become chronic in later stages. In order to improve the quality of life of oncological patients, anti-cancer treatments are often accompanied by analgesic therapies. The P2 X receptor are adenosine triphosphate(ATP) gated ion channels expressed by several cells including neurons, cancer and immune cells. Purinergic signaling through P2 X receptors recently emerged as possible common pathway for cancer onset/growth and pain sensitivity. Indeed, tumor microenvironment is rich in extracellular ATP, which has a role in both tumor development and pain sensation. The study of the different mechanisms by which P2 X receptors favor cancer progression and relative pain, represents an interesting challenge to design integrated therapeutic strategies for oncological patients. This review summarizes recent findings linking P2 X receptors and ATP to cancer growth, progression and related pain. Special attention has been paid to the role of P2X2, P2X3, P2X4 and P2X7 in the genesisof cancer pain and to the function of P2X7 in tumor growth and metastasis. Therapeutic implications of the administration of different P2 X receptor blockers to alleviate cancer-associated pain sensations contemporarily reducing tumor progression are also discussed.

  3. Juvenile hormone receptors in insect larval epidermis: Identification by photoaffinity labeling

    Energy Technology Data Exchange (ETDEWEB)

    Palli, S.R.; Osir, E.O.; Edwards, M.; Hiruma, K.; Riddiford, L.M. (Univ. of Washington, Seattle (USA)); Eng, W.; Boehm, M.F.; Kulscar, P.; Ujvary, I.; Prestwich, G.D. (State Univ. of New York, Stony Brook (USA))

    1990-01-01

    Tritiated photoaffinity analogs of the natural lepidopteran juvenile hormones, JH I and II (epoxy({sup 3}H)bishomofarnesyl diazoacetate (({sup 3}H)EHDA) and epoxy({sup 3}H)homofarnesyl diazoacetate (({sup 3}H)EHDA)), and of the JH analog methoprene (({sup 3}H)methoprene diazoketone (({sup 3}H)MDK)) were synthesized and used to identify specific JH binding proteins in the larval epidermis of the tobacco hornworm (Manduca sexta). EBDA and EHDA specifically photolabeled a 29-kDa nuclear protein (pI 5.8). This protein and a second 29-kDa protein (pI 6.0) were labeled by MDK, but excess unlabeled methoprene or MDK only prevented binding to the latter. These 29-kDa proteins are also present in larval fat body but not in epidermis from either wandering stage or allatectomized larvae, which lack high-affinity JH binding sites. A 29-kDa nuclear protein with the same developmental specificity as this JH binder bound the DNA of two larval endocuticle genes. A 38-kDa cytosolic protein was also specifically photolabeled by these photoaffinity analogs. The 29-kDa nuclear protein is likely the high-affinity receptor for JH that mediates its genomic action, whereas the 38-kDa cytosolic protein may serve as an intracellular carrier for these highly lipophilic hormones and hormone analogs.

  4. Juvenile hormone receptors in insect larval epidermis: Identification by photoaffinity labeling

    International Nuclear Information System (INIS)

    Tritiated photoaffinity analogs of the natural lepidopteran juvenile hormones, JH I and II (epoxy[3H]bishomofarnesyl diazoacetate ([3H]EHDA) and epoxy[3H]homofarnesyl diazoacetate ([3H]EHDA)), and of the JH analog methoprene ([3H]methoprene diazoketone ([3H]MDK)) were synthesized and used to identify specific JH binding proteins in the larval epidermis of the tobacco hornworm (Manduca sexta). EBDA and EHDA specifically photolabeled a 29-kDa nuclear protein (pI 5.8). This protein and a second 29-kDa protein (pI 6.0) were labeled by MDK, but excess unlabeled methoprene or MDK only prevented binding to the latter. These 29-kDa proteins are also present in larval fat body but not in epidermis from either wandering stage or allatectomized larvae, which lack high-affinity JH binding sites. A 29-kDa nuclear protein with the same developmental specificity as this JH binder bound the DNA of two larval endocuticle genes. A 38-kDa cytosolic protein was also specifically photolabeled by these photoaffinity analogs. The 29-kDa nuclear protein is likely the high-affinity receptor for JH that mediates its genomic action, whereas the 38-kDa cytosolic protein may serve as an intracellular carrier for these highly lipophilic hormones and hormone analogs

  5. Developmental and Cell Cycle Quiescence Is Mediated by the Nuclear Hormone Receptor Coregulator DIN-1S in the Caenorhabditis elegans Dauer Larva.

    Science.gov (United States)

    Colella, Eileen; Li, Shaolin; Roy, Richard

    2016-08-01

    When faced with suboptimal growth conditions, Caenorhabditis elegans larvae can enter a diapause-like stage called "dauer" that is specialized for dispersal and survival. The decision to form a dauer larva is controlled by three parallel signaling pathways, whereby a compromise of TGFβ, cyclic guanosine monophosphate, or insulin/IGF-like signaling (ILS) results in dauer formation. Signals from these pathways converge on DAF-12, a nuclear hormone receptor that triggers the changes required to initiate dauer formation. DAF-12 is related to the vitamin D, liver-X, and androstane receptors, and like these human receptors, it responds to lipophilic hormone ligands. When bound to its ligand, DAF-12 acquires transcriptional activity that directs reproductive development, while unliganded DAF-12 forms a dauer-specifying complex with its interacting protein DIN-1S to regulate the transcription of genes required for dauer development. We report here that din-1S is required in parallel to par-4/LKB1 signaling within the gonad to establish cell cycle quiescence during the onset of the dauer stage. We show that din-1S is important for postdauer reproduction when ILS is impaired and is necessary for long-term dauer survival in response to reduced ILS. Our work uncovers several previously uncharacterized functions of DIN-1S in executing and maintaining many of the cellular and physiological processes required for appropriate dauer arrest, while also shedding light on the coordination of nuclear hormone signaling, the LKB1/AMPK signaling cascade, and ILS/TGFβ in the control of cell cycle quiescence and tissue growth: a key feature that is often misregulated in a number of hormone-dependent cancers. PMID:27260305

  6. Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response.

