Identification of protein expression alterations in gefitinib-resistant human lung adenocarcinoma: PCNT and mPR play key roles in the development of gefitinib-associated resistance

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Lin, Chi-Chen [Institute of Biomedical Science, National Chung-Hsing University, Taichung, Taiwan (China); Institute of Biomedical Science, and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taiwan (China); Department of Medical Research and Education, Taichung Veterans General Hospital, Taichung, Taiwan (China); Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan (China); Chen, Jing-Ting [Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan (China); Lin, Meng-Wei [Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan (China); Department of Applied Science, National Hsinchu University of Education, Hsinchu, Taiwan (China); Chan, Chia-Hao [Department of Obstetrics and Gynecology, Hsinchu Mackay Memorial Hospital, Hsinchu 30071, Taiwan (China); Wen, Yueh-Feng [Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan (China); Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan (China); Wu, Shin-Bei [Department of Applied Science, National Hsinchu University of Education, Hsinchu, Taiwan (China); Chung, Ting-Wen [Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan (China); Lyu, Kevin W. [Lutheran Medical Center, Brooklyn, NY (United States); Global Scholars Program, St. George' s University/Northumbria University, Newcastle upon Tyne (United Kingdom); Chou, Hsiu-Chuan, E-mail: chouhc@mail.nhcue.edu.tw [Department of Applied Science, National Hsinchu University of Education, Hsinchu, Taiwan (China); and others

2015-11-01

Gefitinib is the first-line chemotherapeutic drug for treating non-small cell lung cancer (NSCLC), which comprises nearly 85% of all lung cancer cases worldwide. However, most patients eventually develop drug resistance after 12–18 months of treatment. Hence, investigating the drug resistance mechanism and resistance-associated biomarkers is necessary. Two lung adenocarcinoma cell lines, PC9 and gefitinib-resistant PC9/Gef, were established for examining resistance mechanisms and identifying potential therapeutic targets. Two-dimensional differential gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used for examining global protein expression changes between PC9 and PC9/Gef. The results revealed that 164 identified proteins were associated with the formation of gefitinib resistance in PC9 cells. Additional studies using RNA interference showed that progesterone receptor membrane component 1 and pericentrin proteins have major roles in gefitinib resistance. In conclusion, the proteomic approach enabled identifying of numerous proteins involved in gefitinib resistance. The results provide useful diagnostic markers and therapeutic candidates for treating gefitinib-resistant NSCLC. - Highlights: • 164 proteins associated with gefitinib resistance were identified through proteomic analysis. • In this study, a lung adenocarcinoma and its gefitinib resistant partner were established. • mPR and PCNT proteins have evidenced to play important roles in gefitinib resistance.

Identification of protein expression alterations in gefitinib-resistant human lung adenocarcinoma: PCNT and mPR play key roles in the development of gefitinib-associated resistance

International Nuclear Information System (INIS)

Lin, Chi-Chen; Chen, Jing-Ting; Lin, Meng-Wei; Chan, Chia-Hao; Wen, Yueh-Feng; Wu, Shin-Bei; Chung, Ting-Wen; Lyu, Kevin W.; Chou, Hsiu-Chuan

2015-01-01

Gefitinib is the first-line chemotherapeutic drug for treating non-small cell lung cancer (NSCLC), which comprises nearly 85% of all lung cancer cases worldwide. However, most patients eventually develop drug resistance after 12–18 months of treatment. Hence, investigating the drug resistance mechanism and resistance-associated biomarkers is necessary. Two lung adenocarcinoma cell lines, PC9 and gefitinib-resistant PC9/Gef, were established for examining resistance mechanisms and identifying potential therapeutic targets. Two-dimensional differential gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used for examining global protein expression changes between PC9 and PC9/Gef. The results revealed that 164 identified proteins were associated with the formation of gefitinib resistance in PC9 cells. Additional studies using RNA interference showed that progesterone receptor membrane component 1 and pericentrin proteins have major roles in gefitinib resistance. In conclusion, the proteomic approach enabled identifying of numerous proteins involved in gefitinib resistance. The results provide useful diagnostic markers and therapeutic candidates for treating gefitinib-resistant NSCLC. - Highlights: • 164 proteins associated with gefitinib resistance were identified through proteomic analysis. • In this study, a lung adenocarcinoma and its gefitinib resistant partner were established. • mPR and PCNT proteins have evidenced to play important roles in gefitinib resistance.

Breast Cancer Resistance to Cyclophosphamide and Other Oxazaphosphorines.

Science.gov (United States)

1997-10-01

human breast adenocarcinoma MCF-7/0 cells. d-Limonene, a monoterpene abundantly present in citrus fruits and various other foods common to most diets...and ARE-B. e.g., catechol, inducers, Figure 12 and Table 3, vide supra. Given the foregoing, the expectation was that the monoterpenes would induce the...less effectively than ALDH-1 (data not shown). r I r I I (I) o 300 7 I~Cl) S20 E -- 0 1 O 25 cc 1 2 3 1 2 3 Monoterpene , log iM Monoterpene , log pM

Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer.

OpenAIRE

Canonici, A; Gijsen, M; Mullooly, M; Bennett, R; Bouguern, N; Pedersen, K; O'Brien, NA; Roxanis, I; Li, J-L; Bridge, E; Finn, R; Siamon, D; McGowan, P; Duffy, MJ; O'Donovan, N

2013-01-01

Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. ...

Functional miRNAs in breast cancer drug resistance

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Hu WZ

2018-03-01

Full Text Available Weizi Hu,1–3,* Chunli Tan,1–3,* Yunjie He,4 Guangqin Zhang,2 Yong Xu,3,5 Jinhai Tang1 1Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 2School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 3Nanjing Medical University Affiliated Cancer Hospital, 4The First Clinical School of Nanjing Medical University, 5Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, People’s Republic of China *These authors contributed equally to this work Abstract: Owing to improved early surveillance and advanced therapy strategies, the current death rate due to breast cancer has decreased; nevertheless, drug resistance and relapse remain obstacles on the path to successful systematic treatment. Multiple mechanisms responsible for drug resistance have been elucidated, and miRNAs seem to play a major part in almost every aspect of cancer progression, including tumorigenesis, metastasis, and drug resistance. In recent years, exosomes have emerged as novel modes of intercellular signaling vehicles, initiating cell–cell communication through their fusion with target cell membranes, delivering functional molecules including miRNAs and proteins. This review particularly focuses on enumerating functional miRNAs involved in breast cancer drug resistance as well as their targets and related mechanisms. Subsequently, we discuss the prospects and challenges of miRNA function in drug resistance and highlight valuable approaches for the investigation of the role of exosomal miRNAs in breast cancer progression and drug resistance. Keywords: microRNA, exosome, breast cancer, drug resistance

Neurinoma del plexo braquial simulando metastasis de adenocarcinoma de mama Schwannoma of the brachial plexus resembling a breast adenocarcinoma metastasis

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Gregorio Rodríguez Boto

2011-10-01

Full Text Available Los neurinomas del plexo braquial son tumores infrecuentes que pueden confundirse con otras lesiones de índole tumoral. Se presenta el caso de una mujer de 40 años, tratada previamente de un adenocarcinoma de mama derecha en el pasado, que en el estudio de extensión realizado 5 años después se detectó una lesión localizada en el plexo braquial derecho. La paciente se encontraba asintomática. El diagnóstico radiológico de presunción fue metástasis de adenocarcinoma mamario. Se realizó un abordaje axilar derecho descubriendo una lesión bien delimitada en el plexo braquial. Con ayuda de la monitorización neurofisiológica intraoperatoria, se observó que la lesión dependía de la rama cubital y se pudo realizar una resección completa preservando la función de dicho nervio. El estudio anatomopatológico confirmó que se trataba de un neurinoma, descartando así la existencia de metástasis. La evolución postoperatoria fue satisfactoria. Seis años después de la intervención no existe recidiva tumoral. En nuestro conocimiento este es el primer caso publicado en la literatura de un neurinoma del plexo braquial dependiente de la rama cubital. La monitorización neurofisiológica intraoperatoria resulta fundamental para abordar este tipo de lesiones con baja morbilidad.Schwa nomas originating from the brachial plexus, although rare, may be mistaken for another type of tumour. A 40 year-old woman, who had been treated years earlier for a breast adenocarcinoma, showed in the 5-year follow-up magnetic resonance examination a localized lesion in the right brachial plexus. The presumptive radiological diagnosis was a metastasis from the primary adenocarcinoma. Following surgical access via the right axilla, a well-circumscribed mass in the brachial plexus was detected. Under intraoperative electrophysiological guidance, the lesion was observed to depend on the ulnar nerve and its complete resection was possible without compromising nerve

Systematic drug screening reveals specific vulnerabilities and co-resistance patterns in endocrine-resistant breast cancer.

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Kangaspeska, Sara; Hultsch, Susanne; Jaiswal, Alok; Edgren, Henrik; Mpindi, John-Patrick; Eldfors, Samuli; Brück, Oscar; Aittokallio, Tero; Kallioniemi, Olli

2016-07-04

The estrogen receptor (ER) inhibitor tamoxifen reduces breast cancer mortality by 31 % and has served as the standard treatment for ER-positive breast cancers for decades. However, 50 % of advanced ER-positive cancers display de novo resistance to tamoxifen, and acquired resistance evolves in 40 % of patients who initially respond. Mechanisms underlying resistance development remain poorly understood and new therapeutic opportunities are urgently needed. Here, we report the generation and characterization of seven tamoxifen-resistant breast cancer cell lines from four parental strains. Using high throughput drug sensitivity and resistance testing (DSRT) with 279 approved and investigational oncology drugs, exome-sequencing and network analysis, we for the first time, systematically determine the drug response profiles specific to tamoxifen resistance. We discovered emerging vulnerabilities towards specific drugs, such as ERK1/2-, proteasome- and BCL-family inhibitors as the cells became tamoxifen-resistant. Co-resistance to other drugs such as the survivin inhibitor YM155 and the chemotherapeutic agent paclitaxel also occurred. This study indicates that multiple molecular mechanisms dictate endocrine resistance, resulting in unexpected vulnerabilities to initially ineffective drugs, as well as in emerging co-resistances. Thus, combatting drug-resistant tumors will require patient-tailored strategies in order to identify new drug vulnerabilities, and to understand the associated co-resistance patterns.

Correlation of matrix metalloproteinases and their inhibitors with hypoxia and angiogenesis in premenopausal patients with adenocarcinoma of the breast.

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Vinothini, Govindarajah; Aravindraja, Chairmandurai; Chitrathara, K; Nagini, Siddavaram

2011-08-01

The present study was designed to correlate the expression of proteins regulating invasion and angiogenesis in patients with adenocarcinoma of the breast. Seventy-five premenopausal breast cancer patients histologically categorized as grades I, II and III were chosen for the study. We analyzed the expression of MMP-2, and -9 and their inhibitors TIMP-2 and RECK together with HIF-1α and VEGF in tumor, adjacent tissues and serum samples by immunohistochemical and Western blot analysis. The breast tumors analyzed in the present study were characterized by increased expression of MMP-2, -9, HIF-1α and VEGF with differential expression patterns of TIMP-2 and downregulation of RECK. The simultaneous analysis of the expression of these molecular markers is important to understand the intricate network between key molecules involved in invasion and angiogenesis that eventually determines the clinical course of the disease. Copyright © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Pristimerin overcomes adriamycin resistance in breast cancer cells through suppressing Akt signaling

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XIE, GUI'E; YU, XINPEI; LIANG, HUICHAO; CHEN, JINGSONG; TANG, XUEWEI; WU, SHAOQING; LIAO, CAN

2016-01-01

Breast cancer remains a major public health problem worldwide. Chemotherapy serves an important role in the treatment of breast cancer. However, resistance to chemotherapeutic agents, in particular, multi-drug resistance (MDR), is a major cause of treatment failure in cancer. Agents that can either enhance the effects of chemotherapeutics or overcome chemoresistance are urgently needed for the treatment of breast cancer. Pristimerin, a quinonemethide triterpenoid compound isolated from Celastraceae and Hippocrateaceae, has been shown to possess antitumor, anti-inflammatory, antioxidant and insecticidal properties. The aim of the present study was to investigate whether pristimerin can override chemoresistance in MCF-7/adriamycin (ADR)-resistant human breast cancer cells. The results demonstrated that pristimerin indeed displayed potent cytocidal effect on multidrug-resistant MCF-7/ADR breast cancer cells, and that these effects occurred through the suppression of Akt signaling, which in turn led to the downregulation of antiapoptotic effectors and increased apoptosis. These findings indicate that use of pristimerin may represent a potentially promising approach for the treatment of ADR-resistant breast cancer. PMID:27123073

Bioactivation of the citrus flavonoid nobiletin by CYP1 enzymes in MCF7 breast adenocarcinoma cells.

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Surichan, Somchaiya; Androutsopoulos, Vasilis P; Sifakis, Stavros; Koutala, Eleni; Tsatsakis, Aristidis; Arroo, Randolph R J; Boarder, Michael R

2012-09-01

Recent studies have demonstrated cytochrome P450 CYP1-mediated metabolism and CYP1-enzyme induction by naturally occurring flavonoids in cancer cell line models. The arising metabolites often exhibit higher activity than the parent compound. In the present study we investigated the CYP1-mediated metabolism of the citrus polymethoxyflavone nobiletin by recombinant CYP1 enzymes and MCF7 breast adenocarcinoma cells. Incubation of nobiletin in MCF7 cells produced one main metabolite (NM1) resulting from O-demethylation in either A or B rings of the flavone moiety. Among the three CYP1 isoforms, CYP1A1 exhibited the highest rate of metabolism of nobiletin in recombinant CYP microsomal enzymes. The intracellular CYP1-mediated bioconversion of the flavone was reduced in the presence of the CYP1A1 and CYP1B1-selective inhibitors α-napthoflavone and acacetin. In addition nobiletin induced CYP1 enzyme activity, CYP1A1 protein and CYP1B1 mRNA levels in MCF7 cells at a concentration dependent manner. MTT assays in MCF7 cells further revealed that nobiletin exhibited significantly lower IC50 (44 μM) compared to cells treated with nobiletin and CYP1A1 inhibitor (69 μM). FACS analysis demonstrated cell a cycle block at G1 phase that was attenuated in the presence of CYP1A1 inhibitor. Taken together the data suggests that the dietary flavonoid nobiletin induces its own metabolism and in turn enhances its cytostatic effect in MCF7 breast adenocarcinoma cells, via CYP1A1 and CYP1B1 upregulation. Copyright © 2012 Elsevier Ltd. All rights reserved.

Breast abscess caused by penicillin resistant Pneumococci

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Boppe Appalaraju

2011-01-01

Full Text Available Breast abscess is mostly caused by Staphylococcus aureus. A 26-year-old immunocompetent lady was admitted with breast abscess. Incision and drainage (I/D was done and Pneumococci were isolated from the drained pus. The patient was earlier treated with Augmentin which was later changed to linezolid after testing for antibiotic susceptibility. This strain showed a high level of resistance to penicillin. It had been noticed that there was a slow increase in the number of penicillin resistant Pneumococci isolated in our hospitals. The increase in penicillin-resistant Pneumococci correlates with the intensive use of beta-lactam antibiotics. Hence, antibiotics should be used judiciously, avoiding their use particularly in mild self-limiting upper respiratory infections. Attention therefore, should focus on monitoring resistance in Pneumococci to prevent mortality and morbidity associated with this organism, which continues to take a heavy toll on children and the elderly.

Mechanisms of Resistance to Endocrine Therapy in Breast Cancer: Focus on Signaling Pathways, miRNAs and Genetically Based Resistance

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García-Becerra, Rocío; Santos, Nancy; Díaz, Lorenza; Camacho, Javier

2013-01-01

Breast cancer is the most frequent malignancy diagnosed in women. Approximately 70% of breast tumors express the estrogen receptor (ER). Tamoxifen and aromatase inhibitors (AIs) are the most common and effective therapies for patients with ERα-positive breast cancer. Alone or combined with chemotherapy, tamoxifen significantly reduces disease progression and is associated with more favorable impact on survival in patients. Unfortunately, endocrine resistance occurs, either de novo or acquired during the course of the treatment. The mechanisms that contribute to hormonal resistance include loss or modification in the ERα expression, regulation of signal transduction pathways, altered expression of specific microRNAs, balance of co-regulatory proteins, and genetic polymorphisms involved in tamoxifen metabolic activity. Because of the clinical consequences of endocrine resistance, new treatment strategies are arising to make the cells sensitive to tamoxifen. Here, we will review the current knowledge on mechanisms of endocrine resistance in breast cancer cells. In addition, we will discuss novel therapeutic strategies to overcome such resistance. Undoubtedly, circumventing endocrine resistance should help to improve therapy for the benefit of breast cancer patients. PMID:23344024

Endocrine resistance in breast cancer – an overview and update

Science.gov (United States)

Clarke, Robert; Tyson, John J.; Dixon, J. Michael

2015-01-01

Tumors that express detectable levels of the product of the ESR1 gene (estrogen receptor-α; ERα) represent the single largest molecular subtype of breast cancer. More women eventually die from ERα+ breast cancer than from either HER2+ disease (almost half of which also express ERα) and/or from triple negative breast cancer (ERα-negative, progesterone receptor-negative, and HER2-negative). Antiestrogens and aromatase inhibitors are largely indistinguishable from each other in their abilities to improve overall survival and almost 50% of ERα+ breast cancers will eventually fail one or more of these endocrine interventions. The precise reasons why these therapies fail in ERα+ breast cancer remain largely unknown. Pharmacogenetic explanations for Tamoxifen resistance are controversial. The role of ERα mutations in endocrine resistance remains unclear. Targeting the growth factors and oncogenes most strongly correlated with endocrine resistance has proven mostly disappointing in their abilities to improve overall survival substantially, particularly in the metastatic setting. Nonetheless, there are new concepts in endocrine resistance that integrate molecular signaling, cellular metabolism, and stress responses including endoplasmic reticulum stress and the unfolded protein response (UPR) that provide novel insights and suggest innovative therapeutic targets. Encouraging evidence that drug combinations with CDK4/CDK6 inhibitors can extend recurrence free survival may yet translate to improvements in overall survival. Whether the improvements seen with immunotherapy in other cancers can be achieved in breast cancer remains to be determined, particularly for ERα+ breast cancers. This review explores the basic mechanisms of resistance to endocrine therapies, concluding with some new insights from systems biology approaches further implicating autophagy and the UPR in detail, and a brief discussion of exciting new avenues and future prospects. PMID:26455641

Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer.

Science.gov (United States)

Canonici, Alexandra; Gijsen, Merel; Mullooly, Maeve; Bennett, Ruth; Bouguern, Noujoude; Pedersen, Kasper; O'Brien, Neil A; Roxanis, Ioannis; Li, Ji-Liang; Bridge, Esther; Finn, Richard; Siamon, Dennis; McGowan, Patricia; Duffy, Michael J; O'Donovan, Norma; Crown, John; Kong, Anthony

2013-10-01

Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. We confirmed that neratinib was significantly more active in HER2-amplified than HER2 non-amplified cell lines. Neratinib decreased the activation of the 4 HER receptors and inhibited downstream pathways. However, HER3 and Akt were reactivated at 24 hours, which was prevented by the combination of trastuzumab and neratinib. Neratinib also decreased pHER2 and pHER3 in acquired trastuzumab resistant cells. Neratinib in combination with trastuzumab had a greater growth inhibitory effect than either drug alone in 4 HER2 positive cell lines. Furthermore, trastuzumab in combination with neratinib was growth inhibitory in SKBR3 and BT474 cells which had acquired resistance to trastuzumab as well as in a BT474 xenograft model. Innately trastuzumab resistant cell lines showed sensitivity to neratinib, but the combination did not enhance response compared to neratinib alone. Levels of HER2 and phospho-HER2 showed a direct correlation with sensitivity to neratinib. Our data indicate that neratinib is an effective anti-HER2 therapy and counteracted both innate and acquired trastuzumab resistance in HER2 positive breast cancer. Our results suggest that combined treatment with trastuzumab and neratinib is likely to be more effective than either treatment alone for both trastuzumab-sensitive breast cancer as well as HER2-positive tumors with acquired resistance to trastuzumab.

Systematic drug screening reveals specific vulnerabilities and co-resistance patterns in endocrine-resistant breast cancer

International Nuclear Information System (INIS)

Kangaspeska, Sara; Hultsch, Susanne; Jaiswal, Alok; Edgren, Henrik; Mpindi, John-Patrick; Eldfors, Samuli; Brück, Oscar; Aittokallio, Tero; Kallioniemi, Olli

2016-01-01

The estrogen receptor (ER) inhibitor tamoxifen reduces breast cancer mortality by 31 % and has served as the standard treatment for ER-positive breast cancers for decades. However, 50 % of advanced ER-positive cancers display de novo resistance to tamoxifen, and acquired resistance evolves in 40 % of patients who initially respond. Mechanisms underlying resistance development remain poorly understood and new therapeutic opportunities are urgently needed. Here, we report the generation and characterization of seven tamoxifen-resistant breast cancer cell lines from four parental strains. Using high throughput drug sensitivity and resistance testing (DSRT) with 279 approved and investigational oncology drugs, exome-sequencing and network analysis, we for the first time, systematically determine the drug response profiles specific to tamoxifen resistance. We discovered emerging vulnerabilities towards specific drugs, such as ERK1/2-, proteasome- and BCL-family inhibitors as the cells became tamoxifen-resistant. Co-resistance to other drugs such as the survivin inhibitor YM155 and the chemotherapeutic agent paclitaxel also occurred. This study indicates that multiple molecular mechanisms dictate endocrine resistance, resulting in unexpected vulnerabilities to initially ineffective drugs, as well as in emerging co-resistances. Thus, combatting drug-resistant tumors will require patient-tailored strategies in order to identify new drug vulnerabilities, and to understand the associated co-resistance patterns. The online version of this article (doi:10.1186/s12885-016-2452-5) contains supplementary material, which is available to authorized users

The identification of new genes related to cisplatin resistance in ovarian adenocarcinoma cell line A2780

International Nuclear Information System (INIS)

Solar, P.; Fedorocko, P.; Sytkowski, A.; Hodorova, I.

2006-01-01

Ovarian cancer cells are usually sensitive to platinum-based chemotherapy, such as cisplatin (CDDP), initially but typically become resistant to the drug over time. The phenomenon of clinical drug resistance represents a serious problem for successful disease treatment, and the molecular mechanism(s) are not fully understood. In search of novel mechanisms that may lead to the development of CDDP chemoresistance we have applied subtractive hybridization based on the PCR-select cDNA subtraction. In current study we have used subtractive hybridization to identify differentially-expressed genes in CDDP resistant CP70 and C200 cells versus CDDP-sensitive A2780 human ovarian adenocarcinoma cells. We have analyzed 256 randomly selected clones. Subtraction efficiency was determined by dot blot and DNA sequencing. Confirmation of differentially expressed cDNAs was done by virtual northern blot analysis, and 17 genes that were differentially expressed in both CDDP resistant cell lines versus CDDP sensitive A2780 cells were identified. The expression of 10 of these genes was undetectable or detected with low expression in sensitive A2780 cells in comparison to resistant ones. These genes included ARHGDIB, RANBP2, ASPH, PRTFDC1, SSX2IP, MBNL1, DNAJC15, MMP10, TCTE1L and one unidentified sequence. Additional 7 genes that were more highly expressed in resistant CP70 and C200 vs. A2780 cells included ANXA2, USP8, HSPCA, TRA1, CNAP1, ATP2B1 and COX2. Interestingly, multi-drug resistance associated p-glycoprotein (p170) was not detected by the western blot in CDDP resistant CP70 and C200 cells. Our identified genes are involved in diverse processes, such as stress response, chromatin condensation, protection from protein degradation, invasiveness of cells, alterations of Ca 2+ homeostasis and others which may contribute to CDDP resistance of ovarian adenocarcinoma cells. Further characterization of these genes and gene products should yield important insights into the biology of

A Petiveria alliacea standardized fraction induces breast adenocarcinoma cell death by modulating glycolytic metabolism.

Science.gov (United States)

Hernández, John Fredy; Urueña, Claudia Patricia; Cifuentes, Maria Claudia; Sandoval, Tito Alejandro; Pombo, Luis Miguel; Castañeda, Diana; Asea, Alexzander; Fiorentino, Susana

2014-05-14

Folk medicine uses aqueous and alcoholic extracts from Petiveria alliacea (Phytolaccaceae) in leukemia and breast cancer treatment in the Caribbean, Central and South America. Herein, we validated the biological activity of a Petiveria alliacea fraction using a metastatic breast adenocarcinoma model (4T1). Petiveria alliacea fraction biological activity was determined estimating cell proliferation, cell colony growth capacity and apoptosis (caspase-3 activity, DNA fragmentation and mitochondrial membrane potential) in 4T1 cells. Petiveria alliacea was used at IC₅₀ concentration (29 µg/mL) and 2 dilutions below, doxorubicin at 0.27 µg/mL (positive control) and dibenzyl disulfide at 2.93 µg/mL (IC50 fraction marker compound). Proteomic estimations were analyzed by LC-MS-MS. Protein level expression was confirmed by RT-PCR. Glucose and lactate levels were measured by enzymatic assays. LD50 was established in BALB/c mice and antitumoral activity evaluated in mice transplanted with GFP-tagged 4T1 cells. Mice were treated with Petiveria alliacea fraction via I.P (182 mg/kg corresponding to 1/8 of LD₅₀ and 2 dilutions below). Petiveria alliacea fraction in vitro induces 4T1 cells apoptosis, caspase-3 activation, DNA fragmentation without mitochondria membrane depolarization, and decreases cell colony growth capacity. Also, changes in glycolytic enzymes expression cause a decrease in glucose uptake and lactate production. Fraction also promotes breast primary tumor regression in BALB/c mice transplanted with GFP-tagged 4T1 cells. A fraction of Petiveria alliacea leaves and stems induces in vitro cell death and in vivo tumor regression in a murine breast cancer model. Our results validate in partly, the traditional use of Petiveria alliacea in breast cancer treatment, revealing a new way of envisioning Petiveria alliacea biological activity. The fraction effect on the glycolytic pathway enzymes contributes to explain the antiproliferative and antitumor activities

MENA Confers Resistance to Paclitaxel in Triple-Negative Breast Cancer.