    Science.gov (United States)

    Koizumi, Keiichi; Hojo, Shozo; Akashi, Takuya; Yasumoto, Kazuo; Saiki, Ikuo

    2007-11-01

    The chemotactic cytokines called chemokines are a superfamily of small secreted cytokines that were initially characterized through their ability to prompt the migration of leukocytes. Attention has been focused on the chemokine receptors expressed on cancer cells because cancer cell migration and metastasis show similarities to leukocyte trafficking. CXC chemokine receptor 4 (CXCR4) was first investigated as a chemokine receptor that is associated with lung metastasis of breast cancers. Recently, CXCR4 was reported to be a key molecule in the formation of peritoneal carcinomatosis in gastric cancer. In the present review, we highlight current knowledge about the role of CXCR4 in cancer metastases. In contrast to chemokine receptors expressed on cancer cells, little is known about the roles of cancer cell-derived chemokines. Cancer tissue consists of both cancer cells and various stromal cells, and leukocytes that infiltrate into cancer are of particular importance in cancer progression. Although colorectal cancer invasion is regulated by the chemokine CCL9-induced infiltration of immature myeloid cells into cancer, high-level expression of cancer cell-derived chemokine CXCL16 increases infiltrating CD8(+) and CD4(+) T cells into cancer tissues, and correlates with a good prognosis. We discuss the conflicting biological effects of cancer cell-derived chemokines on cancer progression, using CCL9 and CXCL16 as examples. PMID:17894551

  7. Genome inventory and analysis of nuclear hormone receptors in Tetraodon nigroviridis

    Indian Academy of Sciences (India)

    Raghu Prasad Rao Metpally; Ramakrishnan Vigneshwar; Ramanathan Sowdhamini

    2007-01-01

    Nuclear hormone receptors (NRs) form a large superfamily of ligand-activated transcription factors, which regulate genes underlying a wide range of (patho) physiological phenomena. Availability of the full genome sequence of Tetraodon nigroviridis facilitated a genome wide analysis of the NRs in fish genome. Seventy one NRs were found in Tetraodon and were compared with mammalian and fish NR family members. In general, there is a higher representation of NRs in fish genomes compared to mammalian ones. They showed high diversity across classes as observed by phylogenetic analysis. Nucleotide substitution rates show strong negative selection among fish NRs except for pregnane X receptor (PXR), estrogen receptor (ER) and liver X receptor (LXR). This may be attributed to crucial role played by them in metabolism and detoxification of xenobiotic and endobiotic compounds and might have resulted in slight positive selection. Chromosomal mapping and pairwise comparisons of NR distribution in Tetraodon and humans led to the identification of nine syntenic NR regions, of which three are common among fully sequenced vertebrate genomes. Gene structure analysis shows strong conservation of exon structures among orthologoues. Whereas paralogous members show different splicing patterns with intron gain or loss and addition or substitution of exons played a major role in evolution of NR superfamily.

  8. The Relationship Between Gene Polymorphism of Leptin and Leptin Receptor and Growth Hormone Deficiency.

    Science.gov (United States)

    He, Jinshui; Fang, Yanling; Lin, Xinfu; Zhou, Huowang; Zhu, Shaobo; Zhang, Yugui; Yang, Huicong; Ye, Xiaoling

    2016-01-01

    BACKGROUND Growth hormone deficiency (GHD) is a major cause of congenital short stature. GHD patients have significantly decreased serum leptin levels, which are regulated by gene polymorphism of leptin and leptin receptor. This study thus investigated the relationship between gene polymorphism and susceptibility to GHD. MATERIAL AND METHODS A case-control study was performed using 180 GHD children in addition to 160 healthy controls. After the extraction of whole genomic DNA, the genotypes of leptin and leptin receptor gene loci were analyzed by sequencing for single-nucleotide polymorphism. RESULTS The frequency distribution of all alleles identified in leptin gene (loci rs7799039) and leptin receptor gene (loci rs1137100 and rs1137101) fit Hardy-Weinberg equilibrium. There was a significant difference in allele frequency at loci rs7799039 or rs1137101, as individuals with heterozygous GA allele had lower (rs7799039) or higher (rs1137101) GHD risk. No significant difference in allele frequency was discovered at loci rs1137100 (p>0.05), which was unrelated to GHD susceptibility. CONCLUSIONS Gene polymorphism of leptin (loci rs7799039) and leptin receptor (loci rs1137101) are correlated with GHD susceptibility. PMID:26915772

  9. Identification and characterization of growth hormone receptors in snakehead fish (Ophiocephalus argus cantor) liver.

    Science.gov (United States)

    Sun, X; Zhu, S; Chan, S S; Toresson, G; Cheng, C H

    1997-12-01

    The specific binding of 125I-labeled fish growth hormone (GH) to hepatic membranes prepared from several freshwater fish was assessed. A high level of growth hormone receptor (GHR) was detected on the hepatic membranes of the snakehead fish (Ophiocephalus argus Cantor). Scatchard analysis of the binding data showed a single class of high affinity binding site with a binding affinity (Ka) of 1.45 +/- 0.23 x 10(9) M-1 and a binding capacity (Bmax) of 198 +/- 57 fmol/mg protein. The binding was specific for fish GH and was saturable. In addition, the specific binding was temperature- and time-dependent, reaching a steady state after 16 hr of incubation at 25 degrees . The molecular weight of GHR as measured by Sephadex G-200 column chromatography and Western blot analysis using a monoclonal antibody (Mab263) against GHR was found to be 200-400 and 90-93 kDa, respectively. Two bands at 65 and 89 kDa were identified in ligand crosslinking studies of membrane receptors. A sensitive teleost GH radioreceptor assay (RRA) was developed, using recombinant fish GH and a membrane preparation from snakehead fish liver, capable of measuring bioactive GH in fish sera or other samples.

  10. Effect of two human growth hormone receptor antagonists on glomerulosclerosis in streptozotocin-induced diabetic rats

    Institute of Scientific and Technical Information of China (English)

    Wei LI; Shui-xian SHEN; Li-hua ZHU; En-bi WANG; Zeng-can YE; Jun LIN; Li-he GUO; Fei-hong LUO; Xi-hong LIU; Xin FANG

    2004-01-01

    AIM: To explore the feasibility of human growth hormone (hGH) receptor antagonist in the treatment of end-stage diabetic renal complications. METHODS: Two hGH mutants, hGHA1 (Cys-hGH-dell-4, G120R, K168A, E174A,C182S, de1186-191) and hGHA2 (hGH-H21A, G120R, E174A) were expressed in E coli. The IC50 (Mean±SD)values for the mutants for inhibiting 125I-hGH binding to rabbit growth hormone receptor were (65±10) ng for hGHA1, (27±5.6) ng for hGHA2, and (10±0.6) ng for wild type hGH, respectively. RESULTS: After treatment for 12 weeks, the renal histology analysis showed that treatment with hGHA2 at 4 mg/kg body weight daily markedly suppressed glomerulosclerosis in streptozotocin-induced diabetic Sprague-Dawley (SD) rats; hGHA1 at the same dosage slightly increased the renal damage compared with saline; while wild type hGH at 1 U/kg body weight daily severely worsened the glomerulo-sclerosis in diabetic SD rats. CONCLUSION: The data indicated that hGHA2 inhibited the end-stage glomerulosclerosis in diabetic rats, but hGHA1 mildly increased the glomerulosclerosis.

  11. Influence of music on steroid hormones and the relationship between receptor polymorphisms and musical ability: a pilot study

    OpenAIRE

    Fukui, Hajime; Toyoshima, Kumiko

    2013-01-01

    Studies have shown that music confers plasticity to the brain. In a preliminary pilot study, we examined the effect of music listening on steroid hormones and the relationship between steroid hormone receptor polymorphisms and musical ability. Twenty-one subjects (10 males and 11 females) were recruited and divided into musically talented and control groups. The subjects selected (1) music they preferred (chill-inducing music) and (2) music they did not like. Before and after the experiments,...

  12. 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.

  13. Estrogen receptor prevents p53-dependent apoptosis in breast cancer

    OpenAIRE

    Bailey, Shannon T.; Shin, Hyunjin; Westerling, Thomas; Liu, Xiaole Shirley; Brown, Myles

    2012-01-01

    More than two-thirds of breast cancers express the estrogen receptor (ER) and depend on estrogen for growth and survival. Therapies targeting ER function, including aromatase inhibitors that block the production of estrogens and ER antagonists that alter ER transcriptional activity, play a central role in the treatment of ER+ breast cancers of all stages. In contrast to ER− breast cancers, which frequently harbor mutations in the p53 tumor suppressor, ER+ breast cancers are predominantly wild...

  14. Expression of OATP family members in hormone-related cancers: potential markers of progression.

    Directory of Open Access Journals (Sweden)

    Heather Pressler

    Full Text Available The organic anion transporting polypeptide (OATP family of transporters has been implicated in prostate cancer disease progression probably by transporting hormones or drugs. In this study, we aimed to elucidate the expression, frequency, and relevance of OATPs as a biomarker in hormone-dependent cancers. We completed a study examining SLCO1B3, SLCO1B1 and SLCO2B1 mRNA expression in 381 primary, independent patient samples representing 21 cancers and normal tissues. From a separate cohort, protein expression of OATP1B3 was examined in prostate, colon, and bladder tissue. Based on expression frequency, SLCO2B1 was lower in liver cancer (P = 0.04 which also trended lower with decreasing differentiation (P = 0.004 and lower magnitude in pancreatic cancer (P = 0.05. SLCO2B1 also had a higher frequency in thyroid cancer (67% than normal (0% and expression increased with stage (P = 0.04. SLCO1B3 was expressed in 52% of cancerous prostate samples and increased SLCO1B3 expression trended with higher Gleason score (P = 0.03. SLCO1B3 expression was also higher in testicular cancer (P = 0.02. SLCO1B1 expression was lower in liver cancer (P = 0.04 which trended lower with liver cancer grade (P = 0.0004 and higher with colon cancer grade (P = 0.05. Protein expression of OATP1B3 was examined in normal and cancerous prostate, colon, and bladder tissue samples from an independent cohort. The results were similar to the transcription data, but showed distinct localization. OATPs correlate to differentiation in certain hormone-dependent cancers, thus may be useful as biomarkers for assessing clinical treatment and stage of disease.

  15. Effects of steroid sex hormones and adriamycin on human bladder cancer cells in culture.

    Directory of Open Access Journals (Sweden)

    Yoshimoto,Jun

    1982-02-01

    Full Text Available The effects of steroid sex hormones on the established cell lines derived from human urinary bladder cancer, T24, and from human transitional cell cancer of the urinary tract, 253J, were examined using the colony formation method. Of the seven kinds of steroid hormones tested, estradiol-17 beta was intensively cytotoxic for both cells. The cytotoxic effect was depended on the dose and time of treatment. The combined effect of Adriamycin and estradiol-17 beta on T24 cells could be recognized at low concentrations of Adriamycin (less than or equal to 10(-3 micrograms/ml after exposure for 24 h.

  16. Low concentrations of bisphenol a suppress thyroid hormone receptor transcription through a nongenomic mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Sheng, Zhi-Guo [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085 (China); Tang, Yuan [Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, 30 Yanzheng Street, Chongqing 400038 (China); Liu, Yu-Xiang [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085 (China); Yuan, Ye; Zhao, Bao-Quan [Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850 (China); Chao, Xi-Juan [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085 (China); Zhu, Ben-Zhan, E-mail: bzhu@rcees.ac.cn [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085 (China)