Science.gov (United States)

Oudin, Madeleine J; Barbier, Lucie; Schäfer, Claudia; Kosciuk, Tatsiana; Miller, Miles A; Han, Sangyoon; Jonas, Oliver; Lauffenburger, Douglas A; Gertler, Frank B

2017-01-01

Taxane therapy remains the standard of care for triple-negative breast cancer. However, high frequencies of recurrence and progression in treated patients indicate that metastatic breast cancer cells can acquire resistance to this drug. The actin regulatory protein MENA and particularly its invasive isoform, MENA INV , are established drivers of metastasis. MENA INV expression is significantly correlated with metastasis and poor outcome in human patients with breast cancer. We investigated whether MENA isoforms might play a role in driving resistance to chemotherapeutics. We find that both MENA and MENA INV confer resistance to the taxane paclitaxel, but not to the widely used DNA-damaging agents doxorubicin or cisplatin. Furthermore, paclitaxel treatment does not attenuate growth of MENA INV -driven metastatic lesions. Mechanistically, MENA isoform expression alters the ratio of dynamic and stable microtubule populations in paclitaxel-treated cells. MENA expression also increases MAPK signaling in response to paclitaxel treatment. Decreasing ERK phosphorylation by co-treatment with MEK inhibitor restored paclitaxel sensitivity by driving microtubule stabilization in MENA isoform-expressing cells. Our results reveal a novel mechanism of taxane resistance in highly metastatic breast cancer cells and identify a combination therapy to overcome such resistance. Mol Cancer Ther; 16(1); 143-55. ©2016 AACR. ©2016 American Association for Cancer Research.

Increased STAT1 signaling in endocrine-resistant breast cancer.

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Rui Huang

Full Text Available Proteomic profiling of the estrogen/tamoxifen-sensitive MCF-7 cell line and its partially sensitive (MCF-7/LCC1 and fully resistant (MCF-7/LCC9 variants was performed to identify modifiers of endocrine sensitivity in breast cancer. Analysis of the expression of 120 paired phosphorylated and non-phosphorylated epitopes in key oncogenic and tumor suppressor pathways revealed that STAT1 and several phosphorylated epitopes (phospho-STAT1(Tyr701 and phospho-STAT3(Ser727 were differentially expressed between endocrine resistant and parental controls, confirmed by qRT-PCR and western blotting. The STAT1 inhibitor EGCG was a more effective inhibitor of the endocrine resistant MCF-7/LCC1 and MCF-7/LCC9 lines than parental MCF-7 cells, while STAT3 inhibitors Stattic and WP1066 were equally effective in endocrine-resistant and parental lines. The effects of the STAT inhibitors were additive, rather than synergistic, when tested in combination with tamoxifen in vitro. Expression of STAT1 and STAT3 were measured by quantitative immunofluorescence in invasive breast cancers and matched lymph nodes. When lymph node expression was compared to its paired primary breast cancer expression, there was greater expression of cytoplasmic STAT1 (∼3.1 fold, phospho-STAT3(Ser727 (∼1.8 fold, and STAT5 (∼1.5 fold and nuclear phospho-STAT3(Ser727 (∼1.5 fold in the nodes. Expression levels of STAT1 and STAT3 transcript were analysed in 550 breast cancers from publicly available gene expression datasets (GSE2990, GSE12093, GSE6532. When treatment with tamoxifen was considered, STAT1 gene expression was nearly predictive of distant metastasis-free survival (DMFS, log-rank p = 0.067, while STAT3 gene expression was predictive of DMFS (log-rank p<0.0001. Analysis of STAT1 and STAT3 protein expression in a series of 546 breast cancers also indicated that high expression of STAT3 protein was associated with improved survival (DMFS, p = 0.006. These results suggest

Aberrant Long Noncoding RNAs Expression Profiles Affect Cisplatin Resistance in Lung Adenocarcinoma

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Lijuan Hu

2017-01-01

Full Text Available Background. Long noncoding RNAs (lncRNAs have been shown to be involved in the mechanism of cisplatin resistance in lung adenocarcinoma (LAD. However, the roles of lncRNAs in cisplatin resistance in LAD are not well understood. Methods. We used a high-throughput microarray to compare the lncRNA and mRNA expression profiles in cisplatin resistance cell A549/DDP and cisplatin sensitive cell A549. Several candidate cisplatin resistance-associated lncRNAs were verified by real-time quantitative reverse transcription polymerase chain reaction (PCR analysis. Results. We found that 1,543 lncRNAs and 1,713 mRNAs were differentially expressed in A549/DDP cell and A549 cell, hinting that many lncRNAs were irregular from cisplatin resistance in LAD. We also obtain the fact that 12 lncRNAs were aberrantly expressed in A549/DDP cell compared with A549 cell by quantitative PCR. Among these, UCA1 was the aberrantly expressed lncRNA and can significantly reduce the IC50 of cisplatin in A549/DDP cell after knockdown, while it can increase the IC50 of cisplatin after UCA1 was overexpressed in NCI-H1299. Conclusions. We obtained patterns of irregular lncRNAs and they may play a key role in cisplatin resistance of LAD.

Circular RNA Signature Predicts Gemcitabine Resistance of Pancreatic Ductal Adenocarcinoma

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Feng Shao

2018-06-01

Full Text Available Gemcitabine resistance is currently the main problem of chemotherapy for advanced pancreatic cancer patients. The resistance is thought to be caused by altered drug metabolism or reduced apoptosis of cancer cells. However, the underlying mechanism of Gemcitabine resistance in pancreatic cancer remains unclear. In this study, we established Gemcitabine resistant PANC-1 (PANC-1-GR cell lines and compared the circular RNAs (circRNAs profiles between PANC-1 cells and PANC-1-GR cells by RNA sequencing. Differentially expressed circRNAs were demonstrated using scatter plot and cluster heatmap analysis. Gene ontology and pathway analysis were performed to systemically map the genes which are functionally associated to those differentially expressed circRNAs identified from our data. The expression of the differentially expressed circRNAs picked up by RNAseq in PANC-1-GR cells was further validated by qRT-PCR and two circRNAs were eventually identified as the most distinct targets. Consistently, by analyzing plasma samples form pancreatic ductal adenocarcinoma (PDAC patients, the two circRNAs showed more significant expression in the Gemcitabine non-responsive patients than the responsive ones. In addition, we found that silencing of the two circRNAs could restore the sensitivity of PANC-1-GR cells to Gemcitabine treatment, while over-expression of them could increase the resistance of normal PANC-1 and MIA PACA-2 cells, suggesting that they might serve as drug targets for Gemcitabine resistance. Furthermore, the miRNA interaction networks were also explored based on the correlation analysis of the target microRNAs of these two circRNAs. In conclusion, we successfully established new PANC-1-GR cells, systemically characterized the circRNA and miRNA profiles, and identified two circRNAs as novel biomarkers and potential therapeutic targets for Gemcitabine non-responsive PDAC patients.

Combination therapy of apatinib with icotinib for primary acquired icotinib resistance in patients with advanced pulmonary adenocarcinoma with EGFR mutation.

Science.gov (United States)

Xia, Pinghui; Cao, Jinlin; Lv, Xiayi; Wang, Luming; Lv, Wang; Hu, Jian

2018-05-01

Multi-targeted agents represent the next generation of targeted therapies for solid tumors, and patients with acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs) may also benefit from their combination with TKI therapy. Third-generation targeted drugs, such as osimertinib, are very expensive, thus a more economical solution is required. The aim of this study was to explore the use of apatinib combined with icotinib therapy for primary acquired resistance to icotinib in three patients with advanced pulmonary adenocarcinoma with EGFR mutations. We achieved favorable oncologic outcomes in all three patients, with progression-free survival of four to six months. Unfortunately, the patients ultimately had to cease combination therapy because of intolerable adverse effects of hand and foot syndrome and oral ulcers. Combination therapy of apatinib with icotinib for primary acquired resistance to icotinib may be an option for patients with advanced pulmonary adenocarcinoma with EGFR mutations, but physicians must also be aware of the side effects caused by such therapy. © 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Nuclear respiratory factor-1 and bioenergetics in tamoxifen-resistant breast cancer cells

International Nuclear Information System (INIS)

Radde, Brandie N.; Ivanova, Margarita M.; Mai, Huy Xuan; Alizadeh-Rad, Negin; Piell, Kellianne; Van Hoose, Patrick; Cole, Marsha P.; Muluhngwi, Penn; Kalbfleisch, Ted S.; Rouchka, Eric C.; Hill, Bradford G.; Klinge, Carolyn M.

2016-01-01

Acquired tamoxifen (TAM) resistance is a significant clinical problem in treating patients with estrogen receptor α (ERα)+ breast cancer. We reported that ERα increases nuclear respiratory factor-1 (NRF-1), which regulates nuclear-encoded mitochondrial gene transcription, in MCF-7 breast cancer cells and NRF-1 knockdown stimulates apoptosis. Whether NRF-1 and target gene expression is altered in endocrine resistant breast cancer cells is unknown. We measured NRF-1and metabolic features in a cell model of progressive TAM-resistance. NRF-1 and its target mitochondrial transcription factor A (TFAM) were higher in TAM-resistant LCC2 and LCC9 cells than TAM-sensitive MCF-7 cells. Using extracellular flux assays we observed that LCC1, LCC2, and LCC9 cells showed similar oxygen consumption rate (OCR), but lower mitochondrial reserve capacity which was correlated with lower Succinate Dehydrogenase Complex, Subunit B in LCC1 and LCC2 cells. Complex III activity was lower in LCC9 than MCF-7 cells. LCC1, LCC2, and LCC9 cells had higher basal extracellular acidification (ECAR), indicating higher aerobic glycolysis, relative to MCF-7 cells. Mitochondrial bioenergetic responses to estradiol and 4-hydroxytamoxifen were reduced in the endocrine-resistant cells compared to MCF-7 cells. These results suggest the acquisition of altered metabolic phenotypes in response to long term antiestrogen treatment may increase vulnerability to metabolic stress. - Highlights: • NRF-1 and TFAM expression are higher in endocrine-resistant breast cancer cells. • Oxygen consumption rate is similar in endocrine-sensitive and resistant cells. • Mitochondrial reserve capacity is lower in endocrine-resistant cells. • Endocrine-resistant breast cancer cells have increased glycolysis. • Bioenergetic responses to E2 and tamoxifen are lower in endocrine-resistant cells.

Nuclear respiratory factor-1 and bioenergetics in tamoxifen-resistant breast cancer cells

Energy Technology Data Exchange (ETDEWEB)

Radde, Brandie N.; Ivanova, Margarita M.; Mai, Huy Xuan; Alizadeh-Rad, Negin; Piell, Kellianne; Van Hoose, Patrick; Cole, Marsha P.; Muluhngwi, Penn; Kalbfleisch, Ted S. [Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292 (United States); Rouchka, Eric C. [Bioinformatics and Biomedical Computing Laboratory, Department of Computer Engineering and Computer Science, University of Louisville, Louisville, KY 40292 (United States); Hill, Bradford G. [Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40292 (United States); Klinge, Carolyn M., E-mail: carolyn.klinge@louisville.edu [Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292 (United States)

2016-09-10

Acquired tamoxifen (TAM) resistance is a significant clinical problem in treating patients with estrogen receptor α (ERα)+ breast cancer. We reported that ERα increases nuclear respiratory factor-1 (NRF-1), which regulates nuclear-encoded mitochondrial gene transcription, in MCF-7 breast cancer cells and NRF-1 knockdown stimulates apoptosis. Whether NRF-1 and target gene expression is altered in endocrine resistant breast cancer cells is unknown. We measured NRF-1and metabolic features in a cell model of progressive TAM-resistance. NRF-1 and its target mitochondrial transcription factor A (TFAM) were higher in TAM-resistant LCC2 and LCC9 cells than TAM-sensitive MCF-7 cells. Using extracellular flux assays we observed that LCC1, LCC2, and LCC9 cells showed similar oxygen consumption rate (OCR), but lower mitochondrial reserve capacity which was correlated with lower Succinate Dehydrogenase Complex, Subunit B in LCC1 and LCC2 cells. Complex III activity was lower in LCC9 than MCF-7 cells. LCC1, LCC2, and LCC9 cells had higher basal extracellular acidification (ECAR), indicating higher aerobic glycolysis, relative to MCF-7 cells. Mitochondrial bioenergetic responses to estradiol and 4-hydroxytamoxifen were reduced in the endocrine-resistant cells compared to MCF-7 cells. These results suggest the acquisition of altered metabolic phenotypes in response to long term antiestrogen treatment may increase vulnerability to metabolic stress. - Highlights: • NRF-1 and TFAM expression are higher in endocrine-resistant breast cancer cells. • Oxygen consumption rate is similar in endocrine-sensitive and resistant cells. • Mitochondrial reserve capacity is lower in endocrine-resistant cells. • Endocrine-resistant breast cancer cells have increased glycolysis. • Bioenergetic responses to E2 and tamoxifen are lower in endocrine-resistant cells.

Chemosensitivity of irradiated resistant cells of multicellular spheroids in A549 lung adenocarcinoma

International Nuclear Information System (INIS)

Shi Degang; Shi Genming; Huang Gang

2006-01-01

Objective: To investigate the chemosensitivity of irradiated resistant cells of multicellular spheroids in A549 lung adenocarcinoma. Methods: The A549 irradiated resistant cells were the 10th regrowth generations after irradiated with 2.5 Gy of 6 MV X-ray, the control groups were A549 parent cells and MCFY/VCR resistant cells. The 6 kinds of chemotherapeutic drugs were DDP, VDS, 5-FU, HCP, MMC and ADM respectively, with verapamil (VPL) as reverse agent. The treatment effect was compared with MTT assay, and the multidrug resistant gene expressions of mdrl and MRP were measured with RT-PCR method. Results: A549 cells and irradiated resistant cells were resistant to DDP, but sensitivity to VDS,5-FU, HCP, MMC and ADM. The inhibitory rates of VPL to the above two cells were 98% and 25% respectively(P 2 -MG and MRP/β 2 -MG of all A549 cells were about 0 and 0.7 respectively, and those of MCFT/VCR cells were 35 and 4.36. Conclusion: The chemosensitivity of A549 irradiated resistant cells had not changed markedly, the decreased sensitivity to VPL could not be explained by the gene expression of mdrl and MRP. It is conferred that some kinds of changes in the cell membrane and decreased regrowth ability to result in resistance. Unlike multidrug resistance induced by chemotherapy, VPL may be not an ideal reverser to irradiated resistant cells. The new kinds of biological preparation should be sought to combine chemotherapy to treat recurring tumor with irradiated resistance. (authors)

Aurora kinase B is important for antiestrogen resistant cell growth and a potential biomarker for tamoxifen resistant breast cancer

DEFF Research Database (Denmark)

Larsen, Sarah L; Yde, Christina W; Laenkholm, Anne-Vibeke

2015-01-01

BACKGROUND: Resistance to antiestrogen therapy is a major clinical challenge in the treatment of estrogen receptor α (ER)-positive breast cancer. The aim of the study was to explore the growth promoting pathways of antiestrogen resistant breast cancer cells to identify biomarkers and novel treatm...

Molecular characterization of irinotecan (SN-38) resistant human breast cancer cell lines

DEFF Research Database (Denmark)

Jandu, Haatisha; Aluzaite, Kristina; Fogh, Louise

2016-01-01

Background: Studies in taxane and/or anthracycline refractory metastatic breast cancer (mBC) patients have shown approximately 30 % response rates to irinotecan. Hence, a significant number of patients will experience irinotecan-induced side effects without obtaining any benefit. The aim of this ......Background: Studies in taxane and/or anthracycline refractory metastatic breast cancer (mBC) patients have shown approximately 30 % response rates to irinotecan. Hence, a significant number of patients will experience irinotecan-induced side effects without obtaining any benefit. The aim...... or an initial high dose of SN-38 (the active metabolite of irinotecan), respectively. The resistant cell lines were analyzed for cross-resistance to other anti-cancer drugs, global gene expression, growth rates, TOP1 and TOP2A gene copy numbers and protein expression, and inhibition of the breast cancer...... of the BCRP in breast cancer patients scheduled for irinotecan treatment. Moreover, LMP400 should be tested in a clinical setting in breast cancer patients with resistance to irinotecan....

Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1.

Science.gov (United States)

Zhu, Yinghua; Liu, Yujie; Zhang, Chao; Chu, Junjun; Wu, Yanqing; Li, Yudong; Liu, Jieqiong; Li, Qian; Li, Shunying; Shi, Qianfeng; Jin, Liang; Zhao, Jianli; Yin, Dong; Efroni, Sol; Su, Fengxi; Yao, Herui; Song, Erwei; Liu, Qiang

2018-04-23

Tamoxifen resistance is accountable for relapse in many ER-positive breast cancer patients. Most of these recurrent patients receive chemotherapy, but their chemosensitivity is unknown. Here, we report that tamoxifen-resistant breast cancer cells express significantly more BARD1 and BRCA1, leading to resistance to DNA-damaging chemotherapy including cisplatin and adriamycin, but not to paclitaxel. Silencing BARD1 or BRCA1 expression or inhibition of BRCA1 phosphorylation by Dinaciclib restores the sensitivity to cisplatin in tamoxifen-resistant cells. Furthermore, we show that activated PI3K/AKT pathway is responsible for the upregulation of BARD1 and BRCA1. PI3K inhibitors decrease the expression of BARD1 and BRCA1 in tamoxifen-resistant cells and re-sensitize them to cisplatin both in vitro and in vivo. Higher BARD1 and BRCA1 expression is associated with worse prognosis of early breast cancer patients, especially the ones that received radiotherapy, indicating the potential use of PI3K inhibitors to reverse chemoresistance and radioresistance in ER-positive breast cancer patients.

Systematic Functional Characterization of Resistance to PI3K Inhibition in Breast Cancer.

Science.gov (United States)

Le, Xiuning; Antony, Rajee; Razavi, Pedram; Treacy, Daniel J; Luo, Flora; Ghandi, Mahmoud; Castel, Pau; Scaltriti, Maurizio; Baselga, Jose; Garraway, Levi A

2016-10-01

PIK3CA (which encodes the PI3K alpha isoform) is the most frequently mutated oncogene in breast cancer. Small-molecule PI3K inhibitors have shown promise in clinical trials; however, intrinsic and acquired resistance limits their utility. We used a systematic gain-of-function approach to identify genes whose upregulation confers resistance to the PI3K inhibitor BYL719 in breast cancer cells. Among the validated resistance genes, Proviral Insertion site in Murine leukemia virus (PIM) kinases conferred resistance by maintaining downstream PI3K effector activation in an AKT-independent manner. Concurrent pharmacologic inhibition of PIM and PI3K overcame this resistance mechanism. We also observed increased PIM expression and activity in a subset of breast cancer biopsies with clinical resistance to PI3K inhibitors. PIM1 overexpression was mutually exclusive with PIK3CA mutation in treatment-naïve breast cancers, suggesting downstream functional redundancy. Together, these results offer new insights into resistance to PI3K inhibitors and support clinical studies of combined PIM/PI3K inhibition in a subset of PIK3CA-mutant cancers. PIM kinase overexpression confers resistance to small-molecule PI3K inhibitors. Combined inhibition of PIM and PI3K may therefore be warranted in a subset of breast cancers. Cancer Discov; 6(10); 1134-47. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1069. ©2016 American Association for Cancer Research.

Adenocarcinoma of the Lung Acquiring Resistance to Afatinib by Transformation to Small Cell Carcinoma: A Case Report

Directory of Open Access Journals (Sweden)

Jun Nishimura

2017-07-01

Full Text Available A 65-year-old woman visited our hospital due to right chest pain and dyspnea on exertion. Chest radiography revealed decreased permeability of the right lung. Computed tomography demonstrated a huge mass in the right upper lobe and right pleural effusion. Right pleural effusion cytology yielded a diagnosis of adenocarcinoma and was positive for mutation of epidermal growth factor receptor (EGFR; exon 21 L858R. Afatinib was selected for the initial treatment. Multiple tumors regressed remarkably, but then rapidly progressed 3 months later. We performed re-biopsy to detect the mechanism of resistance to afatinib. Histopathology revealed a mixture of small cell carcinoma (SCC and adenocarcinoma harboring same EGFR mutation. To the best of our knowledge, this is the first report of transformation to SCC after treatment with afatinib.

Functional screen for genes responsible for tamoxifen resistance in human breast cancer cells

NARCIS (Netherlands)

Meijer, Danielle; van Agthoven, Ton; Bosma, Peter T.; Nooter, Kees; Dorssers, Lambert C. J.

2006-01-01

Antiestrogens, such as tamoxifen, are widely used for endocrine treatment of estrogen receptor-positive breast cancer. However, as breast cancer progresses, development of tamoxifen resistance is inevitable. The mechanisms underlying this resistance are not well understood. To identify genes

CD44-engineered mesoporous silica nanoparticles for overcoming multidrug resistance in breast cancer

International Nuclear Information System (INIS)

Wang, Xin; Liu, Ying; Wang, Shouju; Shi, Donghong; Zhou, Xianguang; Wang, Chunyan; Wu, Jiang; Zeng, Zhiyong; Li, Yanjun; Sun, Jing; Wang, Jiandong; Zhang, Longjiang; Teng, Zhaogang; Lu, Guangming

2015-01-01

Graphical abstract: - Highlights: • CD44-engineered mesoporous silica nanoparticles are synthesized. • The mechanism of CD44-engineered mesoporous silica nanoparticles is revealed. • This new delivery system increased the drug accumulation in vitro and in vivo. • This new delivery system offers an effective approach to treat multidrug resistance. - Abstract: Multidrug resistance is a major impediment for the successful chemotherapy in breast cancer. CD44 is over-expressed in multidrug resistant human breast cancer cells. CD44 monoclonal antibody exhibits anticancer potential by inhibiting proliferation and regulating P-glycoprotein-mediated drug efflux activity in multidrug resistant cells. Thereby, CD44 monoclonal antibody in combination with chemotherapeutic drug might be result in enhancing chemosensitivity and overcoming multidrug resistance. The purpose of this study is to investigate the effects of the CD44 monoclonal antibody functionalized mesoporous silica nanoparticles containing doxorubicin on human breast resistant cancer MCF-7 cells. The data showed that CD44-modified mesoporous silica nanoparticles increased cytotoxicity and enhanced the downregulation of P-glycoprotein in comparison to CD44 antibody. Moreover, CD44-engineered mesoporous silica nanoparticles provided active target, which promoted more cellular uptake of DOX in the resistant cells and more retention of DOX in tumor tissues than unengineered counterpart. Animal studies of the resistant breast cancer xenografts demonstrated that CD44-engineered drug delivery system remarkably induced apoptosis and inhibited the tumor growth. Our results indicated that the CD44-engineered mesoporous silica nanoparticle-based drug delivery system offers an effective approach to overcome multidrug resistance in human breast cancer

Breast cancer resistance protein is localized at the plasma membrane in mitoxantrone- and topotecan-resistant cell lines

NARCIS (Netherlands)

Scheffer, GL; Maliepaard, M; Pijnenborg, ACLM; van Gastelen, MA; Schroeijers, AB; Allen, JD; Ross, DD; van der Valk, P; Dalton, WS; Schellens, JHM; Scheper, RJ; de Jong, MC

2000-01-01

Tumor cells may display a multidrug resistant phenotype by overexpression of ATP-binding cassette transporters such as multidrug resistance (,MDR1) P-glycoprotein, multidrug resistance protein 1 (MRP1), and breast cancer resistance protein (BCRP). The presence of BCRP has thus far been reported

Reduced expression of p27 is a novel mechanism of docetaxel resistance in breast cancer cells

International Nuclear Information System (INIS)

Brown, Iain; Shalli, Kawan; McDonald, Sarah L; Moir, Susan E; Hutcheon, Andrew W; Heys, Steven D; Schofield, Andrew C

2004-01-01

Docetaxel is one of the most effective chemotherapeutic agents in the treatment of breast cancer. Breast cancers can have an inherent or acquired resistance to docetaxel but the causes of this resistance remain unclear. However, apoptosis and cell cycle regulation are key mechanisms by which most chemotherapeutic agents exert their cytotoxic effects. We created two docetaxel-resistant human breast cancer cell lines (MCF-7 and MDA-MB-231) and performed cDNA microarray analysis to identify candidate genes associated with docetaxel resistance. Gene expression changes were validated at the RNA and protein levels by reverse transcription PCR and western analysis, respectively. Gene expression cDNA microarray analysis demonstrated reduced p27 expression in docetaxel-resistant breast cancer cells. Although p27 mRNA expression was found to be reduced only in MCF-7 docetaxel-resistant sublines (2.47-fold), reduced expression of p27 protein was noted in both MCF-7 and MDA-MB-231 docetaxel-resistant breast cancer cells (2.83-fold and 3.80-fold, respectively). This study demonstrates that reduced expression of p27 is associated with acquired resistance to docetaxel in breast cancer cells. An understanding of the genes that are involved in resistance to chemotherapy may allow further development in modulating drug resistance, and may permit selection of those patients who are most likely to benefit from such therapies

Taxane resistance in breast cancer: mechanisms, predictive biomarkers and circumvention strategies.

Science.gov (United States)

Murray, S; Briasoulis, E; Linardou, H; Bafaloukos, D; Papadimitriou, C

2012-11-01

Taxanes are established in the treatment of metastatic breast cancer (MBC) and early breast cancer (EBC) as potent chemotherapy agents. However, their therapeutic usefulness is limited by de-novo refractoriness or acquired resistance, which are common drawbacks to most anti-cancer cytotoxics. Considering that the taxanes will remain principle chemotherapeutic agents for the treatment of breast cancer, we reviewed known mechanisms of resistance in with an outlook of optimizing their clinical use. We searched the PubMed and MEDLINE databases for articles (from inception through to 9th January 2012; last search 10/01/2012) and journals known to publish information relevant to taxane chemotherapy. We imposed no language restrictions. Search terms included: cancer, breast cancer, response, resistance, taxane, paclitaxel, docetaxel, taxol. Due to the possibility of alternative mechanisms of resistance all combination chemotherapy treated data sets were removed from our overview. Over-expression of the MDR-1 gene product Pgp was extensively studied in vitro in association with taxane resistance, but data are conflicting. Similarly, the target components microtubules, which are thought to mediate refractoriness through alterations of the expression pattern of tubulins or microtubule associated proteins and the expression of alternative tubulin isoforms, failed to confirm such associations. Little consensus has been generated for reported associations between taxane-sensitivity and mutated p53, or taxane-resistance and overexpression of Bcl-2, Bcl-xL or NFkB. In contrary sufficient in vitro data support an association of spindle assembly checkpoint (SAC) defects with resistance. Clinical data have been limited and inconsistent, which relate to the variety of methods used, lack of standardization of cut-offs for quantitation, differences in clinical endpoints measured and in methods of tissue collection preparation and storage, and study/patient heterogeneity. The most

UCH-L1-containing exosomes mediate chemotherapeutic resistance transfer in breast cancer.

Science.gov (United States)

Ning, Kuan; Wang, Teng; Sun, Xu; Zhang, Pengfei; Chen, Yun; Jin, Jian; Hua, Dong

2017-06-01

Chemotherapy resistance has become a serious challenge in the treatment of breast cancer. Previous studies showed cells can transfer proteins, including those responsible for drug resistance to adjacent cells via exosomes. The switches of drug resistance via exosomes transfer were assessed by CellTiter-Blue Viability assay, flow cytometry, and immunostaining analysis. Relative protein levels of Ubiquitin carboxyl terminal hydrolase-L1 (UCH-L1), P-glycoprotein (P-gp), extracellular-signal regulated protein kinase1/2 (ERK1/2), and phospho-extracellular-signal regulated protein kinase1/2 (p-ERK1/2) were measured by Western blot. Immunohistochemistry was performed on 93 breast cancer samples to assess the associations of UCH-L1 levels with immunofluorescence value of UCH-L1 in circulating exosomes. The Adriamycin-resistant human breast cancer cells (MCF7/ADM) secreted exosomes carrying UCH-L1 and P-gp proteins into the extracellular microenvironment then integrated into Adriamycin-sensitive human breast cancer cells (MCF7/WT) in a time-dependent manner, transferring the chemoresistance phenotype. Notably, in blood samples from patients with breast cancer, the level of exosomes carrying UCH-L1 before chemotherapy was significantly negatively correlated with prognosis. Our study demonstrated that UCH-L1-containing exosomes can transfer chemoresistance to recipient cells and these exosomes may be useful as non-invasive diagnostic biomarkers for detection of chemoresitance in breast cancer patients, achieving more effective and individualized chemotherapy. © 2017 Wiley Periodicals, Inc.

The stepwise evolution of the exome during acquisition of docetaxel resistance in breast cancer cells

DEFF Research Database (Denmark)

Hansen, Stine Ninel; Ehlers, Natasja Spring; Zhu, Shida

2016-01-01

Background: Resistance to taxane-based therapy in breast cancer patients is a major clinical problem that may be addressed through insight of the genomic alterations leading to taxane resistance in breast cancer cells. In the current study we used whole exome sequencing to discover somatic genomic...... alterations, evolving across evolutionary stages during the acquisition of docetaxel resistance in breast cancer cell lines. Results: Two human breast cancer in vitro models (MCF-7 and MDA-MB-231) of the step-wise acquisition of docetaxel resistance were developed by exposing cells to 18 gradually increasing...... resistance relevant genomic variation appeared to arise midway towards fully resistant cells corresponding to passage 31 (5 nM docetaxel) for MDA-MB-231 and passage 16 (1.2 nM docetaxel) for MCF-7, and where the cells also exhibited a period of reduced growth rate or arrest, respectively. MCF-7 cell acquired...

Dissecting the Mechanisms of Drug Resistance in BRCA1/2-Mutant Breast Cancers

Science.gov (United States)

2017-10-01

AWARD NUMBER: W81XWH-16-1-0600 TITLE: Dissecting the Mechanisms of Drug Resistance in BRCA1/2-Mutant Breast Cancers PRINCIPAL INVESTIGATOR: Dr...2017 4. TITLE AND SUBTITLE Dissecting the Mechanisms of Drug Resistance in BRCA1/2- Mutant Breast Cancers 5a. CONTRACT NUMBER W81XWH-16-1-0600 5b...therapeutic modality for targeting homologous recombination (HR) deficient tumors such as BRCA1 and BRCA2-mutated triple negative breast cancers

Integrative analysis of miRNA and gene expression reveals regulatory networks in tamoxifen-resistant breast cancer

DEFF Research Database (Denmark)

Joshi, Tejal; Elias, Daniel; Stenvang, Jan

2016-01-01

Tamoxifen is an effective anti-estrogen treatment for patients with estrogen receptor-positive (ER+) breast cancer, however, tamoxifen resistance is frequently observed. To elucidate the underlying molecular mechanisms of tamoxifen resistance, we performed a systematic analysis of mi......+ breast cancer patients receiving adjuvant tamoxifen mono-therapy. Our results provide new insight into the molecular mechanisms of tamoxifen resistance and may form the basis for future medical intervention for the large number of women with tamoxifen-resistant ER+ breast cancer.......RNA-mediated gene regulation in three clinically-relevant tamoxifen-resistant breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive cell line. Alterations in the expression of 131 miRNAs in tamoxifen-resistant vs. parental cell lines were identified, 22 of which were common to all Tam...

Exosomes in development, metastasis and drug resistance of breast cancer.

Science.gov (United States)

Yu, Dan-dan; Wu, Ying; Shen, Hong-yu; Lv, Meng-meng; Chen, Wei-xian; Zhang, Xiao-hui; Zhong, Shan-liang; Tang, Jin-hai; Zhao, Jian-hua

2015-08-01

Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano-sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life-threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome-delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti-cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti-cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Dynamic Contrast Enhanced MRI in Patients With Advanced Breast or Pancreatic Cancer With Metastases to the Liver or Lung

Science.gov (United States)

2014-05-28

Acinar Cell Adenocarcinoma of the Pancreas; Duct Cell Adenocarcinoma of the Pancreas; Liver Metastases; Lung Metastases; Recurrent Breast Cancer; Recurrent Pancreatic Cancer; Stage IV Breast Cancer; Stage IV Pancreatic Cancer

Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1

Science.gov (United States)

Pirazzoli, Valentina; Nebhan, Caroline; Song, Xiaoling; Wurtz, Anna; Walther, Zenta; Cai, Guoping; Zhao, Zhongming; Jia, Peilin; de Stanchina, Elisa; Shapiro, Erik M.; Gale, Molly; Yin, Ruonan; Horn, Leora; Carbone, David P.; Stephens, Philip J; Miller, Vincent; Gettinger, Scott; Pao, William; Politi, Katerina

2014-01-01

SUMMARY Patients with EGFR-mutant lung adenocarcinomas (LUADs) who initially respond to first-generation TKIs develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. Addition of rapamycin reversed resistance in vivo. Analysis of afatinib+cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib+cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs. PMID:24813888

Leser–Trélat syndrome in malignant mesothelioma and pulmonary adenocarcinoma

DEFF Research Database (Denmark)

Jepsen, Rikke Karlin; Skov, Anne Guldhammer; Skov, Birgit Guldhammer

2014-01-01

The syndrome of Leser–Trélat (LT) is characterized by the sudden appearance of multiple seborrhoeic keratoses (SKs) in association with internal occult malignancy. Usually, the syndrome has been associated with adenocarcinoma, most frequently of the gastrointestinal tract and breast. The pathogen...

USP22 Induces Cisplatin Resistance in Lung Adenocarcinoma by Regulating γH2AX-Mediated DNA Damage Repair and Ku70/Bax-Mediated Apoptosis

Directory of Open Access Journals (Sweden)

Aman Wang

2017-05-01

Full Text Available Resistance to platinum-based chemotherapy is one of the most important reasons for treatment failure in advanced non-small cell lung cancer, but the underlying mechanism is extremely complex and unclear. The present study aimed to investigate the correlation of ubiquitin-specific peptidase 22 (USP22 with acquired resistance to cisplatin in lung adenocarcinoma. In this study, we found that overexpression of USP22 could lead to cisplatin resistance in A549 cells. USP22 and its downstream proteins γH2AX and Sirt1 levels are upregulated in the cisplatin- resistant A549/CDDP cell line. USP22 enhances DNA damage repair and induce cisplatin resistance by promoting the phosphorylation of histone H2AX via deubiquitinating histone H2A. In addition, USP22 decreases the acetylation of Ku70 by stabilizing Sirt1, thus inhibiting Bax-mediated apoptosis and inducing cisplatin resistance. The cisplatin sensitivity in cisplatin-resistant A549/CDDP cells was restored by USP22 inhibition in vivo and vitro. In summary, our findings reveal the dual mechanism of USP22 involvement in cisplatin resistance that USP22 can regulate γH2AX-mediated DNA damage repair and Ku70/Bax-mediated apoptosis. USP22 is a potential target in cisplatin-resistant lung adenocarcinoma and should be considered in future therapeutic practice.

Methotrexate diethyl ester-loaded lipid-core nanocapsules in aqueous solution increased antineoplastic effects in resistant breast cancer cell line

Directory of Open Access Journals (Sweden)

Yurgel VC

2014-03-01

Full Text Available Virginia C Yurgel,1,* Catiuscia P Oliveira,2,* Karine R Begnini,1 Eduarda Schultze,1 Helena S Thurow,1 Priscila MM Leon,1 Odir A Dellagostin,1 Vinicius F Campos,1 Ruy CR Beck,2 Silvia S Guterres,2 Tiago Collares,1 Adriana R Pohlmann,2–4 Fabiana K Seixas11Programa de Pós-Graduação em Biotecnologia (PPGB, Grupo de Pesquisa em Oncologia Celular e Molecular, Laboratório de Genômica Funcional, Biotecnologia/Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil; 2Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; 3Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; 4Centro de Nanociência e Nanotecnologia, CNANO-UFRGS, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil*These authors contributed equally to this workAbstract: Breast cancer is the most frequent cancer affecting women. Methotrexate (MTX is an antimetabolic drug that remains important in the treatment of breast cancer. Its efficacy is compromised by resistance in cancer cells that occurs through a variety of mechanisms. This study evaluated apoptotic cell death and cell cycle arrest induced by an MTX derivative (MTX diethyl ester [MTX(OEt2] and MTX(OEt2-loaded lipid-core nanocapsules in two MTX-resistant breast adenocarcinoma cell lines, MCF-7 and MDA-MB-231. The formulations prepared presented adequate granulometric profile. The treatment responses were evaluated through flow cytometry. Relying on the mechanism of resistance, we observed different responses between cell lines. For MCF-7 cells, MTX(OEt2 solution and MTX(OEt2-loaded lipid-core nanocapsules presented significantly higher apoptotic rates than untreated cells and cells incubated with unloaded lipid-core nanocapsules. For MDA-MB-231

The application of 99Tcm-MIBI scintimammography to diagnose multidrug resistance of breast cancer

International Nuclear Information System (INIS)

Cheng Bing

2002-01-01

The author discussed the main mechanism of multidrug resistance of breast cancer tissues, and the correlation between technetium-99m sestamibi ( 99 Tc m -MIBI) breast imaging results, with the expression of drug resistance proteins P-glycoprotein and glutathione-S-transferase-π in human breast cancer. Through not all the results reported before matched each other, as a kind of a noninvasive simple functional test imaging technology in vitro, SPECT can be used to diagnose P-glycoprotein expression in breast cancer, and can be used to predict chemotherapy response

Acquired Resistance of EGFR-Mutant Lung Adenocarcinomas to Afatinib plus Cetuximab Is Associated with Activation of mTORC1

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Valentina Pirazzoli

2014-05-01

Full Text Available Patients with EGFR-mutant lung adenocarcinomas (LUADs who initially respond to first-generation tyrosine kinase inhibitors (TKIs develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. The addition of rapamycin reversed resistance in vivo. Analysis of afatinib-plus-cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling, including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib plus cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs.

Curcumin promotes apoptosis in A549/DDP multidrug-resistant human lung adenocarcinoma cells through an miRNA signaling pathway

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Zhang, Jian, E-mail: zhangjian197011@yahoo.com [Department of Respiratory Medicine, Xijing Hospital, The Fourth Military Medical University, Xi' an 710032 (China); Zhang, Tao [Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi' an 710038 (China); Ti, Xinyu; Shi, Jieran; Wu, Changgui; Ren, Xinling [Department of Respiratory Medicine, Xijing Hospital, The Fourth Military Medical University, Xi' an 710032 (China); Yin, Hong, E-mail: yinnhong@yahoo.com [The Medical Image Center, Xijing Hospital, The Fourth Military Medical University, Xi' an 710032 (China)

2010-08-13

Research highlights: {yields} Curcumin had anti-cancer effects on A549/DDP multidrug-resistant human lung adenocarcinoma cells {yields} Curcumin promotes apoptosis in A549/DDP cells through a miRNA signaling pathway {yields} Curcumin induces A549/DDP cell apoptosis by downregulating miR-186* {yields} miR-186* may serve as a potential gene therapy target for refractory lung cancer that is sensitive to curcumin -- Abstract: Curcumin extracted from the rhizomes of Curcuma longa L. has been shown to have inhibitory effects on cancers through its anti-proliferative and pro-apoptotic activities. Emerging evidence demonstrates that curcumin can overcome drug resistance to classical chemotherapies. Thus, the mechanisms underlying the anti-tumor activities of curcumin require further study. In our study, we first demonstrated that curcumin had anti-cancer effects on A549/DDP multidrug-resistant human lung adenocarcinoma cells. Further studies showed that curcumin altered miRNA expression; in particular, significantly downregulated the expression of miR-186* in A549/DDP. In addition, transfection of cells with a miR-186* inhibitor promoted A549/DDP apoptosis, and overexpression of miR-186* significantly inhibited curcumin-induced apoptosis in A549/DDP cells. These observations suggest that miR-186* may serve as a potential gene therapy target for refractory lung cancer that is sensitive to curcumin.

Curcumin promotes apoptosis in A549/DDP multidrug-resistant human lung adenocarcinoma cells through an miRNA signaling pathway

International Nuclear Information System (INIS)

Zhang, Jian; Zhang, Tao; Ti, Xinyu; Shi, Jieran; Wu, Changgui; Ren, Xinling; Yin, Hong

2010-01-01

Research highlights: → Curcumin had anti-cancer effects on A549/DDP multidrug-resistant human lung adenocarcinoma cells → Curcumin promotes apoptosis in A549/DDP cells through a miRNA signaling pathway → Curcumin induces A549/DDP cell apoptosis by downregulating miR-186* → miR-186* may serve as a potential gene therapy target for refractory lung cancer that is sensitive to curcumin -- Abstract: Curcumin extracted from the rhizomes of Curcuma longa L. has been shown to have inhibitory effects on cancers through its anti-proliferative and pro-apoptotic activities. Emerging evidence demonstrates that curcumin can overcome drug resistance to classical chemotherapies. Thus, the mechanisms underlying the anti-tumor activities of curcumin require further study. In our study, we first demonstrated that curcumin had anti-cancer effects on A549/DDP multidrug-resistant human lung adenocarcinoma cells. Further studies showed that curcumin altered miRNA expression; in particular, significantly downregulated the expression of miR-186* in A549/DDP. In addition, transfection of cells with a miR-186* inhibitor promoted A549/DDP apoptosis, and overexpression of miR-186* significantly inhibited curcumin-induced apoptosis in A549/DDP cells. These observations suggest that miR-186* may serve as a potential gene therapy target for refractory lung cancer that is sensitive to curcumin.

TNFα-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer.

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Mercogliano, María F; De Martino, Mara; Venturutti, Leandro; Rivas, Martín A; Proietti, Cecilia J; Inurrigarro, Gloria; Frahm, Isabel; Allemand, Daniel H; Deza, Ernesto Gil; Ares, Sandra; Gercovich, Felipe G; Guzmán, Pablo; Roa, Juan C; Elizalde, Patricia V; Schillaci, Roxana

2017-02-01

Although trastuzumab administration improved the outcome of HER2-positive breast cancer patients, resistance events hamper its clinical benefits. We demonstrated that TNFα stimulation in vitro induces trastuzumab resistance in HER2-positive breast cancer cell lines. Here, we explored the mechanism of TNFα-induced trastuzumab resistance and the therapeutic strategies to overcome it. Trastuzumab-sensitive breast cancer cells, genetically engineered to stably overexpress TNFα, and de novo trastuzumab-resistant tumors, were used to evaluate trastuzumab response and TNFα-blocking antibodies effectiveness respectively. Immunohistochemistry and antibody-dependent cell cytotoxicity (ADCC), together with siRNA strategy, were used to explore TNFα influence on the expression and function of its downstream target, mucin 4 (MUC4). The clinical relevance of MUC4 expression was studied in a cohort of 78 HER2-positive breast cancer patients treated with adjuvant trastuzumab. TNFα overexpression turned trastuzumab-sensitive cells and tumors into resistant ones. Histopathologic findings revealed mucin foci in TNFα-producing tumors. TNFα induced upregulation of MUC4 that reduced trastuzumab binding to its epitope and impaired ADCC. Silencing MUC4 enhanced trastuzumab binding, increased ADCC, and overcame trastuzumab and trastuzumab-emtansine antiproliferative effects in TNFα-overexpressing cells. Accordingly, administration of TNFα-blocking antibodies downregulated MUC4 and sensitized de novo trastuzumab-resistant breast cancer cells and tumors to trastuzumab. In HER2-positive breast cancer samples, MUC4 expression was found to be an independent predictor of poor disease-free survival (P = 0.008). We identified TNFα-induced MUC4 expression as a novel trastuzumab resistance mechanism. We propose MUC4 expression as a predictive biomarker of trastuzumab efficacy and a guide to combination therapy of TNFα-blocking antibodies with trastuzumab. Clin Cancer Res; 23(3); 636-48. �

Neurological manifestation of colonic adenocarcinoma

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Uzair Chaudhary

2012-04-01

Full Text Available Paraneoplastic neurologic disorders are extremely rare in cancer patients and are most commonly associated with certain tumors, such as ovarian cancer, small cell lung cancer, and breast cancer. We report here a paraneoplastic neurological syndrome in a 53-year-old man with colonic adenocarcinoma with a solitary liver metastasis. His paraneoplastic syndrome was successfully treated by methylprednisolone and primary oncologic therapies including neoadjuvant chemotherapy and definitive surgery. This is also the first documented case of simultaneous manifestation of a sensory neuropathy and limbic encephalitis with colon cancer.

APC selectively mediates response to chemotherapeutic agents in breast cancer

International Nuclear Information System (INIS)

VanKlompenberg, Monica K.; Bedalov, Claire O.; Soto, Katia Fernandez; Prosperi, Jenifer R.

2015-01-01

The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in up to 70 % of sporadic breast cancers depending on subtype; however, the effects of APC mutation on tumorigenic properties remain unexplored. Using the Apc Min/+ mouse crossed to the Polyoma middle T antigen (PyMT) transgenic model, we identified enhanced breast tumorigenesis and alterations in genes critical in therapeutic resistance independent of Wnt/β-catenin signaling. Apc mutation changed the tumor histopathology from solid to squamous adenocarcinomas, resembling the highly aggressive human metaplastic breast cancer. Mechanistic studies in tumor-derived cell lines demonstrated that focal adhesion kinase (FAK)/Src/JNK signaling regulated the enhanced proliferation downstream of Apc mutation. Despite this mechanistic information, the role of APC in mediating breast cancer chemotherapeutic resistance is currently unknown. We have examined the effect of Apc loss in MMTV-PyMT mouse breast cancer cells on gene expression changes of ATP-binding cassette transporters and immunofluorescence to determine proliferative and apoptotic response of cells to cisplatin, doxorubicin and paclitaxel. Furthermore we determined the added effect of Src or JNK inhibition by PP2 and SP600125, respectively, on chemotherapeutic response. We also used the Aldefluor assay to measure the population of tumor initiating cells. Lastly, we measured the apoptotic and proliferative response to APC knockdown in MDA-MB-157 human breast cancer cells after chemotherapeutic treatment. Cells obtained from MMTV-PyMT;Apc Min/+ tumors express increased MDR1 (multidrug resistance protein 1), which is augmented by treatment with paclitaxel or doxorubicin. Furthermore MMTV-PyMT;Apc Min/+ cells are more resistant to cisplatin and doxorubicin-induced apoptosis, and show a larger population of ALDH positive cells. In the human metaplastic breast cancer cell line MDA-MB-157, APC knockdown led to paclitaxel and cisplatin

Comparative Proteomic Analysis of Human Lung Adenocarcinoma Cisplatin-resistant Cell Strain A549/CDDP

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Sien SHI

2009-11-01

Full Text Available Background and objective Chemotherapy plays an important role in the comprehensive therapy of lung cancer. However, the drug-resistance often causes the failure of the chemotherapy. The aim of this study is to identify differently expressed protein before and after cisplatin resistance of human lung adenocarcinoma cell A549 by proteomic analysis. Methods Cisplatin-resistant cell strain A549/CDDP was established by combining gradually increasing concentration of cisplatin with large dosage impact. Comparative proteomic analysis of A549 and A549/CDDP were carried out by means of two-dimensional gel electrophoresis. The differentially expressed proteins were detected and identified by MALDI-TOF mass spectrometry. Results Eighty-two differentially expressed proteins were screened by analysis the electrophoretic maps of A549 and A549/CDDP. Six differential proteins were analyzed by peptide mass fingerprinting. Glucose regulating protein 75, ribosomal protein S4, mitochondrial ATP synthase F1 complex beta subunit and immunoglobulin heavy chain variable region were identified. All four differentially expressed proteins were over-expressed in A549/CDDP, whereas low-expressed or no-expressed in A549. Conclusion These differentially expressed proteins give some clues to elucidate the mechanism of lung cancer cell resistant of cisplatin, providing the basis of searching for potential target of chemotherapy of lung cancer.

Embryonic transcription factor SOX9 drives breast cancer endocrine resistance.

Science.gov (United States)

Jeselsohn, Rinath; Cornwell, MacIntosh; Pun, Matthew; Buchwalter, Gilles; Nguyen, Mai; Bango, Clyde; Huang, Ying; Kuang, Yanan; Paweletz, Cloud; Fu, Xiaoyong; Nardone, Agostina; De Angelis, Carmine; Detre, Simone; Dodson, Andrew; Mohammed, Hisham; Carroll, Jason S; Bowden, Michaela; Rao, Prakash; Long, Henry W; Li, Fugen; Dowsett, Mitchell; Schiff, Rachel; Brown, Myles

2017-05-30

The estrogen receptor (ER) drives the growth of most luminal breast cancers and is the primary target of endocrine therapy. Although ER blockade with drugs such as tamoxifen is very effective, a major clinical limitation is the development of endocrine resistance especially in the setting of metastatic disease. Preclinical and clinical observations suggest that even following the development of endocrine resistance, ER signaling continues to exert a pivotal role in tumor progression in the majority of cases. Through the analysis of the ER cistrome in tamoxifen-resistant breast cancer cells, we have uncovered a role for an RUNX2-ER complex that stimulates the transcription of a set of genes, including most notably the stem cell factor SOX9, that promote proliferation and a metastatic phenotype. We show that up-regulation of SOX9 is sufficient to cause relative endocrine resistance. The gain of SOX9 as an ER-regulated gene associated with tamoxifen resistance was validated in a unique set of clinical samples supporting the need for the development of improved ER antagonists.

Chemo Resistance of Breast Cancer Stem Cells

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2007-05-01

165-72. 60. Vestergaard J, Pedersen MW, Pedersen N, Ensinger C, Tumer Z, Tommerup N, et al. Hedgehog signaling in small-cell lung cancer : frequent......NUMBER Chemo Resistance of Breast Cancer Stem Cells 5b. GRANT NUMBER W81XWH-04-1-0471 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d

Abrogating endocrine resistance by targeting ERα and PI3K in breast cancer

International Nuclear Information System (INIS)

Fox, Emily M.; Arteaga, Carlos L.; Miller, Todd W.

2012-01-01

Antiestrogen therapies targeting estrogen receptor α (ER) signaling are a mainstay for patients with ER+ breast cancer. While many cancers exhibit resistance to antiestrogen therapies, a large body of clinical and experimental evidence indicates that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway promotes antiestrogen resistance. In addition, continued ligand-independent ER signaling in the setting of estrogen deprivation may contribute to resistance to endocrine therapy. PI3K activates several proteins which promote cell cycle progression and survival. In ER+ breast cancer cells, PI3K promotes ligand-dependent and -independent ER transcriptional activity. Models of antiestrogen-resistant breast cancer often remain sensitive to estrogen stimulation and PI3K inhibition, suggesting that clinical trials with combinations of drugs targeting both the PI3K and ER pathways are warranted. Herein, we review recent findings on the roles of PI3K and ER in antiestrogen resistance, and clinical trials testing drug combinations which target both pathways. We also discuss the need for clinical investigation of ER downregulators in combination with PI3K inhibitors.

A targeted enzyme approach to sensitization of tyrosine kinase inhibitor-resistant breast cancer cells.

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Giordano, Courtney R; Mueller, Kelly L; Terlecky, Laura J; Krentz, Kendra A; Bollig-Fischer, Aliccia; Terlecky, Stanley R; Boerner, Julie L

2012-10-01

Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) of potential use in patients with breast cancer. Unfortunately, in clinical studies, gefitinib is often ineffective indicating that resistance to EGFR inhibitors may be a common occurrence in cancer of the breast. EGFR has been shown to be overexpressed in breast cancer, and in particular remains hyperphosphorylated in cell lines such as MDA-MB-468 that are resistant to EGFR inhibitors. Here, we investigate the cause of this sustained phosphorylation and the molecular basis for the ineffectiveness of gefitinib. We show that reactive oxygen species (ROS), known to damage cellular macromolecules and to modulate signaling cascades in a variety of human diseases including cancers, appear to play a critical role in mediating EGFR TKI-resistance. Furthermore, elimination of these ROS through use of a cell-penetrating catalase derivative sensitizes the cells to gefitinib. These results suggest a new approach for the treatment of TKI-resistant breast cancer patients specifically, the targeting of ROS and attendant downstream oxidative stress and their effects on signaling cascades. Copyright © 2012. Published by Elsevier Inc.