    2012-02-15

    Bisphenol (BPA) is one of the highest-volume chemicals produced worldwide, and human exposure to BPA is thought to be ubiquitous. Various rodent and in vitro studies have shown that thyroid hormone (TH) function can be impaired by BPA. However, it is still unknown if low concentrations of BPA can suppress the thyroid hormone receptor (TR) transcription. The present study aims to investigate the possible suppressing effects of low concentrations of BPA on TR transcription and the involved mechanism(s) in CV-1 cells derived from cercopithecus aethiops monkey kidneys. Using gene reporter assays, BPA at concentrations as low as 10{sup −9} M suppresses TR or steroid receptor coactivator-1(SRC-1)-enhanced TR transcription, but not reducing TR/SRC-1 interaction in mammalian two-hybrid and glutathione S-transferase pull-down studies. It has been further shown that both nuclear receptor co-repressor (N-CoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) are recruited to the TR-β1 by BPA in the presence of physiologic concentrations of T3 or T4. However, the overexpression of β3 integrin or c-Src significantly reduces BPA-induced recruitment of N-CoR/SMRT to TR or suppression of TR transcription. Furthermore, BPA inhibits the T3/T4-mediated interassociation of the β3 integrin/c-Src/MAPK/TR-β1 pathways by the co-immunoprecipitation. These results indicate that low concentrations of BPA suppress the TR transcription by disrupting physiologic concentrations of T3/T4-mediated β3 integrin/c-Src/MAPK/TR-β1 pathways, followed by recruiting N-CoR/SMRT to TR-β1, providing a novel insight regarding the TH disruption effects of low concentration BPA. -- Highlights: ► Environmentally relevant concentrations of BPA suppress TR transcription. ► BPA recruits the N-CoR/SMRT to TR under the physiologic concentrations of T3/T4. ► BPA disrupts T3/T4-mediated β3 integrin/c-Src/MAPK/TR-β1 pathways.

  17. Growth hormone, interferon-gamma, and leukemia inhibitory factor utilize insulin receptor substrate-2 in intracellular signaling

    DEFF Research Database (Denmark)

    Argetsinger, L S; Norstedt, G; Billestrup, Nils;

    1996-01-01

    In this report, we demonstrate that insulin receptor substrate-2 (IRS-2) is tyrosyl-phosphorylated following stimulation of 3T3-F442A fibroblasts with growth hormone (GH), leukemia inhibitory factor and interferon-gamma. In response to GH and leukemia inhibitory factor, IRS-2 is immediately...... indicated that tyrosine residues in GH receptor are not necessary for tyrosyl phosphorylation of IRS-2; however, the regions of GH receptor necessary for IRS-2 tyrosyl phosphorylation are the same as those required for JAK2 association and tyrosyl phosphorylation. The role of IRS-2 as a signaling molecule...... of multiple members of the cytokine family of receptors that activate JAK kinases....

  18. Estrogen receptor alpha polymorphism and risk of cardiovascular disease, cancer, and hip fracture

    DEFF Research Database (Denmark)

    Kjaergaard, Alisa D; Ellervik, Christina; Tybjaerg-Hansen, Anne;

    2007-01-01

    Background- We hypothesized that the estrogen receptor (ESR1) IVS1-397T/C polymorphism affects high-density lipoprotein cholesterol response to hormone replacement therapy and risk of cardiovascular disease (CVD), cancer of reproductive organs, and hip fracture. Methods and Results- We studied...... cross-sectionally 9244 individuals from the Danish general population and followed them up for 23 to 25 years. End points were CVD (ischemic heart disease, myocardial infarction, angina pectoris, ischemic cerebrovascular disease, ischemic stroke, other ischemic cerebrovascular disease, venous...... thromboembolism, deep vein thrombosis, and pulmonary embolism), cancer of reproductive organs (breasts, ovaries, uterus, and prostate), and hip fracture. We also studied patients with ischemic heart disease (n=2495), ischemic cerebrovascular disease (n=856), and breast cancer (n=1256) versus general population...

  19. Intensity Modulated Accelerated Partial Breast Irradiation Before Surgery in Treating Older Patients With Hormone Responsive Stage 0-I Breast Cancer

    Science.gov (United States)

    2016-05-04

    Ductal Breast Carcinoma in Situ; Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; Invasive Ductal Breast Carcinoma; Invasive Ductal Breast Carcinoma With Predominant Intraductal Component; Lobular Breast Carcinoma in Situ; Medullary Ductal Breast Carcinoma With Lymphocytic Infiltrate; Mucinous Ductal Breast Carcinoma; Papillary Ductal Breast Carcinoma; Progesterone Receptor-positive Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Tubular Ductal Breast Carcinoma

  20. Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers.

    Science.gov (United States)

    Georgitsi, M; Karhu, A; Winqvist, R; Visakorpi, T; Waltering, K; Vahteristo, P; Launonen, V; Aaltonen, L A

    2007-01-29

    Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were recently identified in individuals with pituitary adenoma predisposition (PAP). These patients have prolactin (PRL) or growth hormone (GH) oversecreting pituitary adenomas, the latter exhibiting acromegaly or gigantism. Loss-of-heterozygosity (LOH) analysis revealed that AIP is lost in PAP tumours, suggesting that it acts as a tumour-suppressor gene. Aryl hydrocarbon receptor interacting protein is involved in several pathways, but it is best characterised as a cytoplasmic partner of the aryl hydrocarbon receptor (AHR). To examine the possible role of AIP in the genesis of common cancers, we performed somatic mutation screening in a series of 373 colorectal cancers (CRCs), 82 breast cancers, and 44 prostate tumour samples. A missense R16H (47G>A) change was identified in two CRC samples, as well as in the respective normal tissues, but was absent in 209 healthy controls. The remaining findings were silent, previously unreported, changes of the coding, non-coding, or untranslated regions of AIP. These results suggest that somatic AIP mutations are not common in CRC, breast, and prostate cancers. PMID:17242703

  1. Reproductive factors, hormone use and gastric cancer risk: The Singapore Chinese Health Study.

    Science.gov (United States)

    Wang, Zhensheng; Butler, Lesley M; Wu, Anna H; Koh, Woon-Puay; Jin, Aizhen; Wang, Renwei; Yuan, Jian-Min

    2016-06-15

    Gastric cancer incidence varies greatly worldwide, but is consistently twice as high in men than in women. The hormone-related factors hypothesized to be associated with lower risk of gastric cancer in women have not been fully explored in populations with a high background risk of gastric cancer. The Singapore Chinese Health Study (SCHS) is a prospective cohort study in which 34,022 of the participants enrolled between 1993 and 1998 were women between 45 and 74 years of age. Information on reproductive histories, hormone replacement therapy (HRT) and oral contraceptive (OC) use was collected through in-person interviews at baseline. As of December 31, 2013, 269 incident gastric cancer cases were identified. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate gastric cancer risk associations. Older age at natural menopause (≥55 versus 3 years and 0.67 (0.47-0.94) for ever use of OCs, compared with never use. Reproductive factors associated with a longer window of fertility and the use of exogenous hormones were shown to reduce gastric cancer development in a cohort of Chinese women with a high background risk of gastric cancer.