Everolimus downregulates estrogen receptor and induces autophagy in aromatase inhibitor-resistant breast cancer cells

International Nuclear Information System (INIS)

Lui, Asona; New, Jacob; Ogony, Joshua; Thomas, Sufi; Lewis-Wambi, Joan

2016-01-01

mTOR inhibition of aromatase inhibitor (AI)-resistant breast cancer is currently under evaluation in the clinic. Everolimus/RAD001 (Afinitor®) has had limited efficacy as a solo agent but is projected to become part of combination therapy for AI-resistant breast cancer. This study was conducted to investigate the anti-proliferative and resistance mechanisms of everolimus in AI-resistant breast cancer cells. In this study we utilized two AI-resistant breast cancer cell lines, MCF-7:5C and MCF-7:2A, which were clonally derived from estrogen receptor positive (ER+) MCF-7 breast cancer cells following long-term estrogen deprivation. Cell viability assay, colony formation assay, cell cycle analysis and soft agar anchorage-independent growth assay were used to determine the efficacy of everolimus in inhibiting the proliferation and tumor forming potential of MCF-7, MCF-7:5C, MCF-7:2A and MCF10A cells. Confocal microscopy and transmission electron microscopy were used to evaluate LC3-II production and autophagosome formation, while ERE-luciferase reporter, Western blot, and RT-PCR analyses were used to assess ER expression and transcriptional activity. Everolimus inhibited the proliferation of MCF-7:5C and MCF-7:2A cells with relatively equal efficiency to parental MCF-7 breast cancer cells. The inhibitory effect of everolimus was due to G1 arrest as a result of downregulation of cyclin D1 and p21. Everolimus also dramatically reduced estrogen receptor (ER) expression (mRNA and protein) and transcriptional activity in addition to the ER chaperone, heat shock protein 90 protein (HSP90). Everolimus restored 4-hydroxy-tamoxifen (4OHT) sensitivity in MCF-7:5C cells and enhanced 4OHT sensitivity in MCF-7 and MCF-7:2A cells. Notably, we found that autophagy is one method of everolimus insensitivity in MCF-7 breast cancer cell lines. This study provides additional insight into the mechanism(s) of action of everolimus that can be used to enhance the utility of mTOR inhibitors as

Effects of non-thermal mobile phone radiation on breast adenocarcinoma cells

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Zen Fourie

2011-09-01

Full Text Available Mobile phone usage currently exceeds landline communication in Africa. The extent of this usage has raised concerns about the long-term health effects of the ongoing use of mobile phones. To assess the physiological effects of radiation from mobile phones in vitro, MCF-7 breast adenocarcinoma cells were exposed to 2W/kg non-thermal 900-MHz mobile phone radiation. The effects investigated were those on metabolic activity, cell morphology, cell cycle progression, phosphatidylserine (PS externalisation and the generation of reactive oxygen species and nitrogen species. Statistically insignificant increases in mitochondrial dehydrogenase activity were observed in irradiated cells when compared to controls. Fluorescent detection of F-actin demonstrated an increase in F-actin stress fibre formation in irradiated MCF-7 cells. Cell cycle progression revealed no statistically significant variation. A small increase in early and late apoptotic events in irradiated MCF-7 cells was observed. No statistically significant changes were observed in reactive oxygen and reactive nitrogen species generation. In addition, quantitative and qualitative analyses of cell cycle activity and nuclear and cytosolic changes, respectively, revealed no significant changes. In conclusion, exposure to 1 h of 900-MHz irradiation induced an increase in PS externalisation and an increase in the formation of F-actin stress fibres in MCF-7 cells. Data obtained from this study, and their correlation with other studies, provides intriguing links between radio frequency radiation and cellular events and warrant further investigation.

MicroRNA‑663b mediates TAM resistance in breast cancer by modulating TP73 expression.

Science.gov (United States)

Jiang, Hua; Cheng, Lin; Hu, Pan; Liu, Renbin

2018-05-23

Breast cancer is the second leading cause of cancer‑associated mortalities in women. Tamoxifen (TAM) is an endocrine therapy commonly used in the treatment of patients with breast cancer expressing estrogen receptor α. However, treatment often ends in failure due to the emergence of drug resistance. MicroRNAs (miRNAs), a family of small non‑coding RNAs, serve critical roles in the regulation of gene expression and cell events. To date, whether miRNA‑663b could mediate TAM resistance in breast cancer remains unknown. Therefore, the aim of the present study was to investigate the role of miRNA‑663b in TAM resistance in breast cancer. The results demonstrated that miRNA‑663b was upregulated in breast cancer with TAM resistance. Tumor protein 73 (TP73) was a direct target of miRNA‑663b, and was negatively regulated by miRNA‑663b in MCF‑7 cells. Furthermore, it was identified that downregulation of miRNA‑663b inhibited cell proliferation ability and promoted cell apoptosis, resulting in enhanced TAM sensitivity. In addition, these findings suggested that TP73 silencing may have eliminated the effects of miRNA‑663b inhibitor on breast cancer cells. In conclusion, the present study verified a novel molecular link between miRNA‑663b and TP73, and indicated that miRNA‑663b may be a critical therapeutic target in breast cancer.

Metastasis of breast cancer rectum

International Nuclear Information System (INIS)

Suárez, L.; Santander, G.

2004-01-01

Introduction: Metastases to the breast are rare, corresponding approximately to 3% of breast cancers. Primary tumors that spread more commonly are own breast, often following them in melanomas, neuroendocrine, ovarian and lymphoma. Medical history: A 59-year consultation rectoragias repeated and thinning. It is studied and finally intervenes (low anterior resection) diagnosed with rectal cancer whose Histopathology revealed a poorly differentiated adenocarcinoma stage III. Concomitantly the patient has a left breast lump that was studied with mammography, which revealed a dense mass of larger diameter 4 cm in topografiada 3 hour left breast with well defined contours and ultrasonographic structure solid. MI lumpectomy is performed whose pathology reports a poorly differentiated adenocarcinoma with cytoarchitectural features matching the lesion of rectum. Hormone receptors were negative. The patient is treated as a rectal cancer with RT spread over QT (5FU i /c). Died 7 months after diagnosis. Discusion: In literature are reported only 3 cases of breast metastases secondary to rectal cancer; how unusual this presentation justify this report.In this event they occurred in patients with a previous diagnosis of rectal cancer and in the context of systemic lesion progression. In our case clinician early diagnosis of rectal and breast metastases was synchronous. The mammographic image consistent with those described for these cases in the literature.The development of metastases in breast tissue is associated with a poor prognosis as which correlates with the survival of the patient

The lipid content of cisplatin- and doxorubicin-resistant MCF-7 human breast cancer cells.

Science.gov (United States)

Todor, I N; Lukyanova, N Yu; Chekhun, V F

2012-07-01

To perform the comparative study both of qualitative and quantitative content of lipids in parental and drug resistant breast cancer cells. Parental (MCF-7/S) and resistant to cisplatin (MCF-7/CP) and doxorubicin (MCF-7/Dox) human breast cancer cells were used in the study. Cholesterol, total lipids and phospholipids content were determined by means of thin-layer chromatography. It was found that cholesterol as well as cholesterol ethers content are significantly higher but diacylglycerols, triacyl-glycerols content are significantly lower in resistant cell strains than in parental (sensitive) cells. Moreover the analysis of individual phospholipids showed the increase of sphingomyelin, phosphatidylserine, cardiolipin, phosphatidic acid and the decrease of phosphatidy-lethanolamine, phosphatidylcholine in MCF-7/CP and MCF-7/Dox cells. Obtained results allow to suggest that the lipid profile changes can mediate the modulation of membrane fluidity in drug resistant MCF-7 breast cancer cells.

VAV3 mediates resistance to breast cancer endocrine therapy

NARCIS (Netherlands)

H. Aguilar (Helena); A. Urruticoechea (Ander); P. Halonen (Pasi); K. Kiyotani (Kazuma); T. Mushiroda (Taisei); X. Barril (Xavier); J. Serra-Musach (Jordi); A.B.M.M.K. Islam (Abul); L. Caizzi (Livia); L. Di Croce (Luciano); E. Nevedomskaya (Ekaterina); W. Zwart (Wilbert); J. Bostner (Josefine); E. Karlsson (Elin); G. Pérez Tenorio (Gizeh); T. Fornander (Tommy); D.C. Sgroi (Dennis); R. Garcia-Mata (Rafael); M.P.H.M. Jansen (Maurice); N. García (Nadia); N. Bonifaci (Núria); F. Climent (Fina); E. Soler (Eric); A. Rodríguez-Vida (Alejo); M. Gil (Miguel); J. Brunet (Joan); G. Martrat (Griselda); L. Gómez-Baldó (Laia); A.I. Extremera (Ana); J. Figueras; J. Balart (Josep); R. Clarke (Robert); K.L. Burnstein (Kerry); K.E. Carlson (Kathryn); J.A. Katzenellenbogen (John); M. Vizoso (Miguel); M. Esteller (Manel); A. Villanueva (Alberto); A.B. Rodríguez-Peña (Ana); X.R. Bustelo (Xosé); Y. Nakamura (Yusuke); H. Zembutsu (Hitoshi); O. Stål (Olle); R.L. Beijersbergen (Roderick); M.A. Pujana (Miguel)

2014-01-01

textabstractIntroduction: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through

ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer

Science.gov (United States)

Feldinger, Katharina; Generali, Daniele; Kramer-Marek, Gabriela; Gijsen, Merel; Ng, Tzi Bun; Wong, Jack Ho; Strina, Carla; Cappelletti, Mariarosa; Andreis, Daniele; Li, Ji-Liang; Bridges, Esther; Turley, Helen; Leek, Russell; Roxanis, Ioannis; Capala, Jacek; Murphy, Gillian; Harris, Adrian L.; Kong, Anthony

2014-01-01

Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p≤0.001 in BT474; p≤0.01 in SKBR3) and in vivo (p≤0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in naïve and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p≤0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p≤0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p≤0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients. PMID:24952873

Chitosan–Cellulose Multifunctional Hydrogel Beads: Design, Characterization and Evaluation of Cytocompatibility with Breast Adenocarcinoma and Osteoblast Cells

Science.gov (United States)

Trivedi, Poonam; Saloranta-Simell, Tiina; Gradišnik, Lidija; Prabhakar, Neeraj; Smått, Jan-Henrik; Mohan, Tamilselvan; Gericke, Martin; Heinze, Thomas

2018-01-01

Cytocompatible polysaccharide-based functional scaffolds are potential extracellular matrix candidates for soft and hard tissue engineering. This paper describes a facile approach to design cytocompatible, non-toxic, and multifunctional chitosan-cellulose based hydrogel beads utilising polysaccharide dissolution in sodium hydroxide-urea-water solvent system and coagulation under three different acidic conditions, namely 2 M acetic acid, 2 M hydrochloric acid, and 2 M sulfuric acid. The effect of coagulating medium on the final chemical composition of the hydrogel beads is investigated by spectroscopic techniques (ATR–FTIR, Raman, NMR), and elemental analysis. The beads coagulated in 2 M acetic acid displayed an unchanged chitosan composition with free amino groups, while the beads coagulated in 2 M hydrochloric and sulfuric acid showed protonation of amino groups and ionic interaction with the counterions. The ultrastructural morphological study of lyophilized beads showed that increased chitosan content enhanced the porosity of the hydrogel beads. Furthermore, cytocompatibility evaluation of the hydrogel beads with human breast adenocarcinoma cells (soft tissue) showed that the beads coagulated in 2 M acetic acid are the most suitable for this type of cells in comparison to other coagulating systems. The acetic acid fabricated hydrogel beads also support osteoblast growth and adhesion over 192 h. Thus, in future, these hydrogel beads can be tested in the in vitro studies related to breast cancer and for bone regeneration. PMID:29315214

Chitosan-Cellulose Multifunctional Hydrogel Beads: Design, Characterization and Evaluation of Cytocompatibility with Breast Adenocarcinoma and Osteoblast Cells.

Science.gov (United States)

Trivedi, Poonam; Saloranta-Simell, Tiina; Maver, Uroš; Gradišnik, Lidija; Prabhakar, Neeraj; Smått, Jan-Henrik; Mohan, Tamilselvan; Gericke, Martin; Heinze, Thomas; Fardim, Pedro

2018-01-09

Cytocompatible polysaccharide-based functional scaffolds are potential extracellular matrix candidates for soft and hard tissue engineering. This paper describes a facile approach to design cytocompatible, non-toxic, and multifunctional chitosan-cellulose based hydrogel beads utilising polysaccharide dissolution in sodium hydroxide-urea-water solvent system and coagulation under three different acidic conditions, namely 2 M acetic acid, 2 M hydrochloric acid, and 2 M sulfuric acid. The effect of coagulating medium on the final chemical composition of the hydrogel beads is investigated by spectroscopic techniques (ATR-FTIR, Raman, NMR), and elemental analysis. The beads coagulated in 2 M acetic acid displayed an unchanged chitosan composition with free amino groups, while the beads coagulated in 2 M hydrochloric and sulfuric acid showed protonation of amino groups and ionic interaction with the counterions. The ultrastructural morphological study of lyophilized beads showed that increased chitosan content enhanced the porosity of the hydrogel beads. Furthermore, cytocompatibility evaluation of the hydrogel beads with human breast adenocarcinoma cells (soft tissue) showed that the beads coagulated in 2 M acetic acid are the most suitable for this type of cells in comparison to other coagulating systems. The acetic acid fabricated hydrogel beads also support osteoblast growth and adhesion over 192 h. Thus, in future, these hydrogel beads can be tested in the in vitro studies related to breast cancer and for bone regeneration.

Metastasis of breast cancer cells to the bone, lung, and lymph nodes promotes resistance to ionizing radiation

Energy Technology Data Exchange (ETDEWEB)

Hara, Takamitsu [Gunma Prefectural College of Health Sciences, Department of Radiological Technology, School of Radiological Technology, Gunma, Maebashi (Japan); Iwadate, Manabu [Fukushima Medical University, Department of Thyroid and Endocrinology, School of Medicine, Fukushima (Japan); Tachibana, Kazunoshin [Fukushima Medical University, Department of Breast Surgery, School of Medicine, Fukushima (Japan); Waguri, Satoshi [Fukushima Medical University, Department of Anatomy and Histology, School of Medicine, Fukushima (Japan); Takenoshita, Seiichi [Fukushima Medical University, Advanced Clinical Research Center, Fukushima Global Medical Science Center, School of Medicine, Fukushima (Japan); Hamada, Nobuyuki [Central Research Institute of Electric Power Industry (CRIEPI), Radiation Safety Research Center, Nuclear Technology Research Laboratory, Tokyo, Komae (Japan)

2017-10-15

Metastasis represents the leading cause of breast cancer deaths, necessitating strategies for its treatment. Although radiotherapy is employed for both primary and metastatic breast cancers, the difference in their ionizing radiation response remains incompletely understood. This study is the first to compare the radioresponse of a breast cancer cell line with its metastatic variants and report that such metastatic variants are more radioresistant. A luciferase expressing cell line was established from human basal-like breast adenocarcinoma MDA-MB-231 and underwent in vivo selections, whereby a cycle of inoculations into the left cardiac ventricle or the mammary fat pad of athymic nude mice, isolation of metastases to the bone, lung and lymph nodes visualized with bioluminescence imaging, and expansion of obtained cells was repeated twice or three times. The established metastatic cell lines were assessed for cell proliferation, wound healing, invasion, clonogenic survival, and apoptosis. The established metastatic cell lines possessed an increased proliferative potential in vivo and were more chemotactic, invasive, and resistant to X-ray-induced clonogenic inactivation and apoptosis in vitro. Breast cancer metastasis to the bone, lung, and lymph nodes promotes radioresistance. (orig.) [German] Metastasierung ist die Hauptursache fuer den toedlichen Verlauf von Brustkrebserkrankungen. Darauf muessen spezifische Behandlungsstrategien ausgerichtet werden. Sowohl primaere als auch metastatische Brustkrebsarten koennen mit einer Strahlentherapie behandelt werden, allerdings sind die Unterschiede in der Reaktion auf ionisierende Strahlung bis heute nicht vollstaendig verstanden. In dieser Studie wird zum ersten Mal die Strahlenantwort einer Brustkrebszelllinie mit der ihrer metastatischen Varianten verglichen und die erhoehte Strahlenresistenz der metastatischen Varianten gezeigt. Eine Luciferase-exprimierende Zelllinie wurde aus humanen basaloiden Brustadenokarzinomen

Reprogramming of the ERRα and ERα target gene landscape triggers tamoxifen resistance in breast cancer.

Science.gov (United States)

Thewes, Verena; Simon, Ronald; Schroeter, Petra; Schlotter, Magdalena; Anzeneder, Tobias; Büttner, Reinhard; Benes, Vladimir; Sauter, Guido; Burwinkel, Barbara; Nicholson, Robert I; Sinn, Hans-Peter; Schneeweiss, Andreas; Deuschle, Ulrich; Zapatka, Marc; Heck, Stefanie; Lichter, Peter

2015-02-15

Endocrine treatment regimens for breast cancer that target the estrogen receptor-α (ERα) are effective, but acquired resistance remains a limiting drawback. One mechanism of acquired resistance that has been hypothesized is functional substitution of the orphan receptor estrogen-related receptor-α (ERRα) for ERα. To examine this hypothesis, we analyzed ERRα and ERα in recurrent tamoxifen-resistant breast tumors and conducted a genome-wide target gene profiling analysis of MCF-7 breast cancer cell populations that were sensitive or resistant to tamoxifen treatment. This analysis uncovered a global redirection in the target genes controlled by ERα, ERRα, and their coactivator AIB1, defining a novel set of target genes in tamoxifen-resistant cells. Beyond differences in the ERα and ERRα target gene repertoires, both factors were engaged in similar pathobiologic processes relevant to acquired resistance. Functional analyses confirmed a requirement for ERRα in tamoxifen- and fulvestrant-resistant MCF-7 cells, with pharmacologic inhibition of ERRα sufficient to partly restore sensitivity to antiestrogens. In clinical specimens (n = 1041), increased expression of ERRα was associated with enhanced proliferation and aggressive disease parameters, including increased levels of p53 in ERα-positive cases. In addition, increased ERRα expression was linked to reduced overall survival in independent tamoxifen-treated patient cohorts. Taken together, our results suggest that ERα and ERRα cooperate to promote endocrine resistance, and they provide a rationale for the exploration of ERRα as a candidate drug target to treat endocrine-resistant breast cancer. ©2015 American Association for Cancer Research.

Rational combinations of immunotherapy for pancreatic ductal adenocarcinoma.

Science.gov (United States)

Blair, Alex B; Zheng, Lei

2017-06-01

The complex interaction between the immune system, the tumor and the microenvironment in pancreatic ductal adenocarcinoma (PDA) leads to the resistance of PDA to immunotherapy. To overcome this resistance, combination immunotherapy is being proposed. However, rational combinations that target multiple aspects of the complex anti-tumor immune response are warranted. Novel clinical trials will investigate and optimize the combination immunotherapy for PDA.

Distinct apoptotic blocks mediate resistance to panHER inhibitors in HER2+ breast cancer cells.

Science.gov (United States)

Karakas, Bahriye; Ozmay, Yeliz; Basaga, Huveyda; Gul, Ozgur; Kutuk, Ozgur

2018-05-04

Despite the development of novel targeted therapies, de novo or acquired chemoresistance remains a significant factor for treatment failure in breast cancer therapeutics. Neratinib and dacomitinib are irreversible panHER inhibitors, which block their autophosphorylation and downstream signaling. Moreover, neratinib and dacomitinib have been shown to activate cell death in HER2-overexpressing cell lines. Here we showed that increased MCL1 and decreased BIM and PUMA mediated resistance to neratinib in ZR-75-30 and SKBR3 cells while increased BCL-XL and BCL-2 and decreased BIM and PUMA promoted neratinib resistance in BT474 cells. Cells were also cross-resistant to dacomitinib. BH3 profiles of HER2+ breast cancer cells efficiently predicted antiapoptotic protein dependence and development of resistance to panHER inhibitors. Reactivation of ERK1/2 was primarily responsible for acquired resistance in SKBR3 and ZR-75-30 cells. Adding specific ERK1/2 inhibitor SCH772984 to neratinib or dacomitinib led to increased apoptotic response in neratinib-resistant SKBR3 and ZR-75-30 cells, but we did not detect a similar response in neratinib-resistant BT474 cells. Accordingly, suppression of BCL-2/BCL-XL by ABT-737 was required in addition to ERK1/2 inhibition for neratinib- or dacomitinib-induced apoptosis in neratinib-resistant BT474 cells. Our results showed that different mitochondrial apoptotic blocks mediated acquired panHER inhibitor resistance in HER2+ breast cancer cell lines as well as highlighted the potential of BH3 profiling assay in prediction of panHER inhibitor resistance in breast cancer cells. Copyright © 2018 Elsevier B.V. All rights reserved.

APC loss in breast cancer leads to doxorubicin resistance via STAT3 activation.

Science.gov (United States)

VanKlompenberg, Monica K; Leyden, Emily; Arnason, Anne H; Zhang, Jian-Ting; Stefanski, Casey D; Prosperi, Jenifer R

2017-11-28

Resistance to chemotherapy is one of the leading causes of death from breast cancer. We recently established that loss of Adenomatous Polyposis Coli (APC) in the Mouse Mammary Tumor Virus - Polyoma middle T (MMTV-PyMT) transgenic mouse model results in resistance to cisplatin or doxorubicin-induced apoptosis. Herein, we aim to establish the mechanism that is responsible for APC-mediated chemotherapeutic resistance. Our data demonstrate that MMTV-PyMT; Apc Min/+ cells have increased signal transducer and activator of transcription 3 (STAT3) activation. STAT3 can be constitutively activated in breast cancer, maintains the tumor initiating cell (TIC) population, and upregulates multidrug resistance protein 1 (MDR1). The activation of STAT3 in the MMTV-PyMT; Apc Min/+ model is independent of interleukin 6 (IL-6); however, enhanced EGFR expression in the MMTV-PyMT; Apc Min/+ cells may be responsible for the increased STAT3 activation. Inhibiting STAT3 with a small molecule inhibitor A69 in combination with doxorubicin, but not cisplatin, restores drug sensitivity. A69 also decreases doxorubicin enhanced MDR1 gene expression and the TIC population enhanced by loss of APC. In summary, these results have revealed the molecular mechanisms of APC loss in breast cancer that can guide future treatment plans to counteract chemotherapeutic resistance.

"US-detonated nano bombs" facilitate targeting treatment of resistant breast cancer.

Science.gov (United States)

Shi, Jinjin; Liu, Wei; Fu, Yu; Yin, Na; Zhang, Hongling; Chang, Junbiao; Zhang, Zhenzhong

2018-03-28

Reversal of drug resistance and targeted therapy are the keys but remain challenging in resistant breast cancer treatment. Herein, low frequency ultrasound detonated "nano bombs" were rationally designed and used for treatment of resistant breast cancer. For the 'nano bombs', the ammunition (Doxorubicin, DOX) was loaded into the ammunition depot (hollow mesoporous TiO 2 , MTNs), and the safety device (dsDNA) was wrapped on the surface of MTNs to avoid the unexpected DOX release. We found the "US-detonated explosive" abilities of "nano bomb" MTNs (NBMTNs), including explosive generation of ROS, explosive release of DOX, US-triggered lysosome escape and mitochondrial targeting in the in vitro and in vivo studies. More importantly, the drug resistance of MCF-7/ADR cells could be reversed via the inhibition of mitochondrial energy supply approach caused by the "explosion" of NBMTNs. Furthermore, NBMTNs combined the superior chemotherapy efficacy of DOX and potent SDT efficacy in one single platform and significantly enhanced the anticancer efficacy. Our results demonstrate an approach for reversing resistance and specific targeting of tumors using 'US-detonated nano bombs'. Copyright © 2018 Elsevier B.V. All rights reserved.

Yes-Associated Protein Expression Is Correlated to the Differentiation of Prostate Adenocarcinoma

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Myung-Giun Noh

2017-07-01

Full Text Available Background Yes-associated protein (YAP in the Hippo signaling pathway is a growth control pathway that regulates cell proliferation and stem cell functions. Abnormal regulation of YAP was reported in human cancers including liver, lung, breast, skin, colon, and ovarian cancer. However, the function of YAP is not known in prostate adenocarcinoma. The purpose of this study was to investigate the role of YAP in tumorigenesis, differentiation, and prognosis of prostate adenocarcinoma. Methods The nuclear and cytoplasmic expression of YAP was examined in 188 cases of prostate adenocarcinoma using immunohistochemistry. YAP expression levels were evaluated in the nucleus and cytoplasm of the prostate adenocarcinoma and the adjacent normal prostate tissue. The presence of immunopositive tumor cells was evaluated and interpreted in comparison with the patients’ clinicopathologic data. Results YAP expression levels were not significantly different between normal epithelial cells and prostate adenocarcinoma. However, YAP expression level was significantly higher in carcinomas with a high Gleason grades (8–10 than in carcinomas with a low Gleason grades (6–7 (p < .01. There was no statistical correlation between YAP expression and stage, age, prostate-specific antigen level, and tumor volume. Biochemical recurrence (BCR–free survival was significantly lower in patients with high YAP expressing cancers (p = .02. However high YAP expression was not an independent prognostic factor for BCR in the Cox proportional hazards model. Conclusions The results suggested that YAP is not associated with prostate adenocarcinoma development, but it may be associated with the differentiation of the adenocarcinoma. YAP was not associated with BCR.