  2. Estrogen and progesterone hormone receptor status in breast carcinoma: Comparison of immunocytochemistry and immunohistochemistry

    Directory of Open Access Journals (Sweden)

    K Radhika

    2010-01-01

    Full Text Available Context : Estrogen receptors (ER and progesterone receptors (PR play a significant role in the prognosis of breast cancer. For preoperative chemotherapy in locally advanced lesions, trucut biopsy is used to localize the ER and PR receptors by immunohistochemistry. Immunocytochemistry can be a better alternative to immunohistochemistry as it better fixes cells. AIMS : To evaluate the degree of correlation between immunocytochemical (ICC and immunohistochemical (IHC determination of ER and PR in breast cancer. Settings and Design : Fine needle aspiration cytology (FNAC was performed on 100 primary breast cancers immunostained for ER and PR during a period of 1 year 7 months, i.e., from January 2006 to July 2007. Materials and Methods : Papanicolaou-stained slides were destained, fixed in cold acetone and submitted for immunocytochemistry. In the prospective analysis, FNAC smears were straightaway fixed in cold acetone and submitted for ER and PR. Peroxidase, antiperoxidase technique was used for immunocytochemistry. Statistical Analysis : Spearman Rank correlation test was used. Results : Differences between groups were analysed and correlations were studied. Concordance for ER was 50% and for PR was 29%. Both ER and PR were positive in four cases: ER only in three and PR in one, and both were negative in nine cases. Use of the least best buffer and technical errors contributed to the lower ICC rate. Conclusion : Although Immunocytochemistry removes the derogatory step of antigen deterioration, technical errors can cause hindrance in achieving the best of the results.

  3. Polychlorinated biphenyls (PCBs) exert thyroid hormone-like effects in the fetal rat brain but do not bind to thyroid hormone receptors.

    OpenAIRE

    Gauger, Kelly J; Kato, Yoshihisa; Haraguchi, Koichi; Lehmler, Hans-Joachim; Robertson, Larry W.; Bansal, Ruby; Zoeller, R. Thomas

    2004-01-01

    Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants routinely found in human and animal tissues. Developmental exposure to PCBs is associated with neuropsychologic deficits, which may be related to effects on thyroid hormone (TH) signaling in the developing brain. However, PCBs may interfere with TH signaling solely by reducing circulating levels of TH, or they may exert direct effects on TH receptors (TRs). Therefore, we tested whether maternal exposure to a commercial...

  4. Parathyroid hormone/parathyroid hormone-related protein receptor signaling is required for maintenance of the growth plate in postnatal life

    OpenAIRE

    Hirai, Takao; Chagin, Andrei S; Kobayashi, Tatsuya; Mackem, Susan; Kronenberg, Henry M.

    2010-01-01

    Parathyroid hormone (PTH)-related protein (PTHrP), regulated by Indian hedgehog and acting through the PTH/PTHrP receptor (PPR), is crucial for normal cartilage development. These observations suggest a possible role of PPR signaling in the postnatal growth plate; however, the role of PPR signaling in postnatal chondrocytes is unknown. In this study, we have generated tamoxifen-inducible and cartilage-specific PPR KO mice to evaluate the physiological role of PPR signaling in postnatal chondr...

  5. Assessment of hormone-like activities in Ginkgo biloba, Elettaria cardamomum and Plantago ovata extracts using in vitro receptor-specific bioassays.

    Science.gov (United States)

    Real, Macarena; Molina-Molina, José-Manuel; Jimenez, Jesús; Diéguez, Horacio R; Fernández, Mariana F; Olea, Nicolás

    2015-01-01

    Medicinal plants are widely used for the treatment of diseases and for the development of new drugs. This study was designed to determine the presence of hormone-like activities dependent on the activation of human estrogen receptor alpha (hERa) and/or androgen receptor (hAR) in methanol extracts prepared from three medicinal plants historically and currently used for therapeutic purposes: Ginkgo biloba leaves (GBL), Elettaria cardamomum seeds (ECS) and Plantago ovata seeds (POS). After a solid-liquid extraction (SLE) step, their effects on hERa function were assessed in MCF-7 breast cancer cells using the E-Screen bioassay, and their ability to induce hAR-mediated reporter gene expression was evaluated using the androgen-sensitive stable prostatic PALM cell line. Unlike POS extracts, GBL and ECS extracts showed estrogenic (0.07 and 0.20 nM E2Eq mg(-1), respectively) and anti-estrogenic (0.01 and 0.02 μM ICI182780Eq mg(-1), respectively) activities. ECS extracts evidenced androgenic activity (0.30 nM R1881Eq mg(-1)) and POS extracts anti-androgenic activity (22.30 μM ProcEq mg(-1)). According to these findings, these plant extracts may interfere with the endocrine system via one or more hormonal receptors, and further investigation is warranted into their role as endocrine disrupters in humans. PMID:26161806

  6. Androgen receptor and miRNA-126* axis controls follicle-stimulating hormone receptor expression in porcine ovarian granulosa cells.

    Science.gov (United States)

    Du, Xing; Li, Qiqi; Pan, Zengxiang; Li, Qifa

    2016-08-01

    Androgen, which acts via the androgen receptor (AR), plays crucial roles in mammalian ovarian function. Recent studies showed that androgen/AR signaling regulates follicle-stimulating hormone receptor (FSHR) expression in follicles; however, the detailed mechanism underlying this regulation remained unknown. Here, we demonstrate that AR and miR-126* cooperate to inhibit FSHR expression and function in pig follicular granulosa cells (pGCs). In pGCs, overexpression of AR decreased, whereas knockdown increased, FSHR mRNA and protein expression; however, neither manipulation affected FSHR promoter activity. Using a dual-luciferase reporter assay, we found that the FSHR gene is a direct target of miR-126*, which inhibits FSHR expression and increases the rate of AR-induced apoptosis in pGCs. Collectively, our data show for the first time that the AR/miR-126* axis exerts synergetic effects in the regulation of FSHR expression and apoptosis in pGCs. Our findings thus define a novel pathway, AR/miR-126*/FSHR, that regulates mammalian GC functions. PMID:27222597

  7. Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer

    NARCIS (Netherlands)