NF-κB signaling is activated and confers resistance to apoptosis in three-dimensionally cultured EGFR-mutant lung adenocarcinoma cells

International Nuclear Information System (INIS)

Sakuma, Yuji; Yamazaki, Yukiko; Nakamura, Yoshiyasu; Yoshihara, Mitsuyo; Matsukuma, Shoichi; Koizume, Shiro; Miyagi, Yohei

2012-01-01

Highlights: ► EGFR-mutant cells in 3D culture resist EGFR inhibition compared with suspended cells. ► Degradation of IκB and activation of NF-κB are observed in 3D-cultured cells. ► Inhibiting NF-κB enhances the efficacy of the EGFR inhibitor in 3D-cultured cells. -- Abstract: Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells in suspension undergo apoptosis to a greater extent than adherent cells in a monolayer when EGFR autophosphorylation is inhibited by EGFR tyrosine kinase inhibitors (TKIs). This suggests that cell adhesion to a culture dish may activate an anti-apoptotic signaling pathway other than the EGFR pathway. Since the microenvironment of cells cultured in a monolayer are substantially different to that of cells existing in three-dimension (3D) in vivo, we assessed whether two EGFR-mutant lung adenocarcinoma cell lines, HCC827 and H1975, were more resistant to EGFR TKI-induced apoptosis when cultured in a 3D extracellular matrix (ECM) as compared with in suspension. The ECM-adherent EGFR-mutant cells in 3D were significantly less sensitive to treatment with WZ4002, an EGFR TKI, than the suspended cells. Further, a marked degradation of IκBα, the inhibitor of nuclear factor (NF)-κB, was observed only in the 3D-cultured cells, leading to an increase in the activation of NF-κB. Moreover, the inhibition of NF-κB with pharmacological inhibitors enhanced EGFR TKI-induced apoptosis in 3D-cultured EGFR-mutant cells. These results suggest that inhibition of NF-κB signaling would render ECM-adherent EGFR-mutant lung adenocarcinoma cells in vivo more susceptible to EGFR TKI-induced cell death.

microRNAs in High and Low Responders to Resistance Training in Breast Cancer Survivors.

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Hagstrom, Amanda D; Denham, Joshua

2018-04-26

Accounting for one in three cancer diagnoses, breast cancer is the second most commonly diagnosed cancer in women. Exercise has a well-accepted role in the multi-disciplinary approach to rehabilitating breast cancer survivors. Despite the many known benefits of resistance training on women recovering from breast cancer, the molecular mechanisms are poorly understood. MicroRNAs are small non-coding RNAs that have crucial roles in growth and development. Here, we analysed the abundance of 9 miRNAs, with known roles in muscle physiology and some linked to cancer, in serum samples from 24 breast cancer survivors before and after a 16-week resistance training or usual care intervention. The resistance training group completed supervised thrice-weekly training. miRNA abundance was assessed before and after the intervention period using qPCR. There were no statistically significant changes in any of the miRNAs between groups after the intervention period (all p>0.05). After assessing miRNA abundance in context with high and low responders to resistance training, we observed that relative to low responders, high responders exhibited increased miR-133a-3p and a borderline statistically significant increase in miR-370-3p. Findings from our controlled study indicate the diverse interindividual miRNA responses to resistance training and reveal a discordant regulation between high and low responders. © Georg Thieme Verlag KG Stuttgart · New York.

Micropapillary Lung Cancer with Breast Metastasis Simulating Primary Breast Cancer due to Architectural Distortion on Images

Energy Technology Data Exchange (ETDEWEB)

Ko, Kyung Ran; Hong, Eun Kyung; Lee, See Yeon [Center for Breast Cancer, National Cancer Center, Goyang (Korea, Republic of); Ro, Jae Yoon [The Methodist Hospital, Weill Medical College of Cornell University, Houston (United States)

2012-03-15

A 47-year-old Korean woman with right middle lobe lung adenocarcinoma, malignant pleural effusion, and multiple lymph node and bone metastases, after three months of lung cancer diagnosis, presented with a palpable right breast mass. Images of the right breast demonstrated architectural distortion that strongly suggested primary breast cancer. Breast biopsy revealed metastatic lung cancer with a negative result for estrogen receptor (ER), progesterone receptor (PR) and mammaglobin, and a positive result for thyroid transcription factor-1 (TTF-1). We present a case of breast metastasis from a case of lung cancer with an extensive micropapillary component, which was initially misinterpreted as a primary breast cancer due to unusual image findings with architectural distortion.

NFAT5 promotes proliferation and migration of lung adenocarcinoma cells in part through regulating AQP5 expression

Energy Technology Data Exchange (ETDEWEB)

Guo, Kai, E-mail: gk161@163.com [Department of Respiration, Tangdu Hospital, Fourth Military Medical University, Xi' an 710038 (China); Department of Respiration, 161th Hospital, PLA, Wuhan 430015 (China); Jin, Faguang, E-mail: jinfag@fmmu.edu.cn [Department of Respiration, Tangdu Hospital, Fourth Military Medical University, Xi' an 710038 (China)

2015-09-25

The osmoregulated transcription factor nuclear factor of activated T-cells 5(NFAT5), has been found to play important roles in the development of many kinds of human cancers, including breast cancer, colon carcinoma, renal cell carcinoma and melanoma. The aim of the present study was to determine whether NFAT5 is involved in the proliferation and migration of lung adenocarcinoma cells. We found that NFAT5 was upregulated in lung adenocarcinoma cells and knockdown of NFAT5 decreased proliferation and migration of the cells, accompanied by a significant reduction in the expression of AQP5. AQP5 was upregulated in lung adenocarcinoma cells and knockdown of AQP5 also inhibited proliferation and migration of the cells as knockdown of NFAT5 did. Moreover, overexpression of NFAT5 promoted proliferation and migration of lung adenocarcinoma cells, accompanied by a significant increase in the expression of AQP5. These results indicate that NFAT5 plays important roles in proliferation and migration of human lung adenocarcinoma cells through regulating AQP5 expression, providing a new therapeutic option for lung adenocarcinoma therapy. - Highlights: • NFAT5 expression is higher in lung adenocarcinoma cells compared with normal cells. • NFAT5 knockdown decreases proliferation and migration of lung adenocarcinoma cells. • Knockdown of NFAT5 reduces AQP5 expression in human lung adenocarcinoma cells. • Overexpression of NFAT5 promotes proliferation and migration of lung adenocarcinoma cells. • Overexpression of NFAT5 increases AQP5 expression in human lung adenocarcinoma cells.

NFAT5 promotes proliferation and migration of lung adenocarcinoma cells in part through regulating AQP5 expression

International Nuclear Information System (INIS)

Guo, Kai; Jin, Faguang

2015-01-01

The osmoregulated transcription factor nuclear factor of activated T-cells 5(NFAT5), has been found to play important roles in the development of many kinds of human cancers, including breast cancer, colon carcinoma, renal cell carcinoma and melanoma. The aim of the present study was to determine whether NFAT5 is involved in the proliferation and migration of lung adenocarcinoma cells. We found that NFAT5 was upregulated in lung adenocarcinoma cells and knockdown of NFAT5 decreased proliferation and migration of the cells, accompanied by a significant reduction in the expression of AQP5. AQP5 was upregulated in lung adenocarcinoma cells and knockdown of AQP5 also inhibited proliferation and migration of the cells as knockdown of NFAT5 did. Moreover, overexpression of NFAT5 promoted proliferation and migration of lung adenocarcinoma cells, accompanied by a significant increase in the expression of AQP5. These results indicate that NFAT5 plays important roles in proliferation and migration of human lung adenocarcinoma cells through regulating AQP5 expression, providing a new therapeutic option for lung adenocarcinoma therapy. - Highlights: • NFAT5 expression is higher in lung adenocarcinoma cells compared with normal cells. • NFAT5 knockdown decreases proliferation and migration of lung adenocarcinoma cells. • Knockdown of NFAT5 reduces AQP5 expression in human lung adenocarcinoma cells. • Overexpression of NFAT5 promotes proliferation and migration of lung adenocarcinoma cells. • Overexpression of NFAT5 increases AQP5 expression in human lung adenocarcinoma cells

Intracranial microcapsule chemotherapy delivery for the localized treatment of rodent metastatic breast adenocarcinoma in the brain.

Science.gov (United States)

Upadhyay, Urvashi M; Tyler, Betty; Patta, Yoda; Wicks, Robert; Spencer, Kevin; Scott, Alexander; Masi, Byron; Hwang, Lee; Grossman, Rachel; Cima, Michael; Brem, Henry; Langer, Robert

2014-11-11

Metastases represent the most common brain tumors in adults. Surgical resection alone results in 45% recurrence and is usually accompanied by radiation and chemotherapy. Adequate chemotherapy delivery to the CNS is hindered by the blood-brain barrier. Efforts at delivering chemotherapy locally to gliomas have shown modest increases in survival, likely limited by the infiltrative nature of the tumor. Temozolomide (TMZ) is first-line treatment for gliomas and recurrent brain metastases. Doxorubicin (DOX) is used in treating many types of breast cancer, although its use is limited by severe cardiac toxicity. Intracranially implanted DOX and TMZ microcapsules are compared with systemic administration of the same treatments in a rodent model of breast adenocarcinoma brain metastases. Outcomes were animal survival, quantified drug exposure, and distribution of cleaved caspase 3. Intracranial delivery of TMZ and systemic DOX administration prolong survival more than intracranial DOX or systemic TMZ. Intracranial TMZ generates the more robust induction of apoptotic pathways. We postulate that these differences may be explained by distribution profiles of each drug when administered intracranially: TMZ displays a broader distribution profile than DOX. These microcapsule devices provide a safe, reliable vehicle for intracranial chemotherapy delivery and have the capacity to be efficacious and superior to systemic delivery of chemotherapy. Future work should include strategies to improve the distribution profile. These findings also have broader implications in localized drug delivery to all tissue, because the efficacy of a drug will always be limited by its ability to diffuse into surrounding tissue past its delivery source.

Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan

NARCIS (Netherlands)

Jonker, JW; Smit, JW; Brinkhuis, RF; Maliepaard, M; Beijnen, JH; Schellens, JHM; Schinkel, AH

2000-01-01

Background and Methods: Breast cancer resistance protein (BCRP/MXR/ABCP) is a multidrug-resistance protein that is a member of the adenosine triphosphate-binding cassette family of drug transporters. BCRP can render tumor cells resistant to the anticancer drugs topotecan, mitoxantrone, doxorubicin,

Breast self-examination: resistance to change.

Science.gov (United States)

Del Giudice, M Elisabeth; Tannenbaum, David; Goodwin, Pamela J

2005-05-01

To investigate whether Canadian family practitioners routinely teach breast self-examination (BSE) after publication of the 2001 Canadian Preventive Health Task Force guideline advising them to exclude teaching BSE from periodic health examinations. Self-administered cross-sectional mailed survey. Canada. A random sample of English-speaking general practitioners and physicians certified by the College of Family Physicians of Canada. Current and past BSE practices and opinions on the value of BSE. Response rate was 47.4%. Most respondents (88%) were aware of the new recommendations, yet only 16% had changed their usual practice of routinely teaching BSE. Most physicians agreed that before the recommendation they almost always taught BSE (74.3%). Only 9.5% agreed that physicians should follow the recommendation and not routinely teach BSE. A few also agreed that they now spend less time discussing BSE (25.7%) and that the recommendation has influenced them to stop teaching (12.4%) and encouraging (12.9%) women to practise BSE. Physicians who had changed their BSE practices were less likely to agree that BSE increases early detection of breast cancer and more likely to agree that BSE increases benign breast biopsies. They were also more likely to agree that screening mammography in women older than 50 decreases mortality from breast cancer. This survey, which assessed routine teaching of BSE, revealed poor adherence by Canadian family physicians to a well publicized evidence-based guideline update. Resistance to change could in part be attributed to a lack of knowledge of the supporting evidence, a lack of confidence in the evidence to date, and personal experiences with patients within their practices.

Global characterization of signalling networks associated with tamoxifen resistance in breast cancer

DEFF Research Database (Denmark)

Browne, Brigid C.; Hochgräfe, Falko; Wu, Jianmin

2013-01-01

R cells. Phosphorylation of the tyrosine kinase Yes and expression of the actin‐binding protein myristoylated alanine‐rich C‐kinase substrate (MARCKS) were increased two‐ and eightfold in TamR cells respectively, and these proteins were selected for further analysis. Knockdown of either protein in Tam......Acquired resistance to the anti‐estrogen tamoxifen remains a significant challenge in breast cancer management. In this study, we used an integrative approach to characterize global protein expression and tyrosine phosphorylation events in tamoxifen‐resistant MCF7 breast cancer cells (Tam...... was perturbed in TamR cells, together with pathways enriched for proteins associated with growth factor, cell–cell and cell matrix‐initiated signalling. Consistent with known roles for Ras/MAPK and PI3‐kinase signalling in tamoxifen resistance, tyrosine‐phosphorylated MAPK1, SHC1 and PIK3R2 were elevated in Tam...

Nanoparticle Albumin-Bound-Paclitaxel in the Treatment of Metastatic Urethral Adenocarcinoma: The Significance of Molecular Profiling and Targeted Therapy

Directory of Open Access Journals (Sweden)

Yasmin M. Abaza

2014-01-01

Full Text Available Primary urethral cancer is rare and accounts for only 0.003% of all malignancies arising from the female genitourinary tract. Due to the rarity of this disease, no consensus exists regarding the optimal therapeutic approach. Nanoparticle albumin-bound-paclitaxel has been shown to be effective in the treatment of a number of malignancies including metastatic breast, pancreatic, and bladder cancer. We present a 67-year-old woman with advanced metastatic urethral adenocarcinoma resistant to two lines of chemotherapy (ifosfamide/paclitaxel/cisplatin and irinotecan/5-fluorouracil/leucovorin that showed a dramatic response to nanoparticle albumin-bound-paclitaxel. This is the first case report to document the use and efficacy of nanoparticle albumin-bound-paclitaxel in the treatment of unresectable metastatic urethral cancer.

Magnetic resonance imaging findings and prognosis of gastric-type mucinous adenocarcinoma (minimal deviation adenocarcinoma or adenoma malignum) of the uterine corpus: Two case reports.

Science.gov (United States)

Hino, Mayo; Yamaguchi, Ken; Abiko, Kaoru; Yoshioka, Yumiko; Hamanishi, Junzo; Kondoh, Eiji; Koshiyama, Masafumi; Baba, Tsukasa; Matsumura, Noriomi; Minamiguchi, Sachiko; Kido, Aki; Konishi, Ikuo

2016-05-01

Our group previously documented the first, very rare case of primary gastric-type mucinous adenocarcinoma of the uterine corpus. Although this type of endometrial cancer appears to be similar to the gastric-type adenocarcinoma of the uterine cervix, its main symptoms, appearance on magnetic resonance imaging (MRI) and prognosis have not been fully elucidated due to its rarity. We herein describe an additional case of gastric-type mucinous adenocarcinoma of the endometrium and review the relevant literature. The two cases at our institution (Kyoto University Hospital, Kyoto, Japan) involved postmenopausal women with a primary complaint of abnormal genital bleeding. Microscopic examination of the hysterectomy specimens indicated a highly differentiated mucinous adenocarcinoma with a desmoplastic stromal reaction. Immunohistochemistry for HIK1083 and/or MUC6 was positive in both cases, suggesting a gastric phenotype. Both patients were diagnosed at an advanced stage, they relapsed or recurred immediately after adjuvant chemotherapy, and eventually succumbed to the disease. The main symptom of gastric-type mucinous adenocarcinoma of the uterine cervix is watery discharge, whereas abnormal genital bleeding in addition to watery discharge is mainly observed in the mucinous type of endometrial adenocarcinoma. Cystic cavities in the tumor are present on MRI in cases of endometrial origin, and prognosis is very poor due to resistance to chemotherapy. Thus, gastric-type mucinous adenocarcinoma of the uterine endometrium exhibits a clinical behavior that is similar to tumors originating from the uterine cervix, but is associated with distinguishing clinical symptoms. The incidence of gastric-type endometrial adenocarcinoma may be higher than expected.

Effect of 8 Weeks Resistance Training on Some Antioxidant/Oxidative Indexes in Postmenopausal Women with Breast Cancer

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F. Fathollahi Shoorabeh

2017-04-01

Full Text Available Aims: Breast cancer is the most common cancer among women that usually begins with abnormal growth and division of different breast cells. There is some evidence that there is an inverse relationship between levels of antioxidants and the risk of breast cancer. The purpose of this study was to investigate the effect of 8 weeks resistance training on some antioxidant/oxidative indexes in postmenopausal women with breast cancer. Materials & Methods: In this semi-experimental study, in 2014, 30 postmenopausal women with breast cancer in Khorramabad city were selected by available sampling method and randomly divided into 2 groups: experimental group (n=16 and control group (n=14. The experimental group performed resistance training for 8 weeks, which started from 30% 1RM (one repetition maximum and reached 45-50% 1RM at the end of the eighth week. Blood samples were taken from subjects for the measurement of superoxide dismutase (SOD, glutathione peroxidase (GPX and malondialdehyde (MDA serum levels, 48 hours before and after the training protocol. Data were analyzed by SPSS 19 software using independent t-test and dependent t-test. Findings: After performing 8 weeks of resistance training, serum levels of SOD and GPX significantly increased and MDA levels decreased significantly (p0.05. Conclusion: Resistance training for 8 weeks increases antioxidant indexes and decreases oxidative indexes in postmenopausal women with breast cancer.

Effect of 8 Weeks Resistance Training on Some Antioxidant/Oxidative Indexes in Postmenopausal Women with Breast Cancer

Directory of Open Access Journals (Sweden)

Fathollahi Shoorabeh F.

2017-12-01

Full Text Available Aims Breast cancer is the most common cancer among women that usually begins with abnormal growth and division of different breast cells. There is some evidence that there is an inverse relationship between levels of antioxidants and the risk of breast cancer. The purpose of this study was to investigate the effect of 8 weeks resistance training on some antioxidant/oxidative indexes in postmenopausal women with breast cancer. Materials & Methods In this semi-experimental study, in 2014, 30 postmenopausal women with breast cancer in Khorramabad city were selected by available sampling method and randomly divided into 2 groups: experimental group (n=16 and control group (n=14. The experimental group performed resistance training for 8 weeks, which started from 30% 1RM (one repetition maximum and reached 45-50% 1RM at the end of the eighth week. Blood samples were taken from subjects for the measurement of superoxide dismutase (SOD, glutathione peroxidase (GPX and malondialdehyde (MDA serum levels, 48 hours before and after the training protocol. Data were analyzed by SPSS 19 software using independent t-test and dependent t-test. Findings After performing 8 weeks of resistance training, serum levels of SOD and GPX significantly increased and MDA levels decreased significantly (p0.05. Conclusion Resistance training for 8 weeks increases antioxidant indexes and decreases oxidative indexes in postmenopausal women with breast cancer.

Up-regulation of HOXB cluster genes are epigenetically regulated in tamoxifen-resistant MCF7 breast cancer cells.

Science.gov (United States)

Yang, Seoyeon; Lee, Ji-Yeon; Hur, Ho; Oh, Ji Hoon; Kim, Myoung Hee

2018-05-28

Tamoxifen (TAM) is commonly used to treat estrogen receptor (ER)-positive breast cancer. Despite the remarkable benefits, resistance to TAM presents a serious therapeutic challenge. Since several HOX transcription factors have been proposed as strong candidates in the development of resistance to TAM therapy in breast cancer, we generated an in vitro model of acquired TAM resistance using ER-positive MCF7 breast cancer cells (MCF7-TAMR), and analyzed the expression pattern and epigenetic states of HOX genes. HOXB cluster genes were uniquely up-regulated in MCF7-TAMR cells. Survival analysis of in slico data showed the correlation of high expression of HOXB genes with poor response to TAM in ER-positive breast cancer patients treated with TAM. Gain- and loss-of-function experiments showed that the overexpression of multi HOXB genes in MCF7 renders cancer cells more resistant to TAM, whereas the knockdown restores TAM sensitivity. Furthermore, activation of HOXB genes in MCF7-TAMR was associated with histone modifications, particularly the gain of H3K9ac. These findings imply that the activation of HOXB genes mediate the development of TAM resistance, and represent a target for development of new strategies to prevent or reverse TAM resistance.

Exosomes from adriamycin-resistant breast cancer cells transmit drug resistance partly by delivering miR-222.

Science.gov (United States)

Yu, Dan-Dan; Wu, Ying; Zhang, Xiao-Hui; Lv, Meng-Meng; Chen, Wei-Xian; Chen, Xiu; Yang, Su-Jin; Shen, Hongyu; Zhong, Shan-Liang; Tang, Jin-Hai; Zhao, Jian-Hua

2016-03-01

Breast cancer (BCa) is one of the major deadly cancers in women. However, treatment of BCa is still hindered by the acquired-drug resistance. It is increasingly reported that exosomes take part in the development, metastasis, and drug resistance of BCa. However, the specific role of exosomes in drug resistance of BCa is poorly understood. In this study, we investigate whether exosomes transmit drug resistance through delivering miR-222. We established an adriamycin-resistant variant of Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line (MCF-7/Adr) from a drug-sensitive variant (MCF-7/S). Exosomes were isolated from cell supernatant by ultracentrifugation. Cell viability was assessed by MTT assay and apoptosis assay. Individual miR-222 molecules in BCa cells were detected by fluorescence in situ hybridization (FISH). Then, FISH was combined with locked nucleic acid probes and enzyme-labeled fluorescence (LNA-ELF-FISH). Individual miR-222 could be detected as bright photostable fluorescent spots and then the quantity of miR-222 per cell could be counted. Stained exosomes were taken in by the receipt cells. MCF-7/S acquired drug resistance after co-culture with exosomes from MCF-7/Adr (A/exo) but did not after co-culture with exosomes from MCF-7/S (S/exo). The quantity of miR-222 in A/exo-treated MCF-7/S was significantly greater than in S/exo-treated MCF-7/S. MCF-7/S transfected with miR-222 mimics acquired adriamycin resistance while MCF-7/S transfected with miR-222 inhibitors lost resistance. In conclusion, exosomes are effective in transmitting drug resistance and the delivery of miR-222 via exosomes may be a mechanism.

Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer.

LENUS (Irish Health Repository)

Mohd Sharial, M S N

2012-12-01

Approximately 15%-23% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), which leads to the activation of signaling pathways that stimulate cell proliferation and survival. HER2-targeted therapy has substantially improved outcomes in patients with HER2-positive breast cancer. However, both de novo and acquired resistance are observed.

Mechanisms of Acquired Resistance to Trastuzumab Emtansine in Breast Cancer Cells.

Science.gov (United States)

Li, Guangmin; Guo, Jun; Shen, Ben-Quan; Bumbaca Yadav, Daniela; Sliwkowski, Mark X; Crocker, Lisa M; Lacap, Jennifer A; Lewis Phillips, Gail D

2018-04-25

The receptor tyrosine kinase HER2 is overexpressed in approximately 20% of breast cancer, and its amplification is associated with reduced survival. Trastuzumab emtansine (Kadcyla®, T-DM1), an antibody-drug conjugate that is comprised of trastuzumab covalently linked to the anti-mitotic agent DM1 through a stable linker, was designed to selectively deliver DM1 to HER2-overexpressing tumor cells. T-DM1 is approved for the treatment of patients with HER2-positive metastatic breast cancer following progression on trastuzumab and a taxane. Despite the improvement in clinical outcome, many patients who initially respond to T-DM1 treatment eventually develop progressive disease. The mechanisms that contribute to T-DM1 resistance are not fully understood. To this end, we developed T-DM1-resistant in vitro models to examine the mechanisms of acquired T-DM1 resistance. We demonstrate that decreased HER2 and up-regulation of MDR1 contribute to T-DM1 resistance in KPL-4 T-DM1 resistant cells. In contrast, both loss of SLC46A3 and PTEN deficiency play a role in conferring resistance in BT-474M1 T-DM1 resistant cells. Our data suggest that these two cell lines acquire resistance through distinct mechanisms. Furthermore, we show that the KPL-4 T-DM1 resistance can be overcome by treatment with an inhibitor of MDR1, whereas a PI3K inhibitor can rescue PTEN loss-induced resistance in T-DM1-resistant BT-474M1 cells. Our results provide a rationale for developing therapeutic strategies to enhance T-DM1 clinical efficacy by combining T-DM1 and other inhibitors that target signaling transduction or resistance pathways. Copyright ©2018, American Association for Cancer Research.

Differential effect of EGFR inhibitors on tamoxifen-resistant breast cancer cells.

Science.gov (United States)

Kim, Sangmin; Lee, Jeongmin; Oh, Soo Jin; Nam, Seok Jin; Lee, Jeong Eon

2015-09-01

Although tamoxifen is the most common and effective therapy for treatment of estrogen receptor-α (ER-α) breast cancer patients, resistance of endocrine therapy occurs, either de novo or acquired during therapy. Here, we investigated the clinical value of epidermal growth factor receptor (EGFR) in tamoxifen-resistant (TamR) patients and the differential effect of EGFR inhibitors, neratinib and gefitinib, on TamR breast cancer cell model. The morphology of TamR MCF7 cells showed mesenchymal phenotypes and did not induce cell death by tamoxifen treatment compared with tamoxifen‑sensitive (TamS) MCF7 cells. In addition, mesenchymal marker proteins, including N-cadherin (N-cad), fibronectin (FN), and Slug, significantly increased in TamR cells. In contrast, ER-α and E-cadherin (E-cad) were greatly decreased. We also found that the levels of EGFR and HER2 expression were increased in TamR cells. Furthermore, we observed that EGFR expression was directly involved with poor prognosis of tamoxifen-treated breast cancer patients using the GSE1378 date set. Thus, we treated TamR and TamS cells with EGFR inhibitors, neratinib and gefitinib, respectively. Interestingly, neratinib induced apoptotic cell death of TamR but not gefitinib. Cleaved PARP-1 expression was also increased by neratinib treatment in TamR cells. Therefore, we suggest that neratinib may be a potential therapeutic drug for treating TamR breast cancer.