    Kroon, Jan; Puhr, Martin; Buijs, Jeroen T.; Van Der Horst, Geertje; Lemhemmer, Daniël; Marijt, Koen A.; Hwang, Ming S.; Masood, Motasim; Grimm, Stefan; Storm, Gert; Metselaar, Josbert M.; Meijer, Onno C.; Culig, Zoran; Van Der Pluijm, Gabri

    2016-01-01

    Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCA). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance. I

  8. Identification of a gonadotropin-releasing hormone receptor orthologue in Caenorhabditis elegans

    Directory of Open Access Journals (Sweden)

    Sgro Jean-Yves

    2006-11-01

    Full Text Available Abstract Background The Caenorhabditis elegans genome is known to code for at least 1149 G protein-coupled receptors (GPCRs, but the GPCR(s critical to the regulation of reproduction in this nematode are not yet known. This study examined whether GPCRs orthologous to human gonadotropin-releasing hormone receptor (GnRHR exist in C. elegans. Results Our sequence analyses indicated the presence of two proteins in C. elegans, one of 401 amino acids [GenBank: NP_491453; WormBase: F54D7.3] and another of 379 amino acids [GenBank: NP_506566; WormBase: C15H11.2] with 46.9% and 44.7% nucleotide similarity to human GnRHR1 and GnRHR2, respectively. Like human GnRHR1, structural analysis of the C. elegans GnRHR1 orthologue (Ce-GnRHR predicted a rhodopsin family member with 7 transmembrane domains, G protein coupling sites and phosphorylation sites for protein kinase C. Of the functionally important amino acids in human GnRHR1, 56% were conserved in the C. elegans orthologue. Ce-GnRHR was actively transcribed in adult worms and immunoanalyses using antibodies generated against both human and C. elegans GnRHR indicated the presence of a 46-kDa protein, the calculated molecular mass of the immature Ce-GnRHR. Ce-GnRHR staining was specifically localized to the germline, intestine and pharynx. In the germline and intestine, Ce-GnRHR was localized specifically to nuclei as revealed by colocalization with a DNA nuclear stain. However in the pharynx, Ce-GnRHR was localized to the myofilament lattice of the pharyngeal musculature, suggesting a functional role for Ce-GnRHR signaling in the coupling of food intake with reproduction. Phylogenetic analyses support an early evolutionary origin of GnRH-like receptors, as evidenced by the hypothesized grouping of Ce-GnRHR, vertebrate GnRHRs, a molluscan GnRHR, and the adipokinetic hormone receptors (AKHRs and corazonin receptors of arthropods. Conclusion This is the first report of a GnRHR orthologue in C. elegans, which

  9. Thyroid hormone and retinoid X receptor function and expression during sea lamprey (Petromyzon marinus) metamorphosis.

    Science.gov (United States)

    Manzon, Lori A; Youson, John H; Holzer, Guillaume; Staiano, Leopoldo; Laudet, Vincent; Manzon, Richard G

    2014-08-01

    Sea lampreys (Petromyzon marinus) are members of the ancient class Agnatha and undergo a metamorphosis that transforms blind, sedentary, filter-feeding larvae into free-swimming, parasitic juveniles. Thyroid hormones (THs) appear to be important for lamprey metamorphosis, however, serum TH concentrations are elevated in the larval phase, decline rapidly during early metamorphosis and remain low until metamorphosis is complete; these TH fluctuations are contrary to those of other metamorphosing vertebrates. Moreover, thyroid hormone synthesis inhibitors (goitrogens) induce precocious metamorphosis and exogenous TH treatments disrupt natural metamorphosis in P. marinus. Given that THs exert their effects by binding to TH nuclear receptors (TRs) that often act as heterodimers with retinoid X receptors (RXRs), we cloned and characterized these receptors from P. marinus and examined their expression during metamorphosis. Two TRs (PmTR1 and PmTR2) and three RXRs (PmRXRs) were isolated from P. marinus cDNA. Phylogenetic analyses group the PmTRs together on a branch prior to the gnathostome TRα/β split. The three RXRs also group together, but our data indicated that these transcripts are most likely either allelic variants of the same gene locus, or the products of a lamprey-specific duplication event. Importantly, these P. marinus receptors more closely resemble vertebrate as opposed to invertebrate chordate receptors. Functional analysis revealed that PmTR1 and PmTR2 can activate transcription of TH-responsive genes when treated with nanomolar concentrations of TH and they have distinct pharmacological profiles reminiscent of vertebrate TRβ and TRα, respectively. Also similar to other metamorphosing vertebrates, expression patterns of the PmTRs during lamprey metamorphosis suggest that PmTR1 has a dynamic, tissue-specific expression pattern that correlates with tissue morphogenesis and biochemical changes and PmTR2 has a more uniform expression pattern. This TR

  10. Common soil of smoking-associated and hormone-related cancers: estrogen deficiency

    Directory of Open Access Journals (Sweden)

    Zsuzsanna Suba

    2011-12-01

    Full Text Available Accumulation of non-smoker, non-drinker elderly postmenopausal female patients among smokingassociated oral cancer cases raised the plausible idea: estrogen deficiency maybe a cancer risk factor. On the other hand, the extremely rare cases of young women with oral cancer regularly exhibited hormonal disorders, such as irregular menstrual cycles and infertility. Furthermore, in the history of middle-aged female, oral cancer cases a primary ovarian failure or complete hysterectomy was a conspicuously frequent finding suggestive of an estrogen deficient milieu. There were many striking contradictions concerning the associations of female sexual steroids and cancer risk as well. Until now, breast and endometrial cancers were regarded as typically estrogen-induced tumors, particularly in postmenopausal cases. However, unexplained beneficial anti-cancer effects of hormonereplacement therapy were reported against cancers at several sites, even tumors of the highly hormone-responsive organs. Re-evaluation of results of the experimental and epidemiological studies, which endeavored to justify the carcinogenic capacity of estrogen, exhibited many shortcomings and controversies. The new findings both on smoking associated and on hormone related cancers added up to the same conversion; not estrogen but rather its deficiency might provoke cancer initiation. Thorough review of the literary data justified that the exquisite regulatory capacity of estrogen and its surveillance on growth, development, differentiation, and metabolism are indispensable, whereas an estrogen-deficient milieu may induce a breakdown in gene-regulation. Recognition of the anticancer capacity of estrogen may provide new insights into the etiology of malignancies and leads to new strategies for cancer prevention and cure.