Functional genetic research for radiation and drug resistant adenocarcinoma and its application

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Kim, In Gyu; Kim, Kug Chan; Jung, Il Lae; Chul, Shin Byung; Kook, Park Hyo; Lee, Hee Min

2012-01-15

The work scope of 'Functional genetic research for radiation and drug resistant adenocarcinoma and its application' had contained the research about effect of transgelin(SM22a), neurotensin, metallothionein-1G transgelin-2 genes on the cell death triggered ionizing radiation, cisplatin, MMS, luteolin and H{sub 2}O{sub 2}(toxic agents), which are highly expressed in radiation-induced mutant cells. In this study, to elucidate the role of these proteins in the ionizing radiation (toxic chemicals)-induced cell death, we utilized sensed (or antisense, small interference RNA) cells, which overexpress (or down-regulate) RNAs associated with these proteins biosynthesis, and investigated the effects of these genes on the cytotoxicity caused by ionizing radiation, H{sub 2}O{sub 2} and toxic chemicals. We also investigated the functions of downstream target genes of transgelin such as IGF-1Rβ/PI3K/AKT pathway and transgelin/metallothioneine in A-549 and HepG2 cells because such target genes are able to potentiate the cell-killing or cell protecting effects against radiation.

Functional genetic research for radiation and drug resistant adenocarcinoma and its application

International Nuclear Information System (INIS)

Kim, In Gyu; Kim, Kug Chan; Jung, Il Lae; Chul, Shin Byung; Kook, Park Hyo; Lee, Hee Min

2012-01-01

The work scope of 'Functional genetic research for radiation and drug resistant adenocarcinoma and its application' had contained the research about effect of transgelin(SM22a), neurotensin, metallothionein-1G transgelin-2 genes on the cell death triggered ionizing radiation, cisplatin, MMS, luteolin and H 2 O 2 (toxic agents), which are highly expressed in radiation-induced mutant cells. In this study, to elucidate the role of these proteins in the ionizing radiation (toxic chemicals)-induced cell death, we utilized sensed (or antisense, small interference RNA) cells, which overexpress (or down-regulate) RNAs associated with these proteins biosynthesis, and investigated the effects of these genes on the cytotoxicity caused by ionizing radiation, H 2 O 2 and toxic chemicals. We also investigated the functions of downstream target genes of transgelin such as IGF-1Rβ/PI3K/AKT pathway and transgelin/metallothioneine in A-549 and HepG2 cells because such target genes are able to potentiate the cell-killing or cell protecting effects against radiation

Prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma

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Che K

2017-02-01

Full Text Available Keying Che,1,* Yang Zhao,2,3,* Xiao Qu,1 Zhaofei Pang,1 Yang Ni,4 Tiehong Zhang,4 Jiajun Du,1,5 Hongchang Shen4 1Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 2Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Collaborative Innovation Center of Cancer Medicine, Fudan University Shanghai Cancer Center, 3Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 4Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, 5Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, People’s Republic of China *These authors contributed equally to this work Purpose: Gastric carcinoma (GC is a highly aggressive cancer and one of the leading causes of cancer-related deaths worldwide. Histopathological evaluation pertaining to invasiveness is likely to provide additional information in relation to patient outcome. In this study, we aimed to evaluate the prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma.Materials and methods: Hematoxylin and eosin-stained slides generated from 296 gastric adenocarcinoma patients with full clinical and pathological and follow-up information were systematically reviewed. The patients were grouped on the basis of tumor budding, single cell invasion, large cell invasion, mitotic count, and fibrosis. The association between histopathological parameters, different classification systems, and overall survival (OS was statistically analyzed.Results: Among the 296 cases that were analyzed, high-grade tumor budding was observed in 49.0% (145 of them. Single cell invasion and large cell invasion were observed in 62.8% (186 and 16.9% (50 of the cases, respectively. Following univariate analysis, patients with high-grade tumor budding had shorter OS than those with low-grade tumor budding (hazard ratio [HR]: 2.260, P<0

A review of obesity, insulin resistance, and the role of exercise in breast cancer patients.

Science.gov (United States)

Ghose, Abhimanyu; Kundu, Ria; Toumeh, Anis; Hornbeck, Catherine; Mohamed, Iman

2015-01-01

Breast cancer, the most common female malignancy in the world, has a strong association with obesity and insulin resistance. The importance of these risk factors goes up significantly in patients already affected by this cancer as they negatively affect the prognosis, recurrence rate, and survival by various mechanisms. The literature on the role of physical activity and aerobic exercise on modifying the above risks is debatable with data both for and against it. In this article, we have reviewed the risks of obesity and insulin resistance in breast cancer patients and the controversy associated with the impact of exercise. Ultimately, we have concluded that a randomized control trial is necessary with an individualized aerobic exercise program for a minimum duration of 20 wk on breast cancer patients, who are undergoing or recently completed chemotherapy, to study its effects on insulin resistance, weight, and clinical outcome.

Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer

Science.gov (United States)

Nafi, Siti Norasikin Mohd; Generali, Daniele; Kramer-Marek, Gabriela; Gijsen, Merel; Strina, Carla; Cappelletti, Mariarosa; Andreis, Daniele; Haider, Syed; Li, Ji-Liang; Bridges, Esther; Capala, Jacek; Ioannis, Roxanis; Harris, Adrian L; Kong, Anthony

2014-01-01

The role of HER4 in breast cancer is controversial and its role in relation to trastuzumab resistance remains unclear. We showed that trastuzumab treatment and its acquired resistance induced HER4 upregulation, cleavage and nuclear translocation. However, knockdown of HER4 by specific siRNAs increased trastuzumab sensitivity and reversed its resistance in HER2 positive breast cancer cells. Preventing HER4 cleavage by a γ-secretase inhibitor and inhibiting HER4 tyrosine kinase activity by neratinib decreased trastuzumab-induced HER4 nuclear translocation and enhanced trastuzumab response. There was also increased nuclear HER4 staining in the tumours from BT474 xenograft mice and human patients treated with trastuzumab. Furthermore, nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was shown to be an independent poor prognostic factor in HER2 positive breast cancer. Our data suggest that HER4 plays a key role in relation to trastuzumab resistance in HER2 positive breast cancer. Therefore, our study provides novel findings that HER4 activation, cleavage and nuclear translocation influence trastuzumab sensitivity and resistance in HER2 positive breast cancer. Nuclear HER4 could be a potential prognostic and predictive biomarker and understanding the role of HER4 may provide strategies to overcome trastuzumab resistance in HER2 positive breast cancer. PMID:25153719

Minor drug-resistant HIV type-1 variants in breast milk and plasma of HIV type-1-infected Ugandan women after nevirapine single-dose prophylaxis.

Science.gov (United States)

Pilger, Daniel; Hauser, Andrea; Kuecherer, Claudia; Mugenyi, Kizito; Kabasinguzi, Rose; Somogyi, Sybille; Harms, Gundel; Kunz, Andrea

2011-01-01

Nevirapine single-dose (NVP-SD) reduces mother-to-child transmission of HIV type-1 (HIV-1), but frequently induces resistance mutations in the HIV-1 genome. Little is known about drug-resistant HIV-1 variants in the breast milk of women who have taken NVP-SD. Blood and breast milk samples of 39 HIV-1-infected Ugandan women were taken 6-12 weeks after NVP-SD intake. Samples were analysed by population sequencing and allele-specific real-time PCR (AS-PCR) with detection limits for NVP-resistant HIV-1 variants (K103N and Y181C) of D n = 5, G n = 2 and C n = 1). A total of 7 (37%) and 10 (53%) women carried NVP-resistant virus in breast milk and plasma, respectively. Overall, 71% (5/7) women with NVP-resistant HIV-1 in breast milk displayed >1 drug-resistant variant. Resistance in breast milk was higher at week 6 (6/13 samples [46%]) compared with week 12 (1/6 samples [17%]). In total, 10 drug-resistant populations harbouring the K103N and/or Y181C mutation were detected in the 19 breast milk samples; 7 (70%) were caused by resistant minorities (< 5% of the total HIV-1 population). In the four women with drug-resistant virus in both plasma and breast milk, the mutation patterns differed between the two compartments. Minor populations of drug-resistant HIV-1 were frequently found in breast milk of Ugandan women after exposure to NVP-SD. Further studies need to explore the role of minor drug-resistant variants in the postnatal transmission of (resistant) HIV-1.

Presentation of Axillary Metastases from Occult Breast Carcinoma

Institute of Scientific and Technical Information of China (English)

Xin Wang

2007-01-01

Axillary presentation from occult breast cancer is uncommon and continues to be a diagnostic and therapeutic challenge to physicians.Once the diagnosis of adenocarcinoma metastatic to an axillary lymph node has been confirmed,a preoperative workup should be done.The current experience is based on several relatively small retrospective reviews and case reports.It is difficult to determine the best management of occult breast cancer.However,treatmenl of axillary Iymph node dissection is recommended for local control and complete staging information.Treatment of breast should be a choice between breast conservation with whole-breast radiotherapy and mastectomy.Adjuvant systemic treatment should be offered.

PI3K inhibition to overcome endocrine resistance in breast cancer.

Science.gov (United States)

Keegan, Niamh M; Gleeson, Jack P; Hennessy, Bryan T; Morris, Patrick G

2018-01-01

Activation of the phosphatidylinositol-3 kinase (PI3K) pathway is a critical step in oncogenesis and plays a role in the development of treatment resistance for both estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) positive breast cancers. Hence, there have been efforts to therapeutically inhibit this pathway. Areas covered: Several inhibitors of PI3K are now progressing through clinical trials with varying degrees of efficacy and toxicity to date. Numerous unresolved questions remain concerning the optimal isoform selectivity of PI3K inhibitors and use of predictive biomarkers. This review examines the most important PI3K inhibitors in ER positive breast cancer to date, with a particular focus on their role in overcoming endocrine therapy resistance and the possible use of PIK3CA mutations as a predictive biomarker. Expert opinion: We discuss some of the emerging challenges and questions encountered during the development of PI3K inhibitors from preclinical to phase III studies, including other novel biomarkers and future combinations to overcome endocrine resistance.

Treatment of Murine Tumor Models of Breast Adenocarcinoma by Continuous Dual-Frequency Ultrasound

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Amir Hoshang Barati

2009-03-01

Full Text Available Introduction: Acoustic transient cavitation is the primary mechanism of sonochemical reaction and has potential use for tumor treatment. In this study, the in vivo anti-tumor effect of simultaneous dual-frequency ultrasound at low-level intensity (ISATA < 6 W/cm2 was investigated in a spontaneous murine model of breast adenocarcinoma in Balb/c mice. Materials and Methods: Forty tumor bearing mice were divided into four groups (10 in each group. The treated groups received 15 or 30 minutes of combined dual-frequency ultrasound in continuous mode (1 MHzcon + 150 kHzcon respectively. The control and the sham groups contained the untreated mice. The tumor growth delay parameters including tumor volume, relative tumor volume, T5 and T2 (the needed time for each tumor to reach 5 and 2 times the initial tumor volume, respectively, survival period and percent of tumor growth inhibition ratio were measured on different days after treatment. Results: The results showed that the 30 min treatment was effective in tumor growth delay and percent of tumor growth inhibitory ratio compared to the sham and the control groups. The tumor volume growth and relative volume of tumors in the same treated group showed an anti-tumor effect relative to the sham and the control groups. There was a significant difference in tumor volume growth between this 30 min treatment group and the sham group 12 days after treatment (p-value

Expression and clinical significance of fibroblast growth factor 1 in gastric adenocarcinoma

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Liu NQ

2015-03-01

Full Text Available Naiqing Liu,1,2,* Jingyu Zhang,2,* Shuxiang Sun,2 Liguang Yang,2 Zhongjin Zhou,2 Qinli Sun,2 Jun Niu11Department of General Surgery, Qilu Hospital Affiliated to Shandong University, Jinan, People’s Republic of China; 2Department of General Surgery, Yishui Central Hospital, Linyi, People’s Republic of China*These authors contributed equally to this workBackground: The clinical significance of fibroblast growth factor 1 (FGF1 has been revealed in several cancers, including ovarian cancer, breast cancer, and bladder cancer. However, the clinical significance of FGF1 in gastric adenocarcinoma has not been explored.Patients and methods: In our experiments, we systematically evaluated FGF1 expression in 178 cases of gastric adenocarcinoma with immunohistochemistry, and subsequently analyzed the correlation between FGF1 expression and clinicopathologic features. Moreover, FGF1 expression in tumor tissue and corresponding adjacent tissue was detected and compared by real-time polymerase chain reaction. The Kaplan–Meier method and the Cox-regression model were used with univariate and multivariate analysis, respectively, to evaluate the prognostic value of FGF1 in gastric adenocarcinoma.Results: Higher FGF1 expression rate is 56.7% (101/178 in gastric adenocarcinoma. FGF1 expression in gastric adenocarcinoma was significantly higher than adjacent tissue (P<0.0001. Expression of FGF1 is significantly associated with lymph node invasion (P<0.001, distant metastasis (P=0.013, and differentiation (P=0.015. Moreover, FGF1 overexpression was closely related to unfavorable overall survival rate (P=0.021, and can be identified to be an independent unfavorable prognostic factor (P=0.004.Conclusion: FGF1 is an independent prognostic factor, indicating that FGF1 could be a potential molecular drug target in gastric adenocarcinoma.Keywords: fibroblast growth factor 1, gastric adenocarcinoma, prognosis, biomarker, lymph node, gene fusion

Squamous cell carcinoma of the breast: a case report

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Hofstee Mans

2008-12-01

Full Text Available Abstract Background Squamous cells are normally not found inside the breast, so a primary squamous cell carcinoma of the breast is an exceptional phenomenon. There is a possible explanation for these findings. Case presentation A 72-year-old woman presented with a breast abnormality suspected for breast carcinoma. After the operation the pathological examination revealed a primary squamous cell carcinoma of the breast. Conclusion The presentation of squamous cell carcinoma could be similar to that of an adenocarcinoma. However, a squamous cell carcinoma of the breast could also develop from a complicated breast cyst or abscess. Therefore, pathological examination of these apparent benign abnormalities is mandatory.

Predictive role of GSTP1-containing exosomes in chemotherapy-resistant breast cancer.

Science.gov (United States)

Yang, Su-Jin; Wang, Dan-Dan; Li, Jian; Xu, Han-Zi; Shen, Hong-Yu; Chen, Xiu; Zhou, Si-Ying; Zhong, Shan-Liang; Zhao, Jian-Hua; Tang, Jin-Hai

2017-08-05

Anthracycline/taxane-based chemotherapy regimens are usually used as neoadjuvant chemotherapies to decrease tumour size and prevent metastasis of advanced breast cancer. However, patients have a high risk of developing chemo-resistance during treatment through still unknown mechanisms. Glutathione S-transferase P1 (GSTP1), which belongs to the family of phase II metabolic enzymes, has been reported to function in detoxifying several anti-cancer drugs by conjugating them with glutathione. Previous studies have identified GSTP1 as a predictor of prognosis and chemo-resistance in breast cancer patients, but the mechanisms governing GSTP1-dependent drug resistance are still unclear. We have found that GSTP1 expression is much higher in adriamycin-resistant cells and their corresponding exosomes. The role of GSTP1-containing exosomes in conferring drug resistance was analysed through cell apoptosis and immunofluorescence staining assays. Furthermore, we analysed 42 cases of paired breast cancer tissues collected before and after anthracycline/taxane-based neoadjuvant chemotherapy by immunohistochemistry. Higher GSTP1 expression was shown in the progressive disease (PD)/stable disease (SD) group than in the partial response (PR)/complete response (CR) group both in the samples collected before and after the chemotherapy treatment. Interestingly, GSTP1 partly re-localized from the cell nucleus to the cytoplasm upon treatment, and similar results were obtained for the exosomal marker Tumour susceptibility gene 101 protein (TSG101), which also increased in the cytoplasm after chemotherapy. After analysing the serum exosomes of 30 patients treated with anthracycline/taxane-based neoadjuvant chemotherapy, we discovered that the levels of GSTP1 in exosomes from patients in the PD/SD group were significantly higher than those in the PR/CR group. Here, for the first time, we investigated a novel role for GSTP1-containing exosomes and their capability to transfer drug resistance

Breast cancer cells with acquired antiestrogen resistance are sensitized to cisplatin-induced cell death

DEFF Research Database (Denmark)

Yde, Christina Westmose; Gyrd-Hansen, Mads; Lykkesfeldt, Anne E

2007-01-01

Antiestrogens are currently used for treating breast cancer patients who have estrogen receptor-positive tumors. However, patients with advanced disease will eventually develop resistance to the drugs. Therefore, compounds effective on antiestrogen-resistant tumors will be of great importance for...

GP88 (PC-Cell Derived Growth Factor, progranulin stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells

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Sabnis Gauri

2011-06-01

Full Text Available Abstract Background Aromatase inhibitors (AI that inhibit breast cancer cell growth by blocking estrogen synthesis have become the treatment of choice for post-menopausal women with estrogen receptor positive (ER+ breast cancer. However, some patients display de novo or acquired resistance to AI. Interactions between estrogen and growth factor signaling pathways have been identified in estrogen-responsive cells as one possible reason for acquisition of resistance. Our laboratory has characterized an autocrine growth factor overexpressed in invasive ductal carcinoma named PC-Cell Derived Growth Factor (GP88, also known as progranulin. In the present study, we investigated the role GP88 on the acquisition of resistance to letrozole in ER+ breast cancer cells Methods We used two aromatase overexpressing human breast cancer cell lines MCF-7-CA cells and AC1 cells and their letrozole resistant counterparts as study models. Effect of stimulating or inhibiting GP88 expression on proliferation, anchorage-independent growth, survival and letrozole responsiveness was examined. Results GP88 induced cell proliferation and conferred letrozole resistance in a time- and dose-dependent fashion. Conversely, naturally letrozole resistant breast cancer cells displayed a 10-fold increase in GP88 expression when compared to letrozole sensitive cells. GP88 overexpression, or exogenous addition blocked the inhibitory effect of letrozole on proliferation, and stimulated survival and soft agar colony formation. In letrozole resistant cells, silencing GP88 by siRNA inhibited cell proliferation and restored their sensitivity to letrozole. Conclusion Our findings provide information on the role of an alternate growth and survival factor on the acquisition of aromatase inhibitor resistance in ER+ breast cancer.

Characterization of acquired paclitaxel resistance of breast cancer cells and involvement of ABC transporters

International Nuclear Information System (INIS)

Němcová-Fürstová, Vlasta; Kopperová, Dana; Balušíková, Kamila; Ehrlichová, Marie; Brynychová, Veronika; Václavíková, Radka; Daniel, Petr; Souček, Pavel; Kovář, Jan

2016-01-01

Development of taxane resistance has become clinically very important issue. The molecular mechanisms underlying the resistance are still unclear. To address this issue, we established paclitaxel-resistant sublines of the SK-BR-3 and MCF-7 breast cancer cell lines that are capable of long-term proliferation in 100 nM and 300 nM paclitaxel, respectively. Application of these concentrations leads to cell death in the original counterpart cells. Both sublines are cross-resistant to doxorubicin, indicating the presence of the MDR phenotype. Interestingly, resistance in both paclitaxel-resistant sublines is circumvented by the second-generation taxane SB-T-1216. Moreover, we demonstrated that it was not possible to establish sublines of SK-BR-3 and MCF-7 cells resistant to this taxane. It means that at least the tested breast cancer cells are unable to develop resistance to some taxanes. Employing mRNA expression profiling of all known human ABC transporters and subsequent Western blot analysis of the expression of selected transporters, we demonstrated that only the ABCB1/PgP and ABCC3/MRP3 proteins were up-regulated in both paclitaxel-resistant sublines. We found up-regulation of ABCG2/BCRP and ABCC4 proteins only in paclitaxel-resistant SK-BR-3 cells. In paclitaxel-resistant MCF-7 cells, ABCB4/MDR3 and ABCC2/MRP2 proteins were up-regulated. Silencing of ABCB1 expression using specific siRNA increased significantly, but did not completely restore full sensitivity to both paclitaxel and doxorubicin. Thus we showed a key, but not exclusive, role for ABCB1 in mechanisms of paclitaxel resistance. It suggests the involvement of multiple mechanisms in paclitaxel resistance in tested breast cancer cells. - Highlights: • Expression of all ABC transporters in paclitaxel-resistant sublines of SK-BR-3 and MCF-7 cells was analyzed. • SK-BR-3 and MCF-7 cells are unable to develop resistance to some taxanes. • Some taxanes are able to overcome developed resistance to

Characterization of acquired paclitaxel resistance of breast cancer cells and involvement of ABC transporters

Energy Technology Data Exchange (ETDEWEB)

Němcová-Fürstová, Vlasta, E-mail: vlasta.furstova@lf3.cuni.cz [Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic); Kopperová, Dana; Balušíková, Kamila [Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic); Ehrlichová, Marie; Brynychová, Veronika; Václavíková, Radka [Toxicogenomics Unit, National Institute of Public Health, Prague (Czech Republic); Daniel, Petr [Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic); Souček, Pavel [Toxicogenomics Unit, National Institute of Public Health, Prague (Czech Republic); Kovář, Jan [Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic)

2016-11-01

Development of taxane resistance has become clinically very important issue. The molecular mechanisms underlying the resistance are still unclear. To address this issue, we established paclitaxel-resistant sublines of the SK-BR-3 and MCF-7 breast cancer cell lines that are capable of long-term proliferation in 100 nM and 300 nM paclitaxel, respectively. Application of these concentrations leads to cell death in the original counterpart cells. Both sublines are cross-resistant to doxorubicin, indicating the presence of the MDR phenotype. Interestingly, resistance in both paclitaxel-resistant sublines is circumvented by the second-generation taxane SB-T-1216. Moreover, we demonstrated that it was not possible to establish sublines of SK-BR-3 and MCF-7 cells resistant to this taxane. It means that at least the tested breast cancer cells are unable to develop resistance to some taxanes. Employing mRNA expression profiling of all known human ABC transporters and subsequent Western blot analysis of the expression of selected transporters, we demonstrated that only the ABCB1/PgP and ABCC3/MRP3 proteins were up-regulated in both paclitaxel-resistant sublines. We found up-regulation of ABCG2/BCRP and ABCC4 proteins only in paclitaxel-resistant SK-BR-3 cells. In paclitaxel-resistant MCF-7 cells, ABCB4/MDR3 and ABCC2/MRP2 proteins were up-regulated. Silencing of ABCB1 expression using specific siRNA increased significantly, but did not completely restore full sensitivity to both paclitaxel and doxorubicin. Thus we showed a key, but not exclusive, role for ABCB1 in mechanisms of paclitaxel resistance. It suggests the involvement of multiple mechanisms in paclitaxel resistance in tested breast cancer cells. - Highlights: • Expression of all ABC transporters in paclitaxel-resistant sublines of SK-BR-3 and MCF-7 cells was analyzed. • SK-BR-3 and MCF-7 cells are unable to develop resistance to some taxanes. • Some taxanes are able to overcome developed resistance to

Identification of a putative protein-profile associating with tamoxifen therapy-resistance in breast cancer

NARCIS (Netherlands)

A. Umar (Arzu); J.W.M. Martens (John); J.A. Foekens (John); L. Paša-Tolić (Ljiljana); H. Kang; A.M. Timmermans (Mieke); M.P. Look (Maxime); M.E. Meijer van Gelder (Marion); N. Jaitly (Navdeep); M.A. den Bakker (Michael)

2009-01-01

textabstractTamoxifen-resistance is a major cause of death in patients with recurrent breast cancer. Current clinical parameters can correctly predict therapy response in only half of the treated patients. Identification of proteins that associate with tamoxifen-resistance is a first step towards

Quercetin and doxorubicin co-encapsulated biotin receptor-targeting nanoparticles for minimizing drug resistance in breast cancer.

Science.gov (United States)

Lv, Li; Liu, Chunxia; Chen, Chuxiong; Yu, Xiaoxia; Chen, Guanghui; Shi, Yonghui; Qin, Fengchao; Ou, Jiebin; Qiu, Kaifeng; Li, Guocheng

2016-05-31

The combination of a chemotherapeutic drug with a chemosensitizer has emerged as a promising strategy for cancers showing multidrug resistance (MDR). Herein we describe the simultaneous targeted delivery of two drugs to tumor cells by using biotin-decorated poly(ethylene glycol)-b-poly(ε-caprolactone) nanoparticles encapsulating the chemotherapeutic drug doxorubicin and the chemosensitizer quercetin (BNDQ). Next, the potential ability of BNDQ to reverse MDR in vitro and in vivo was investigated. Studies demonstrated that BNDQ was more effectively taken up with less efflux by doxorubicin-resistant MCF-7 breast cancer cells (MCF-7/ADR cells) than by the cells treated with the free drugs, single-drug-loaded nanoparticles, or non-biotin-decorated nanoparticles. BNDQ exhibited clear inhibition of both the activity and expression of P-glycoprotein in MCF-7/ADR cells. More importantly, it caused a significant reduction in doxorubicin resistance in MCF-7/ADR breast cancer cells both in vitro and in vivo, among all the groups. Overall, this study suggests that BNDQ has a potential role in the treatment of drug-resistant breast cancer.

A Novel Approach to Detect Therapeutic Resistance in Breast Cancer

Science.gov (United States)

2008-09-01

Resistance in Breast Cancer PRINCIPAL INVESTIGATOR: Kamila Czene, Ph.D. CONTRACTING ORGANIZATION: Karolinska Institutet ...ORGANIZATION REPORT NUMBER Karolinska Institutet Stockholm, Sweden 9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10...analysis. The digital image analysis algorithms and software that have been developed at Karolinska Institutet consists of an optimized combination of

TFF3-dependent resistance of human colorectal adenocarcinoma cells HT-29/B6 to apoptosis is mediated by miR-491-5p regulation of lncRNA PRINS

OpenAIRE

Hanisch, Carlos; Sharbati, Jutta; Kutz-Lohroff, Barbara; Huber, Otmar; Einspanier, Ralf; Sharbati, Soroush

2017-01-01

Tumour necrosis factor-? (TNF-?) is a double-edged cytokine associated with pathogenesis of inflammatory-related cancers being also able to induce cancer cell death. In the process of tumour development or metastasis, cancer cells can become resistant to TNF-?. In trefoil factor 3 (TFF3) overexpressing colorectal adenocarcinoma cells (HT-29/B6), we observed enhanced resistance against TNF-?/interferon gamma-induced apoptosis. TFF3 is a secreted small peptide that supports intestinal tissue re...