  11. Polymorphisms of genes coding for ghrelin and its receptor in relation to anthropometry, circulating levels of IGF-I and IGFBP-3, and breast cancer risk : a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)

    NARCIS (Netherlands)

    Dossus, Laure; Mckay, James D.; Canzian, Federico; Wilkening, Stefan; Rinaldi, Sabina; Biessy, Carine; Olsen, Anja; Tjonneland, Anne; Jakobsen, Marianne U.; Overvad, Kim; Clavel-Chapelon, Francoise; Boutron-Ruault, Marie-Christine; Fournier, Agnes; Linseisen, Jakob; Lukanova, Annekatrin; Boeing, Heiner; Fisher, Eva; Trichopoulou, Antonia; Georgila, Christina; Trichopoulos, Dimitrios; Palli, Domenico; Krogh, Vittorio; Tumino, Rosario; Vineis, Paolo; Quiros, Jose Ramon; Sala, Nuria; Martinez-Garcia, Carmen; Dorronsoro, Miren; Chirlaque, Maria-Dolores; Barricarte, Aurelio; van Duijnhoven, Franzel J. B.; Bueno-de-Mesquita, H. B.; van Gils, Carla H.; Peeters, Petra H. M.; Hallmans, Goran; Lenner, Per; Bingham, Sheila; Khaw, Kay Tee; Key, Tim J.; Travis, Ruth C.; Ferrari, Pietro; Jenab, Mazda; Riboli, Elio; Kaaks, Rudolf

    2008-01-01

    Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, has two major functions: the stimulation of the growth hormone production and the stimulation of food intake. Accumulating evidence also suggests a role of ghrelin in cancer development. We conducted a case-control study on

  12. Synthesis and bioassay of radiolabeled, chiral probes for juvenile hormone receptor study

    Energy Technology Data Exchange (ETDEWEB)

    Eng, W.

    1987-01-01

    Four different types of compounds were synthesized for the detailed study on interactions between insect juvenile hormone (JH) and the corresponding binding proteins, receptor proteins and catabolic enzymes: (1) High specific activity /sup 3/H-labeled, chiral alkyldiazoacetates with their skeletons approaching those of natural JH I and JH II were synthesized as photoaffinity labels for probing JH receptor proteins in Lepidoptera. Compared with epoxy farnesyl diazoacetate (EFDA), epoxy bishomofarnesyl diazoacetate (EBDA) and epoxy homofarnesyl diazoacetate (EHDA) have largely increased affinity to Manduca sexta JH binding proteins (JHBP) as demonstrated by gel electrophoresis. (2) Chiral JH I and JH II acids, as well as 12-hydroxy-JH I and JH II were synthesized. The hydroxy groups in these compounds provide tether points for attachment to proteins to serve as antigens with most of the recognition sites preserved to be used in JH radioimmunoassays. (3) The first radioiodine-labeled JH, (/sup 125/I)-12-iodo-JH I, was synthesized, both in no-carrier-added and carrier-added forms, as one of the probes for JH receptor study. (4) Four alkylthioltrifluoropropanones with skeletons approaching that of JH III and functional groups mimicking the JH epoxide moiety were synthesized as inhibitors for JH esterase (JHE).

  13. Structure and chromosomal localization of the human antidiuretic hormone receptor gene

    Energy Technology Data Exchange (ETDEWEB)

    Seibold, A.; Brabet, P.; Rosenthal, W.; Birnbaumer, M. (Baylor College of Medicine, Houston, TX (United States))

    1992-11-01

    Applying a genomic DNA-expression approach, the authors cloned the gene and cDNA coding for the human antidiuretic hormone receptor, also called vasopressin V2 receptor' (V2R). The nucleotide sequence of both cloned DNAs provided the information to elucidate the structure of the isolated transcriptional unit. The structure of this gene is unusual in that it is the first G protein-coupled receptor gene that contains two very small intervening sequences, the second of which separates the region encoding the seventh transmembrane region from the rest of the open reading frame. The sequence information was used to synthesize appropriate oligonucleotides to be used as primers in the PCR. The V2R gene was localized by PCR using DNA from hybrid cells as template. The gene was found to reside in the q28-qter portion of the human X chromosome, a region identified as the locus for congential nephrogenic diabetes insipidus. 27 refs., 4 figs.

  14. Hormone- and DNA-binding mechanisms of the recombinant human estrogen receptor.

    Science.gov (United States)

    Obourn, J D; Koszewski, N J; Notides, A C

    1993-06-22

    We have investigated the hormone- and DNA-binding mechanisms of the wild-type human estrogen receptor (hER) overproduced in insect cells using a baculovirus expression system. The recombinant hER was indistinguishable in size (67 kDa) and immunogenically from the native human estrogen receptor in MCF-7 breast carcinoma cells. The recombinant hER was purified to 70-80% homogeneity with a two-step procedure that included ammonium sulfate precipitation and oligonucleotide affinity chromatography using a unique Teflon affinity matrix. The recombinant hER bound estradiol with a positively cooperative mechanism. At hER concentrations in excess of 13 nM the Hill coefficient reached a maximal value of 1.6, whereas, at lower hER concentrations, the Hill coefficient approached 1.0, suggesting that the hER was dissociated to the monomeric species and site-site interactions were diminished. The hER specifically bound an estrogen responsive element (ERE) from chicken vitellogenin II gene as measured by the gel mobility assay, ethylation, and thymine interference footprinting. Specific interference patterns suggest a two-fold symmetry of the hER binding to the ERE with each monomer of the hER bound in the major groove of the DNA. These data indicate that the recombinant hER is valuable to define the biochemical and structural properties of the native estrogen receptor. PMID:8512933

  15. 'Charting a new course for prostate cancer' - currying favor for docetaxel in hormone-sensitive metastatic prostate cancer.

    Science.gov (United States)

    Voskoboynik, Mark; Staffurth, John; Malik, Zafar; Sweeney, Christopher; Chowdhury, Simon

    2014-11-01

    Docetaxel has an established role in the treatment of metastatic castrate-resistant prostate cancer. A number of recent treatments have been shown to improve the survival outcomes for this group of patients and many with improved toxicity profiles, bringing the role of docetaxel into question. We discuss the results and implications of the CHAARTED study that demonstrated a significant improvement in overall survival with docetaxel in metastatic hormone-sensitive prostate cancer. PMID:25353342

  16. Use of early chemotherapy for hormone-sensitive prostate cancer: time for CHAARTED

    OpenAIRE

    Aragon-Ching, Jeanny B.

    2015-01-01

    CHAARTED was an ECOG-led phase III trial looking at early chemotherapy with the use of docetaxel in addition to androgen deprivation therapy (ADT) versus ADT alone in hormone-sensitive prostate cancer. The positive results of the trial showing marked improvement in overall survival in those who received chemotherapy with ADT have revolutionized the treatment of metastatic castration-sensitive prostate cancer. In addition to overall survival, secondary endpoints such as time to castration resi...

  17. A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements.

    OpenAIRE

    Baes, M.; Gulick, T; Choi, H. S.; Martinoli, M G; Simha, D; Moore, D D

    1994-01-01

    We have identified and characterized a new orphan member of the nuclear hormone receptor superfamily, called MB67, which is predominantly expressed in liver. MB67 binds and transactivates the retinoic acid response elements that control expression of the retinoic acid receptor beta 2 and alcohol dehydrogenase 3 genes, both of which consist of a direct repeat hexamers related to the consensus AGGTCA, separated by 5 bp. MB67 binds these elements as a heterodimer with the 9-cis-retinoic acid rec...

  18. Managing arthralgia in a postmenopausal woman taking an aromatase inhibitor for hormone-sensitive early breast cancer: a case study

    Directory of Open Access Journals (Sweden)

    Bryce J

    2012-03-01

    Full Text Available Jane Bryce1, Martina Bauer2, Peyman Hadji21National Cancer Institute, Naples, Italy; 2Philipps University of Marburg, Marburg, GermanyBackground: In order to reduce the risk of recurrence, adjuvant treatment with an aromatase inhibitor (AI is recommended for postmenopausal women following surgery for hormone receptor-positive breast cancer. AIs are associated with improved disease-free survival compared with tamoxifen. The adverse events associated with AIs resemble those of menopause, such as bone density loss and musculoskeletal symptoms.Purpose: We examine the case of a postmenopausal woman who was prescribed anastrozole, a nonsteroidal AI, as adjuvant therapy following surgery for estrogen and progesterone receptor-positive (ER and PgR+ breast cancer.Methods and sample: A 58-year-old postmenopausal woman diagnosed with ER and PgR+ breast cancer was prescribed anastrozole as adjuvant therapy following a right-inferior quadrantectomy. After experiencing joint pain and stiffness, she was prescribed paracetamol and a topical nonsteroidal anti-inflammatory drug. She was also counseled on nonpharmacological interventions. However, she continued to experience symptoms, and reported that she was not taking anastrozole regularly.Results: The case study patient ultimately found relief by switching to letrozole, another aromatase inhibitor. This approach is supported by recent studies examining the benefits of switching strategies between aromatase inhibitors in order to relieve symptoms of arthralgia/myalgia.Conclusions: Both adherence and strategies for managing aromatase inhibitor-associated arthralgia are key to deriving maximal clinical benefit from AI therapy. Switching from one aromatase inhibitor to another may provide a viable option in managing adverse events and enhancing adherence to medication.Keywords: adherence, anastrozole, aromatase inhibitor, arthralgia, breast cancer, letrozole

  19. Antibodies to the extracellular receptor domain restore the hormone-insensitive kinase and conformation of the mutant insulin receptor valine 382.

    Science.gov (United States)

    Lebrun, C; Baron, V; Kaliman, P; Gautier, N; Dolais-Kitabgi, J; Taylor, S; Accili, D; Van Obberghen, E

    1993-05-25

    A mutation substituting a valine for phenylalanine at residue 382 in the insulin receptor alpha-subunit has been found in two sisters with a genetic form of extreme insulin resistance. This receptor mutation impairs the ability of the hormone to activate autophosphorylation of solubilized receptors and phosphorylation of substrates (Accili, D., Mosthaf, L., Ullrich, A., and Taylor, S. I. (1991) J. Biol. Chem. 266, 434-439). We have previously demonstrated that in native receptors insulin induces a conformational change in the receptor beta-subunit, which is thought to be necessary for receptor activation (Baron, V., Gautier, N., Komoriya, A., Hainaut, P., Scimeca, J. C., Mervic, M., Lavielle, S., Dolais-Kitabgi, J., and Van Obberghen, E. (1990) Biochemistry 29, 4634-4641). Hence, it was thought that a defect in this conformational change might explain the functional defect of the mutant receptor. This appears to be the case, as we demonstrate here that the mutant receptor is locked in its inactive configuration. However, we found two monoclonal antibodies, directed to the extracellular domain, which are capable of restoring the mutant receptor kinase activity. The activation of the mutant receptor was accompanied by restoration of conformational changes in the beta-subunit C terminus. From these data, we draw the two following conclusions. (i) A causal link exists between receptor kinase activation and the occurrence of conformational changes. (ii) Ligands other than insulin, such as antibodies, which perturb the extracellular domain, can function as alternative ways to restore the mutant receptor kinase. PMID:8388389

  20. Molecular characterization of thyroid hormone receptor beta from Schistosoma japonicum and assessment of its potential as a vaccine candidate antigen against schistosomiasis in BALB/c mice

    OpenAIRE

    Qiu Chunhui; Liu Shengfa; Hong Yang; Fu Zhiqiang; Wei Meimei; Ai Dezhou; Lin Jiaojiao

    2012-01-01

    Abstract Background Thyroid hormones (TH) modulate growth, development and differentiation and metabolic processes by interacting with thyroid hormone receptors (THRs). The purpose of this study was to identify a novel thyroid hormone receptor beta encoding gene of Schistosoma japonicum (SjTHRβ) and to investigate its potential as a vaccine candidate antigen against schistosomiasis in BALB/c mice. Methods The full-length cDNA sequence of SjTHRβ, its gene organization, and its transcript level...