Urothelial-Type adenocarcinoma of the prostate mimicking metastatic colorectal adenocarcinoma

Directory of Open Access Journals (Sweden)

Brian P. Adley

2006-12-01

Full Text Available Adenocarcinoma arising in urinary bladder or prostatic urethra is uncommon. When they occur, the tumor can be mistaken for metastatic lesions, especially from the colon. Here we report the fifth case of a primary urothelial-type adenocarcinoma arising in the prostate which showed enteric differentiation. The patient was a 55 year-old male whose prostatic needle core biopsy showed a high grade adenocarcinoma which was initially thought to be metastatic colon cancer. A follow-up colonoscopy was unremarkable. Subsequent prostatectomy revealed a high grade adenocarcinoma which was positive for cytokeratins 7 and 20, carcinoembryonic antigen, CDX2, and high molecular weight cytokeratin, and negative for prostate specific antigen, prostate specific acid phosphatase and AMACR. A diagnosis of urothelial-type adenocarcinoma of the prostate was rendered. We review the literature regarding this entity, and discuss the differential diagnosis, emphasizing utility of immunohistochemistry in making the diagnosis. Finally, we speculate on the behavior of these rare tumors.

Role of Rac1 Pathway in Epithelial-to-Mesenchymal Transition and Cancer Stem-like Cell Phenotypes in Gastric Adenocarcinoma.

Science.gov (United States)

Yoon, Changhwan; Cho, Soo-Jeong; Chang, Kevin K; Park, Do Joong; Ryeom, Sandra W; Yoon, Sam S

2017-08-01

Rac1, a Rho GTPase family member, is dysregulated in a variety of tumor types including gastric adenocarcinoma, but little is known about its role in cancer stem-like cells (CSCs). Therefore, Rac1 activity and inhibition were examined in gastric adenocarcinoma cells and mouse xenograft models for epithelial-to-mesenchymal transition (EMT) and CSC phenotypes. Rac1 activity was significantly higher in spheroid-forming or CD44 + gastric adenocarcinoma CSCs compared with unselected cells. Rac1 inhibition using Rac1 shRNA or a Rac1 inhibitor (NSC23766) decreased expression of the self-renewal transcription factor, Sox-2, decreased spheroid formation by 78%-81%, and prevented tumor initiation in immunodeficient mice. Gastric adenocarcinoma CSCs had increased expression of the EMT transcription factor Slug, 4.4- to 8.3-fold greater migration, and 4.2- to 12.6-fold greater invasion than unselected cells, and these increases could be blocked completely with Rac1 inhibition. Gastric adenocarcinoma spheroid cells were resistant to 5-fluorouracil and cisplatin chemotherapy, and this chemotherapy resistance could be reversed with Rac1 shRNA or NSC23766. The PI3K/Akt pathway may be upstream of Rac1, and JNK may be downstream of Rac1. In the MKN-45 xenograft model, cisplatin inhibited tumor growth by 50%, Rac1 inhibition by 35%, and the combination by 77%. Higher Rac1 activity, in clinical specimens from gastric adenocarcinoma patients who underwent potentially curative surgery, correlated with significantly worse survival ( P = 0.017). In conclusion, Rac1 promotes the EMT program in gastric adenocarcinoma and the acquisition of a CSC state. Rac1 inhibition in gastric adenocarcinoma cells blocks EMT and CSC phenotypes, and thus may prevent metastasis and augment chemotherapy. Implications: In gastric adenocarcinoma, therapeutic targeting of the Rac1 pathway may prevent or reverse EMT and CSC phenotypes that drive tumor progression, metastasis, and chemotherapy resistance. Mol

Involvement of miR-30c in resistance to doxorubicin by regulating YWHAZ in breast cancer cells

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Fang, Y. [Department of Central Laboratory, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Shen, H. [Department of Oncology, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Cao, Y. [Department of Central Laboratory, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Li, H. [Department of Central Laboratory, The Fourth Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Qin, R. [Department of Oncology, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Chen, Q. [Department of Central Laboratory, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Long, L. [Department of Oncology, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Zhu, X.L. [Department of Central Laboratory, The Fourth Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Xie, C.J. [Department of Central Laboratory, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Xu, W.L. [Department of Central Laboratory, The Fourth Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China)

2014-01-10

MicroRNAs (miRNAs) are small RNA molecules that modulate gene expression implicated in cancer, which play crucial roles in diverse biological processes, such as development, differentiation, apoptosis, and proliferation. The aim of this study was to investigate whether miR-30c mediated the resistance of breast cancer cells to the chemotherapeutic agent doxorubicin (ADR) by targeting tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ). miR-30c was downregulated in the doxorubicin-resistant human breast cancer cell lines MCF-7/ADR and MDA-MB-231/ADR compared with their parental MCF-7 and MDA-MB-231 cell lines, respectively. Furthermore, we observed that transfection of an miR-30c mimic significantly suppressed the ability of MCF-7/ADR to resist doxorubicin. Moreover, the anti-apoptotic gene YWHAZ was confirmed as a target of miR-30c by luciferase reporter assay, and further studies indicated that the mechanism for miR-30c on the sensitivity of breast cancer cells involved YWHAZ and its downstream p38 mitogen-activated protein kinase (p38MAPK) pathway. Together, our findings provided evidence that miR-30c was one of the important miRNAs in doxorubicin resistance by regulating YWHAZ in the breast cancer cell line MCF-7/ADR.

Epithelial-Mesenchymal Transitions and the Expression of Twist in MCF-7/ADR,Human Multidrug-Resistant Breast Cancer Cells

Institute of Scientific and Technical Information of China (English)

Fei Zhang; Yurong Shi; Lin Zhang; Bin Zhang; Xiyin Wei; Yi Yang; RUi Wang; Ruifang Niu

2007-01-01

OBJECTIVE To study the expression levels of Twist and epithelialmesenchymal transitions in multidrug-resistant MCF-7/ADR breast cancer cells,and to study the relationship between multidrug resistance (MDR) and metastatic potential of the cells.METHODS RT-PCR,immunohislochemical and Western blotting methods were used to examine the changes of expression levels of the transcription factor Twist.E-cadherin and N-cadherin in the MCF-7 breast cancer cell line and its multidrug-resistant variant.MCF-7/ADR.RESULTS In MCF-7 cells,the expression of E-cadherin can be detected,but there is no expression of Twisl or N-cadherin.In MCF-7/ADR cells,E-cadherin expression is lost.bul the expression of two other genes was significantly positive.CONCLUSION Epithelial-mesenchymal transitions induced by Twist,may have a relationship with enhanced invasion and metastatic potential during the development of multidrug-resistant MCF-7/ADR breast cancer cells.

CNTN-1 Enhances Chemoresistance in Human Lung Adenocarcinoma Through Induction of Epithelial-Mesenchymal Transition by Targeting the PI3K/Akt Pathway

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Ruijie Zhang

2017-09-01

Full Text Available Background/Aims: Chemoresistance has been a major obstacle to the effective treatment of lung cancer. Previously, we found that contactin-1 (CNTN-1 is related to cisplatin resistance in lung adenocarcinoma. Here, we aimed to investigate the underlying mechanism behind the role of CNTN-1 in cisplatin resistance in lung adenocarcinoma. Methods: EMT-associated phenotypes, including alterations in cellular morphology and marker (E-cadherin, N-cadherin and Vimentin expression, were compared between A549 cells and A549/DDP cells (a cisplatin-resistant cell line of lung adenocarcinoma with abnormal CNTN-1 expression by using real-time time PCR and Western blotting. Other methods, including CNTN-1 overexpression in A549 cells and CNTN-1 knockdown in A549/DDP cells, were also used to investigate the role of CNTN-1 in mediating the EMT phenotype and thr resulting cisplatin resistance and malignant progression of cancer cells in vitro and in vivo. Results: A549/DDP cells exhibited an EMT phenotype and aggravated malignant behaviors. CNTN-1 knockdown in A549/DDP cells partly reversed the EMT phenotype, increased drug sensitivity, and attenuated the malignant progression whereas CNTN-1 overexpression in A549 cells resulted in the opposite trend. Furthermore, the PI3K/Akt pathway was involved in the effects of CNTN-1 on EMT progression in A549/DDP cells, verified by the xenograft mouse model. Conclusion: CNTN-1 promotes cisplatin resistance in human cisplatin-resistant lung adenocarcinoma through inducing the EMT process by activating the PI3K/Akt signaling pathway. CNTN-1 may be a potential therapeutic target to reverse chemoresistance in cisplatin-resistant lung adenocarcinoma.

Resistive index in breast tumors; usefulness on differentiation between benign and malignant lesions

International Nuclear Information System (INIS)

An, Eun Joo; Choi, Hye Young; Baek, Seung Yon; Kim, Ah Young; Choe, Du Hwan

1996-01-01

We assessed the usefulness of resistive index(RI) on spectral analysis of doppler sonography for differential diagnosis of benign and malignant breast lesions. We retrospectively reviewed 29 benign and 22 malignant lesions of breast, which were examined preoperatively with color and duplex Doppler and were confirmed by histopathologically after operation. We analyzed the average and distribution of RI in benign and malignant lesions. Although, there was no difference in the average values of RI in benign and malignant breast lesions, the distribution of RI was below 0.7 in eighteen cases (62%) of benign lesions, and above 0.7 in eighteen cases (82%) of malignant lesions. Thus, RI is valuable for differentiation between benign and malignant lesions of breast. Measurement of RI in breast disease using color and duplex Doppler study is useful modality adjunct to the conventional ultrasonographic differentiation of benign and malignant lesions

Integrative analysis of miRNA and gene expression reveals regulatory networks in tamoxifen-resistant breast cancer

DEFF Research Database (Denmark)

Joshi, Tejal; Elias, Daniel; Stenvang, Jan

2016-01-01

and 14-3-3 family genes. Integrating the inferred miRNA-target relationships, we investigated the functional importance of 2 central genes, SNAI2 and FYN, which showed increased expression in TamR cells, while their corresponding regulatory miRNA were downregulated. Using specific chemical inhibitors......Tamoxifen is an effective anti-estrogen treatment for patients with estrogen receptor-positive (ER+) breast cancer, however, tamoxifen resistance is frequently observed. To elucidate the underlying molecular mechanisms of tamoxifen resistance, we performed a systematic analysis of miRNA......-mediated gene regulation in three clinically-relevant tamoxifen-resistant breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive cell line. Alterations in the expression of 131 miRNAs in tamoxifen-resistant vs. parental cell lines were identified, 22 of which were common to all Tam...

Clinical Significance of HER-2 Splice Variants in Breast Cancer Progression and Drug Resistance

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Claire Jackson

2013-01-01

Full Text Available Overexpression of human epidermal growth factor receptor (HER-2 occurs in 20–30% of breast cancers and confers survival and proliferative advantages on the tumour cells making HER-2 an ideal therapeutic target for drugs like Herceptin. Continued delineation of tumour biology has identified splice variants of HER-2, with contrasting roles in tumour cell biology. For example, the splice variant 16HER-2 (results from exon 16 skipping increases transformation of cancer cells and is associated with treatment resistance; conversely, Herstatin (results from intron 8 retention and p100 (results from intron 15 retention inhibit tumour cell proliferation. This review focuses on the potential clinical implications of the expression and coexistence of HER-2 splice variants in cancer cells in relation to breast cancer progression and drug resistance. “Individualised” strategies currently guide breast cancer management; in accordance, HER-2 splice variants may prove valuable as future prognostic and predictive factors, as well as potential therapeutic targets.

Surface TRAIL decoy receptor-4 expression is correlated with TRAIL resistance in MCF7 breast cancer cells

International Nuclear Information System (INIS)

Sanlioglu, Ahter D; Dirice, Ercument; Aydin, Cigdem; Erin, Nuray; Koksoy, Sadi; Sanlioglu, Salih

2005-01-01

Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) selectively induces apoptosis in cancer cells but not in normal cells. Despite this promising feature, TRAIL resistance observed in cancer cells seriously challenged the use of TRAIL as a death ligand in gene therapy. The current dispute concerns whether or not TRAIL receptor expression pattern is the primary determinant of TRAIL sensitivity in cancer cells. This study investigates TRAIL receptor expression pattern and its connection to TRAIL resistance in breast cancer cells. In addition, a DcR2 siRNA approach and a complementary gene therapy modality involving IKK inhibition (AdIKKβKA) were also tested to verify if these approaches could sensitize MCF7 breast cancer cells to adenovirus delivery of TRAIL (Ad5hTRAIL). TRAIL sensitivity assays were conducted using Molecular Probe's Live/Dead Cellular Viability/Cytotoxicity Kit following the infection of breast cancer cells with Ad5hTRAIL. The molecular mechanism of TRAIL induced cell death under the setting of IKK inhibition was revealed by Annexin V binding. Novel quantitative Real Time RT-PCR and flow cytometry analysis were performed to disclose TRAIL receptor composition in breast cancer cells. MCF7 but not MDA-MB-231 breast cancer cells displayed strong resistance to adenovirus delivery of TRAIL. Only the combinatorial use of Ad5hTRAIL and AdIKKβKA infection sensitized MCF7 breast cancer cells to TRAIL induced cell death. Moreover, novel quantitative Real Time RT-PCR assays suggested that while the level of TRAIL Decoy Receptor-4 (TRAIL-R4) expression was the highest in MCF7 cells, it was the lowest TRAIL receptor expressed in MDA-MB-231 cells. In addition, conventional flow cytometry analysis demonstrated that TRAIL resistant MCF7 cells exhibited substantial levels of TRAIL-R4 expression but not TRAIL decoy receptor-3 (TRAIL-R3) on surface. On the contrary, TRAIL sensitive MDA-MB-231 cells displayed very low levels of surface TRAIL-R4

Breast as an unusual site of metastasis- series of 3 cases and review of literature.

Science.gov (United States)

Hebbar, Ashwin K; Shashidhar, K; S, Krishna Murthy; Kumar, Veerendra; Arjunan, Ravi

2014-09-01

Background and objectives Metastasis to the breast from extra mammary sites is uncommon with an incidence ranging from 1.2 to 2 % in clinical reports. Approximately 300 cases of breast metastasis from extra mammary sites have been reported, mostly in small series or as a single case report. Gastrointestinal adenocarcinoma metastasising to the breast is also very rare and only 30 cases have been reported in the literature. Metastatic deposits within the breast may be difficult to distinguish from primary breast carcinoma. Radiological features and immunohistochemistry especially for steroid hormone receptors (ER/PR) and expression of gross cystic disease fluid protein (GCDFP) and presence of other immunohistochemistry protein factors in breast metastasis which are specific to primary site may be helpful in differentiating these two conditions. Materials and methods In this series of 3 cases of breast as an unusual site of metastasis, we present different cases of adenocarcinoma of stomach, sigmoid colon and kidney with metastasis to the breast and discuss the differential diagnosis and management plans. Conclusion In conclusion, secondary tumors to the breast are rare and thus differentiating primary tumors from metastatic breast carcinoma is important for rational and optimum therapy and avoidance of unnecessary radical surgery. Palpable breast lump without typical radiological signs of primary breast carcinoma in patients with known primary should be suspected of representing metastasis.

Intra-Tumour Signalling Entropy Determines Clinical Outcome in Breast and Lung Cancer

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Banerji, Christopher R. S.; Severini, Simone; Caldas, Carlos; Teschendorff, Andrew E.

2015-01-01

The cancer stem cell hypothesis, that a small population of tumour cells are responsible for tumorigenesis and cancer progression, is becoming widely accepted and recent evidence has suggested a prognostic and predictive role for such cells. Intra-tumour heterogeneity, the diversity of the cancer cell population within the tumour of an individual patient, is related to cancer stem cells and is also considered a potential prognostic indicator in oncology. The measurement of cancer stem cell abundance and intra-tumour heterogeneity in a clinically relevant manner however, currently presents a challenge. Here we propose signalling entropy, a measure of signalling pathway promiscuity derived from a sample’s genome-wide gene expression profile, as an estimate of the stemness of a tumour sample. By considering over 500 mixtures of diverse cellular expression profiles, we reveal that signalling entropy also associates with intra-tumour heterogeneity. By analysing 3668 breast cancer and 1692 lung adenocarcinoma samples, we further demonstrate that signalling entropy correlates negatively with survival, outperforming leading clinical gene expression based prognostic tools. Signalling entropy is found to be a general prognostic measure, valid in different breast cancer clinical subgroups, as well as within stage I lung adenocarcinoma. We find that its prognostic power is driven by genes involved in cancer stem cells and treatment resistance. In summary, by approximating both stemness and intra-tumour heterogeneity, signalling entropy provides a powerful prognostic measure across different epithelial cancers. PMID:25793737

Intra-tumour signalling entropy determines clinical outcome in breast and lung cancer.

Directory of Open Access Journals (Sweden)

Christopher R S Banerji

2015-03-01

Full Text Available The cancer stem cell hypothesis, that a small population of tumour cells are responsible for tumorigenesis and cancer progression, is becoming widely accepted and recent evidence has suggested a prognostic and predictive role for such cells. Intra-tumour heterogeneity, the diversity of the cancer cell population within the tumour of an individual patient, is related to cancer stem cells and is also considered a potential prognostic indicator in oncology. The measurement of cancer stem cell abundance and intra-tumour heterogeneity in a clinically relevant manner however, currently presents a challenge. Here we propose signalling entropy, a measure of signalling pathway promiscuity derived from a sample's genome-wide gene expression profile, as an estimate of the stemness of a tumour sample. By considering over 500 mixtures of diverse cellular expression profiles, we reveal that signalling entropy also associates with intra-tumour heterogeneity. By analysing 3668 breast cancer and 1692 lung adenocarcinoma samples, we further demonstrate that signalling entropy correlates negatively with survival, outperforming leading clinical gene expression based prognostic tools. Signalling entropy is found to be a general prognostic measure, valid in different breast cancer clinical subgroups, as well as within stage I lung adenocarcinoma. We find that its prognostic power is driven by genes involved in cancer stem cells and treatment resistance. In summary, by approximating both stemness and intra-tumour heterogeneity, signalling entropy provides a powerful prognostic measure across different epithelial cancers.

Circadian and Melatonin Disruption by Exposure to Light at Night Drives Intrinsic Resistance to Tamoxifen Therapy in Breast Cancer

Science.gov (United States)

Dauchy, Robert T.; Xiang, Shulin; Mao, Lulu; Brimer, Samantha; Wren, Melissa A.; Yuan, Lin; Anbalagan, Muralidharan; Hauch, Adam; Frasch, Tripp; Rowan, Brian G.; Blask, David E.; Hill, Steven M.

2014-01-01

Resistance to endocrine therapy is a major impediment to successful treatment of breast cancer. Preclinical and clinical evidence links resistance to anti-estrogen drugs in breast cancer cells with the overexpression and/or activation of various pro-oncogenic tyrosine kinases. Disruption of circadian rhythms by night shift work or disturbed sleep-wake cycles may lead to an increased risk of breast cancer and other diseases. Moreover, light exposure at night (LEN) suppresses the nocturnal production of melatonin that inhibits breast cancer growth. In this study, we used a rat model of ERα+ MCF-7 tumor xenografts to demonstrate how altering light/dark cycles with dim LEN (dLEN) speeds the development of breast tumors, increasing their metabolism and growth and conferring an intrinsic resistance to tamoxifen therapy. These characters were not produced in animals where circadian rhythms were not disrupted, or in animals subjected to dLEN if they received nocturnal melatonin replacement. Strikingly, our results also showed that melatonin acted both as a tumor metabolic inhibitor and a circadian-regulated kinase inhibitor to re-establish the sensitivity of breast tumors to tamoxifen and tumor regression. Together, our findings show how dLEN-mediated disturbances in nocturnal melatonin production can render tumors insensitive to tamoxifen. PMID:25062775

Differential diagnosis and cancer staging of a unique case with multiple nodules in the lung - lung adenocarcinoma, metastasis of colon adenocarcinoma, and colon adenocarcinoma metastasizing to lung adenocarcinoma.

Science.gov (United States)

Bai, Yun; Qiu, Jianxing; Shang, Xueqian; Liu, Ping; Zhang, Ying; Wang, Ying; Xiong, Yan; Li, Ting

2015-05-01

Lung cancer is the most common cancer in the world. Despite this, there have been few cases of simultaneous primary and metastatic cancers in the lung reported, let alone coexisting with tumor-to-tumor metastasis. Herein, we describe an extremely unusual case. A 61-year-old man with a history of colon adenocarcinoma was revealed as having three nodules in the lung 11 months after colectomy. The nodule in the left upper lobe was primary lung adenocarcinoma, the larger one in the right upper lobe was a metastasis of colon adenocarcinoma, and the smaller one in the right upper lobe was colon adenocarcinoma metastasizing to lung adenocarcinoma. Our paper focused on the differential diagnosis and cancer staging of this unique case, and discussed the uncommon phenomenon of the lung acting as a recipient in tumor-to-tumor metastasis.

BMI-1 Promotes Self-Renewal of Radio- and Temozolomide (TMZ)-Resistant Breast Cancer Cells.

Science.gov (United States)

Yan, Yanfang; Wang, Ying; Zhao, Pengxin; Ma, Weiyuan; Hu, Zhigang; Zhang, Kaili

2017-12-01

Breast cancer is a hormone-dependent malignancy and is the most prevalent cause of cancer-related mortality among females. Radiation therapy and chemotherapy are common treatments of breast cancer. However, tumor relapse and metastasis following therapy are major clinical challenges. The importance of B-lymphoma Moloney murine leukemia virus insertion region-1 (BMI-1) was implicated in cell proliferation, stem cell maintenance, and tumor initiation. We established radio- and temozolomide (TMZ)-resistant (IRC-R) MCF-7 and MDA-MB-231 cell lines to investigate the mechanism involved in therapeutic resistance. Cell proliferation and sphere number were dramatically elevated, and BMI-1 was remarkably upregulated, in IRC-R cells compared to parental cells. Silencing BMI-1 by RNA interference only affected the cell proliferation of IRC-R but not parental cells, suggesting the critical role of BMI-1 in radio- and TMZ resistance. We used a xenograft mice model to elucidate that BMI-1 was necessary in tumor development by assessing tumor volume and Ki67 expression. We found that Hedgehog (Hhg) signaling exerted synergized functions together with BMI-1, implicating the importance of BMI-1 in Hhg signaling. Downregulation of BMI-1 could be an effective strategy to suppress tumor growth, which supports the potential clinical use of targeting BMI-1 in breast cancer treatment.

Multidrug Resistance in Breast Cancer: From In Vitro Models to Clinical Studies

International Nuclear Information System (INIS)

Wind, N.S.; Holen, I.

2011-01-01

The development of multidrug resistance (MDR) and subsequent relapse on therapy is a widespread problem in breast cancer, but our understanding of the underlying molecular mechanisms is incomplete. Numerous studies have aimed to establish the role of drug transporter pumps in MDR and to link their expression to response to chemotherapy. The ATP-binding cassette (ABC) transporters are central to breast cancer MDR, and increases in ABC expression levels have been shown to correlate with decreases in response to various chemotherapy drugs and a reduction in overall survival. But as there is a large degree of redundancy between different ABC transporters, this correlation has not been seen in all studies. This paper provides an introduction to the key molecules associated with breast cancer MDR and summarises evidence of their potential roles reported from model systems and clinical studies. We provide possible explanations for why despite several decades of research, the precise role of ABC transporters in breast cancer MDR remains elusive

Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced disease.

Science.gov (United States)

Wardell, Suzanne E; Nelson, Erik R; Chao, Christina A; McDonnell, Donald P

2013-05-01

There is compelling evidence to suggest that drugs that function as pure estrogen receptor (ER-α) antagonists, or that downregulate the expression of ER-α, would have clinical use in the treatment of advanced tamoxifen- and aromatase-resistant breast cancer. Although such compounds are currently in development, we reasoned, based on our understanding of ER-α pharmacology, that there may already exist among the most recently developed selective estrogen receptor modulators (SERM) compounds that would have usage as breast cancer therapeutics. Thus, our objective was to identify among available SERMs those with unique pharmacologic activities and to evaluate their potential clinical use with predictive models of advanced breast cancer. A validated molecular profiling technology was used to classify clinically relevant SERMs based on their impact on ER-α conformation. The functional consequences of these observed mechanistic differences on (i) gene expression, (ii) receptor stability, and (iii) activity in cellular and animal models of advanced endocrine-resistant breast cancer were assessed. The high-affinity SERM bazedoxifene was shown to function as a pure ER-α antagonist in cellular models of breast cancer and effectively inhibited the growth of both tamoxifen-sensitive and -resistant breast tumor xenografts. Interestingly, bazedoxifene induced a unique conformational change in ER-α that resulted in its proteasomal degradation, although the latter activity was dispensable for its antagonist efficacy. Bazedoxifene was recently approved for use in the European Union for the treatment of osteoporosis and thus may represent a near-term therapeutic option for patients with advanced breast cancer. ©2013 AACR.

miR-193b Modulates Resistance to Doxorubicin in Human Breast Cancer Cells by Downregulating MCL-1

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Jingpei Long

2015-01-01

Full Text Available MicroRNAs (miRNAs family, which is involved in cancer development, proliferation, apoptosis, and drug resistance, is a group of noncoding RNAs that modulate the expression of oncogenes and antioncogenes. Doxorubicin is an active cytotoxic agent for breast cancer treatment, but the acquisition of doxorubicin resistance is a common and critical limitation to cancer therapy. The aim of this study was to investigate whether miR-193b mediated the resistance of breast cancer cells to doxorubicin by targeting myeloid cell leukemia-1 (MCL-1. In this study, we found that miR-193b levels were significantly lower in doxorubicin-resistant MCF-7 (MCF-7/DOXR cells than in the parental MCF-7 cells. We observed that exogenous miR-193b significantly suppressed the ability of MCF-7/DOXR cells to resist doxorubicin. It demonstrated that miR-193b directly targeted MCL-1 3′-UTR (3′-Untranslated Regions. Further studies indicated that miR-193b sensitized MCF-7/DOXR cells to doxorubicin through a mechanism involving the downregulation of MCL-1. Together, our findings provide evidence that the modulation of miR-193b may represent a novel therapeutic target for the treatment of breast cancer.

Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer.

Science.gov (United States)

Choi, Hee-Joo; Joo, Hyeong-Seok; Won, Hee-Young; Min, Kyueng-Whan; Kim, Hyung-Yong; Son, Taekwon; Oh, Young-Ha; Lee, Jeong-Yeon; Kong, Gu

2018-04-01

Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)-positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer. Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by invitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and invivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided. RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance invitro and invivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm3, vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm3, P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance-associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1-HDAC1 complex led to insulin-like growth factor-1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity-independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen

Modulation of DNA methylation levels sensitizes doxorubicin-resistant breast adenocarcinoma cells to radiation-induced apoptosis

Energy Technology Data Exchange (ETDEWEB)

Luzhna, Lidia [Department of Biological Sciences, University of Lethbridge, AB, Canada T1K 3M4 (Canada); Kovalchuk, Olga, E-mail: olga.kovalchuk@uleth.ca [Department of Biological Sciences, University of Lethbridge, AB, Canada T1K 3M4 (Canada)

2010-02-05

Chemoresistant tumors often fail to respond to other cytotoxic treatments such as radiation therapy. The mechanisms of chemo- and radiotherapy cross resistance are not fully understood and are believed to be epigenetic in nature. We hypothesize that MCF-7 cells and their doxorubicin-resistant variant MCF-7/DOX cells may exhibit different responses to ionizing radiation due to their dissimilar epigenetic status. Similar to previous studies, we found that MCF-7/DOX cells harbor much lower levels of global DNA methylation than MCF-7 cells. Furthermore, we found that MCF-7/DOX cells had lower background apoptosis levels and were less responsive to radiation than MCF-7 cells. Decreased radiation responsiveness correlated to significant global DNA hypomethylation in MCF-7/DOX cells. Here, for the first time, we show that the radiation resistance of MCF-7/DOX cells can be reversed by an epigenetic treatment - the application of methyl-donor SAM. SAM-mediated reversal of DNA methylation led to elevated radiation sensitivity in MCF-7/DOX cells. Contrarily, application of SAM on the radiation sensitive and higher methylated MCF-7 cells resulted in a decrease in their radiation responsiveness. This data suggests that a fine balance of DNA methylation is needed to insure proper radiation and drug responsiveness.

MicroRNA expression profiles of drug-resistance breast cancer cells and their exosomes.

Science.gov (United States)

Zhong, Shanliang; Chen, Xiu; Wang, Dandan; Zhang, Xiaohui; Shen, Hongyu; Yang, Sujin; Lv, Mengmeng; Tang, Jinhai; Zhao, Jianhua

2016-04-12

Exosomes have been shown to transmit drug resistance through delivering miRNAs. We aimed to explore their roles in breast cancer. Three resistant sublines were established by exposing parental MDA-MB-231 cell line to docetaxel, epirubicin and vinorelbine, respectively. Preneoadjuvant chemotherapy biopsies and paired surgically-resected specimens embedded in paraffin from 23 breast cancer patients were collected. MiRNA expression profiles of the cell lines and their exosomes were evaluated using microarray. The result showed that most miRNAs in exosomes had a lower expression level than that in cells, however, some miRNAs expressed higher in exosomes than in cells, suggesting a number of miRNAs is concentrated in exosomes. Among the dysregulated miRNAs, 22 miRNAs were consistently up-regulated in exosomes and their cells of origin. We further found that 12 of the 22 miRNAs were significantly up-regulated after preneoadjuvant chemotherapy. Further study of the role of these 12 miRNAs in acquisition of drug resistance is needed to clarify their contribution to chemoresistance.

Urachal Adenocarcinoma

African Journals Online (AJOL)

Urachal adenocarcinoma is a rare tumor and represents. 0.17–0.34% of all bladder tumors. Most of the reported cases are in western literature and to the best of our knowledge this is the first case report of urachal adenocarcinoma in sub-Saharan Africa. It has an insidious course and variable clinical presentation. We.

Antiproliferative Evaluation of Isofuranodiene on Breast and Prostate Cancer Cell Lines

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Michela Buccioni

2014-01-01

Full Text Available The anticancer activity of isofuranodiene, extracted from Smyrnium olusatrum, was evaluated in human breast adenocarcinomas MDA-MB 231 and BT 474, and Caucasian prostate adenocarcinoma PC 3 cell lines by MTS assay. MTS assay showed a dose-dependent growth inhibition in the tumor cell lines after isofuranodiene treatment. The best antiproliferative activity of the isofuranodiene was found on PC 3 cells with an IC50 value of 29 μM, which was slightly less than the inhibition against the two breast adenocarcinoma cell lines with IC50 values of 59 and 55 μM on MDA-MB 231 and BT 474, respectively. Hoechst 33258 assay was performed in order to study the growth inhibition mechanism in prostate cancer cell line; the results indicate that isofuranodiene induces apoptosis. Overall, the understudy compound has a good anticancer activity especially towards the PC 3. On the contrary, it is less active on Chinese hamster ovary cells (CHO and human embryonic kidney (HEK 293 appearing as a good candidate as a potential natural anticancer drug with low side effects.

Male breast cancer is rare: an initial presentation may be as an abscess

OpenAIRE

Ventham, N T; Hussien, M I

2010-01-01

Breast cancer in men is rare. Breast cancer presenting initially as an abscess has been described only a handful of times in the literature. We present the first described case of invasive adenocarcinoma presenting as an abscess in a man. An 80-year-old diabetic man presented with symptoms typical of a breast abscess. The abscess failed to respond to percutaneous therapy and excision of breast abscess was performed. Histology revealed an invasive carcinoma. He went on to have a mastectomy. Hi...

NFκBP65 transcription factor modulates resistance to doxorubicin through ABC transporters in breast cancer.

Science.gov (United States)

Velaei, Kobra; Samadi, Nasser; Soltani, Sina; Barazvan, Balal; Soleimani Rad, Jafar

2017-07-01

Shedding light on chemoresistance biology of breast cancer could contribute to enhance the clinical outcome. Intrinsic or acquired resistance to chemotherapy is a major problem in breast cancer treatment. The NFκB pathway by siRNAP65 and JSH-23 as a translocational inhibitor of NFκBP65 in the doxorubicin-resistant MCF-7 (MCF-7/Dox) and MCF-7 cells was blocked. Then, the ABC transporter expression and function were assessed by real-time qRT-PCR and flow cytometry, respectively. Induction of apoptosis was evaluated after inhibition of the NFΚB pathway as well. Our study underlined the upregulation of NFκBP65 and anti-apoptotic Bcl-2 and downregulation of pro-apoptotic Bax in the MCF-7/Dox cells compared with control MCF-7 cells. Here, we showed that interplay between nuclear factor kappa B P65 (NFkBP65) as a transcriptional regulator and ABC transporters in the MCF-7/Dox cancer cells. We found that inhibition of the elevated expression of NFκBP65 in the resistant breast cancer, whether translocational inhibition or silencing by siRNA, decreased the expression and function of MDR1 and MRP1 efflux pumps. Furthermore, the blockade of NFκBP65 promoted apoptosis via modulating Bcl-2 and BAX expression. After inhibition of the NFκBP65 signaling pathway, elevated baseline expression of survival Bcl-2 gene in the resistant breast cells significantly decreased. Suppression of the NFκB pathway has a profound dual impact on promoting the intrinsic apoptotic pathway and reducing ABC transporter function and expression, which are some of the chemoresistance features. It was speculated that the NFκB pathway directly acts on doxorubicin-induced MDR1 and MRP1 expression in MCF-7/Dox cells.

A Novel Docetaxel-Loaded Poly (ɛ-Caprolactone)/Pluronic F68 Nanoparticle Overcoming Multidrug Resistance for Breast Cancer Treatment

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Mei, Lin; Zhang, Yangqing; Zheng, Yi; Tian, Ge; Song, Cunxian; Yang, Dongye; Chen, Hongli; Sun, Hongfan; Tian, Yan; Liu, Kexin; Li, Zhen; Huang, Laiqiang

2009-12-01

Multidrug resistance (MDR) in tumor cells is a significant obstacle to the success of chemotherapy in many cancers. The purpose of this research is to test the possibility of docetaxel-loaded poly (ɛ-caprolactone)/Pluronic F68 (PCL/Pluronic F68) nanoparticles to overcome MDR in docetaxel-resistance human breast cancer cell line. Docetaxel-loaded nanoparticles were prepared by modified solvent displacement method using commercial PCL and self-synthesized PCL/Pluronic F68, respectively. PCL/Pluronic F68 nanoparticles were found to be of spherical shape with a rough and porous surface. The nanoparticles had an average size of around 200 nm with a narrow size distribution. The in vitro drug release profile of both nanoparticle formulations showed a biphasic release pattern. There was an increased level of uptake of PCL/Pluronic F68 nanoparticles in docetaxel-resistance human breast cancer cell line, MCF-7 TAX30, when compared with PCL nanoparticles. The cytotoxicity of PCL nanoparticles was higher than commercial Taxotere® in the MCF-7 TAX30 cell culture, but the differences were not significant ( p > 0.05). However, the PCL/Pluronic F68 nanoparticles achieved significantly higher level of cytotoxicity than both of PCL nanoparticles and Taxotere® ( p < 0.05), indicating docetaxel-loaded PCL/Pluronic F68 nanoparticles could overcome multidrug resistance in human breast cancer cells and therefore have considerable potential for treatment of breast cancer.

The frequency and clinical impact of HER2 alterations in lung adenocarcinoma.

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Eun Kyung Kim

Full Text Available Human epidermal growth factor receptor 2 (HER2 or ErbB2 can be overexpressed, amplified and/or mutated in malignant tumors, and is a candidate for therapeutic targeting. However, molecular associations and clinical significances of these alterations were controversial in lung cancer. In this study, we investigated the frequency and clinicopathological significance of HER2 dysregulation in patients with lung adenocarcinoma. HER2 protein overexpression, gene amplification, and gene mutation were evaluated by immunohistochemistry (IHC, silver in situ hybridization, and direct sequencing, respectively. The H-scoring method and American Society of Clinical Oncology/College of American Pathologists breast cancer guidelines were used to interpret IHC results. Genetic analyses of EGFR and KRAS mutations, and of ALK and ROS1 rearrangements, were also performed. Of the 321 adenocarcinoma patients identified, HER2 overexpression (H-score ≥200 and gene amplification were found in 6 (1.9% and 46 (14.3%, respectively. HER2 overexpression was correlated with papillary predominant histology; furthermore, it indicated poor overall survival and was an independent prognostic factor. HER2 amplification was associated with pleural invasion and showed a tendency towards shorter overall and disease-free survival. High-level gene amplification (HER2/CEP17 ratio ≥5 or copy number ≥10 was a poor prognostic factor for disease-free survival. HER2 mutations were detected in 6.7% (7 of 104 of driver oncogene-negative adenocarcinomas. Our study suggests that HER2 overexpression or amplification is a poor prognostic factor in lung adenocarcinoma, although the frequency of such events is low. Since molecular targeted agents are being tested in clinical trials, awareness of the specific HER2 status can influence the prognostic stratification and treatment of patients with molecularly defined subsets of lung adenocarcinoma.

[Methicillin-resistant Staphylococcus aureus (MRSA) isolation in breast abscesses in a Public Maternity].

Science.gov (United States)

Boccaccio, Cristina; Verdaguer Babic, Virginia; Botto, Liliana; Cervetto, María M; Cetani, Silvia; Paladino, Silvina; Conti, Roxana; Lanzillota, Antonio; Herrera, Rosa; Amarante, Dora

2014-01-01

Mastitis and breast abscess in lactating women are risk factors for early breastfeeding cessation. This pathology is included in the group of skin and soft tissue infections. A descriptive study was performed with an advanced outlook. As of January 2007 through December 2011 a total of 137 breast abscesses were treated in our institution. We analyzed incidence, parity, postpartum days, risk factors, microbiological isolation and the adequacy of initial antibiotic treatment. In that period we observed a steady and significant increase in breast abscesses. Incidence from 0.19 to 0.84% in lactating women 2007 vs. 2011 p = 0.0001 IC 95% (-0.009; 0.003), 70.6% of them primiparous and a mean interval from delivery to breast abscess of 41.9 ± 35.8 days. The most frequent risk factors were sore nipples and breast engorgement. Staphylococcus aureus was isolated in 82.3 to 95.0%. Methicillin resistance was higher than 60%. These strains were susceptible to erythromycin, clindamycin, gentamicin, rifampicin, ciprofloxacin and trimethoprim-sulfamethoxazol. All the cases were surgically drained; the initial empirical treatment was inadequate in 60% of them, 90% of patients could maintain breast feeding after the procedure. these data emphasize the need to prevent risk factors associated to breast abscesses: sore nipples and breast engorgement. In order to determine the adequate antibiotic treatment, bacteriological studies are required at every collection because SAMR prevalence varies according to diverse populations and geographic location.

MicroRNA expression profiles associated with pancreatic adenocarcinoma and ampullary adenocarcinoma

DEFF Research Database (Denmark)

Schultz, Nicolai A; Werner, Jens; Willenbrock, Hanni

2012-01-01

MicroRNAs have potential as diagnostic cancer biomarkers. The aim of this study was (1) to define microRNA expression patterns in formalin-fixed parafin-embedded tissue from pancreatic ductal adenocarcinoma, ampullary adenocarcinoma, normal pancreas and chronic pancreatitis without using micro-di...

Immunohistochemical profiles of claudin-3 in primary and metastatic prostatic adenocarcinoma

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Becich Michael J

2011-01-01

Full Text Available Abstract Background Claudins are integral membrane proteins that are involved in forming cellular tight junctions. One member of the claudin family, claudin-3, has been shown to be overexpressed in breast, ovarian, and pancreatic cancer. Here we use immunohistochemistry to evaluate its expression in benign prostatic hyperplasia (BPH, prostatic intraepithelial neoplasia (PIN, normal tissue adjacent to prostatic adenocarcinoma (NAC, primary prostatic adenocarcinoma (PCa, and metastatic prostatic adenocarcinoma (Mets. Methods Tissue microarrays were immunohistochemically stained for claudin-3, with the staining intensities subsequently quantified and statistically analyzed using a one-way ANOVA with subsequent Tukey tests for multiple comparisons or a nonparametric equivalent. Fifty-three cases of NAC, 17 cases of BPH, 35 cases of PIN, 107 cases of PCa, and 55 cases of Mets were analyzed in the microarrays. Results PCa and Mets had the highest absolute staining for claudin-3. Both had significantly higher staining than BPH (p Conclusions To our knowledge, this represents one of the first studies comparing the immunohistochemical profiles of claudin-3 in PCa and NAC to specimens of PIN, BPH, and Mets. These findings provide further evidence that claudin-3 may serve as an important biomarker for prostate cancer, both primary and metastatic, but does not provide evidence that claudin-3 can be used to predict risk of metastasis.

The antipsychotic drug chlorpromazine enhances the cytotoxic effect of tamoxifen in tamoxifen-sensitive and tamoxifen-resistant human breast cancer cells

DEFF Research Database (Denmark)

Yde, Christina Westmose; Clausen, Mathias Porsmose; Bennetzen, Martin

2009-01-01

, the compound is now also recognized as a multitargeting drug with diverse potential applications, for example, it has antiproliferative properties and it can reverse resistance toward antibiotics in bacteria. Furthermore, chlorpromazine can reverse multidrug resistance caused by overexpression of P......Tamoxifen resistance is a major clinical problem in the treatment of estrogen receptor a-positive breast tumors. It is, at present, unclear what exactly causes tamoxifen resistance. For decades, chlorpromazine has been used for treating psychotic diseases, such as schizophrenia. However......-sensitive breast cancer cell line, MCF-7, and in a tamoxifen-resistant cell line, established from the MCF-7 cells. Tamoxifen-sensitive and tamoxifen-resistant cells were killed equally well by combined treatment with chlorpromazine and tamoxifen. This synergistic effect could be prevented by addition of estrogen...

Expression of p53 protein in Barrett’s adenocarcinoma and adenocarcinoma of the gastric cardia and antrum

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Jovanović Ivan

2005-01-01

Full Text Available Background/Aim. Most studies of esophageal and gastric adenocarcinomas have shown a very high rate of p53 gene mutation and/or protein overexpression, but the influence of the tumor site upon the frequency of p53 protein expression has not been evaluated (gastroesophageal junction, Barret's esophagus, and antrum. The aim of our study was to analyze the correlation between the selected clinico-pthological parameters, and p53 protein overexpression in regards to the particular tumor location. Methods. The material comprised 66 surgical specimens; 10 were Barrett’s carcinomas, 25 adenocarcinomas of the gastric cardia (type II adenocarcinoma of the esophagogastric junction - EGJ, and 31 adenocarcinomas of the antrum. Immunostaining for p53 protein was performed on formalin-fixed, paraffin-embedded tissue sections, using the alkaline phosphatase - antialkaline phosphatase (APAAP method. The cases were considered positive for p53 if at least 5% of the tumor cells expressed this protein by immunostaining. Results. There was no significant difference observed between the studied groups in regards to age, sex, Lauren’s classification and tumor differentiation. There was, however, a significant difference observed in the depth of tumor invasion between Barrrett’s adenocarcinoma and adenocarcinoma of the cardia compared with the adenocarcinoma of the antrum. Namely, at the time of surgery, both Barrett’s adenocarcinomas and adenocarcinomas of the cardia, were significantly more advanced comparing with the adenocarcinomas of the antrum. Overexpression of p53 was found in 40% (4/10 of Barrett’s adenocarcinomas, 72% (18/25 of adenocarcinoma of the cardia and 65% (20/31 of adenocarcinoma of the antrum. No significant differences in p53 expression in relation to sex, type (Lauren of tumor, depth of invasion, lymph node involvement, or tumor differentiation were observed in any of the analyzed groups of tumors. Patients with more advanced Barrett�

MicroRNA-3646 Contributes to Docetaxel Resistance in Human Breast Cancer Cells by GSK-3?/?-Catenin Signaling Pathway

OpenAIRE

Zhang, Xiaohui; Zhong, Shanliang; Xu, Yong; Yu, Dandan; Ma, Tengfei; Chen, Lin; Zhao, Yang; Chen, Xiu; Yang, Sujin; Wu, Yueqin; Tang, Jinhai; Zhao, Jianhua

2016-01-01

Acquisition of resistance to docetaxel (Doc) is one of the most important problems in treatment of breast cancer patients, but the underlying mechanisms are still not fully understood. In present study, Doc-resistant MDA-MB-231 and MCF-7 breast cancer cell lines (MDA-MB-231/Doc and MCF-7/Doc) were successfully established in vitro by gradually increasing Doc concentration on the basis of parental MDA-MB-231 and MCF-7 cell lines (MDA-MB-231/S and MCF-7/S). The potential miRNAs relevant to the ...

Cooverexpression of EpCAM and c-myc genes in malignant breast

Indian Academy of Sciences (India)

oncogene, affects progression, treatment, and diagnosis of many adenocarcinomas. C-myc has been shown to be a downstream target of EpCAM and is also one of the most important proto-oncogenes routinely overexpressed in breast cancer.

Radiation-induced circumscribed superficial morphea after brachytherapy for endometrial adenocarcinoma

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Apoorva Trivedi, BS

2017-12-01

Full Text Available Radiation-induced morphea (RIM is a rare and underrecognized complication of radiation therapy that most commonly occurs in women after treatment for breast cancer. Although not fully understood, RIM is hypothesized to arise from an increase in cytokines that stimulate collagen production and extracellular matrix formation. Most documented cases of RIM occur 1 year after radiation therapy and are localized to areas that were treated for breast cancer. We report on a case of a female patient with stage IB endometrial adenocarcinoma who was treated with 24 Gray of adjuvant brachytherapy. The patient developed a diffuse morpheaform, pruritic eruption only at distant sites from the brachytherapy treatment field. Although treatment for RIM is generally unsatisfactory, our patient experienced improvement in the pruritus and a regression of the lesions while applying topical 0.1% tacrolimus ointment and 0.1% triamcinolone creme. An early diagnosis of RIM can prevent extensive workup, guide treatment, and improve quality of life for patients. Keywords: radiation-induced morphea, postirradiation morphea

Radiographic characteristics of male breast cancer

International Nuclear Information System (INIS)

Kim, Tae Hoon; Kim, Ji Hyung; Oh, Ki Keun; Park, Chang Yun; Kook, Shin Ho

1995-01-01

Our objective was to evaluate mammographic findings of breast cancer in men. This study includes 9 man with breast cancer diagnosed pathologically by radical mastectomy. Clinical and pathologic data were obtained by review of patients medical record. Mammograms were analyzed retrospectively. Of the 9 patients, eight had masses with spiculated margin or schirrous pattern with irregular margin. One patient had no specific evidence of breast cancer mammographically. Microcalcifications were seen in three patients, these calcifications were irregular in shape and were clustered. Of the 8 cases, four patients had the masses at the right breast, four at the left breast. Locations of breast cancer were subareolar (n=4) and were eccentric (n=4) from the nipple. The most common location was the upper outer quadrant. On histologic evaluation, 7 cases were infiltrating ductal carcinomas, one case was mucinous adenocarcinoma, and the remainder was proved as combined form of intraductal and infiltrating ductal carcinoma. Axillary lymph node metastasis were found in 4 cases. Mammographic findings of male breast carcinoma were that of subareolar or eccentrically located mass. Calcifications were same to the patterns of calcification as female breast cancer

Breast carcinoma - diagnostics, therapy and resistance

International Nuclear Information System (INIS)

Kuzma-Richert, A.; Saczko, J.; Kulbacka, J.

2011-01-01

Breast cancer is a pathologically and clinically heterogeneous disease with a variable prognosis. This type of cancer is the most common female cancer in Poland. According to data collected up to 2004, approximately 12,000 new breast cancer cases per year were diagnosed in women in Poland, and approximately 5000 patients died yearly of breast cancer. The authors present the histopathology, diagnostics, classification and general types of systemic therapy of breast cancer. (authors)

Mir-1307 regulates cisplatin resistance by targeting Mdm4 in breast cancer expressing wild type P53.

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Wang, Xinyan; Zhu, Jianwei

2018-04-26

Many chemotherapy regimens are used to treat breast cancer; however, breast cancer cells often develop drug resistance that usually leads to relapse and poor prognosis. MicroRNAs (miRNAs) are short non-coding RNA molecules that post-transcriptionally regulate gene expression and play crucial roles in diverse biological processes, such as development, differentiation, apoptosis, and proliferation. We investigated the roles of miRNAs in the development of drug resistance in human breast cancer cells. MiRNA expression was detected in human breast cancer cell lines MCF-7 and MDA-MB-468 via real time PCR; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide, cell viability, colony formation, and luciferase reporter gene assays; Western blot; and immunohistochemistry. MiR-1307 was downregulated while MDM4 was upregulated in MCF-7/cisplatin (CDDP) and MDA-MB-468/CDDP cells compared with parental MCF-7 and MDA-MB-468 cells. in vitro drug sensitivity assay demonstrated that overexpression of miR-1307 sensitized MCF-7/CDDP cells to CDDP. Luciferase activity assay with a reporter containing sequences from the 3' untranslated region of Mdm4 in MCF-7/CDDP cells suggested that Mdm4 was the direct target gene of miR-1307. Ectopic miR-1307 expression reduced the MDM4 protein level and sensitized MCF-7/CDDP cells to CDDP-induced apoptosis. Our findings suggest, for the first time, that miR-1307 could play a role in the development of CDDP resistance in breast cancer, at least in part by modulating apoptosis by targeting Mdm4. © 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Differentially expressed proteins in human MCF-7 breast cancer cells sensitive and resistant to paclitaxel

Czech Academy of Sciences Publication Activity Database

Pavlíková, N.; Bartoňová, I.; Balušíková, K.; Kopperová, D.; Halada, Petr; Kovář, J.

2015-01-01

Roč. 333, č. 1 (2015), s. 1-10 ISSN 0014-4827 Institutional support: RVO:61388971 Keywords : Breast cancer * Taxane resistance * 2-D electrophoresis Subject RIV: CE - Biochemistry Impact factor: 3.378, year: 2015

Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells.

Science.gov (United States)

Cheng, Ran; Liu, Ya-Jing; Cui, Jun-Wei; Yang, Man; Liu, Xiao-Ling; Li, Peng; Wang, Zhan; Zhu, Li-Zhang; Lu, Si-Yi; Zou, Li; Wu, Xiao-Qin; Li, Yu-Xia; Zhou, You; Fang, Zheng-Yu; Wei, Wei

2017-05-02

Tamoxifen is still the most commonly used endocrine therapy drug for estrogen receptor (ER)-positive breast cancer patients and has an excellent outcome, but tamoxifen resistance remains a great impediment to successful treatment. Recent studies have prompted an anti-tumor effect of aspirin. Here, we demonstrated that aspirin not only inhibits the growth of ER-positive breast cancer cell line MCF-7, especially when combined with tamoxifen, but also has a potential function to overcome tamoxifen resistance in MCF-7/TAM. Aspirin combined with tamoxifen can down regulate cyclinD1 and block cell cycle in G0/G1 phase. Besides, tamoxifen alone represses c-myc, progesterone receptor (PR) and cyclinD1 in MCF-7 cell line but not in MCF-7/TAM, while aspirin combined with tamoxifen can inhibit the expression of these proteins in the resistant cell line. When knocking down c-myc in MCF-7/TAM, cells become more sensitive to tamoxifen, cell cycle is blocked as well, indicating that aspirin can regulate c-myc and cyclinD1 proteins to overcome tamoxifen resistance. Our study discovered a novel role of aspirin based on its anti-tumor effect, and put forward some kinds of possible mechanisms of tamoxifen resistance in ER-positive breast cancer cells, providing a new strategy for the treatment of ER-positive breast carcinoma.

A case of chemotherapy-resistant intestinal-type sinonasal adenocarcinoma treated by gamma knife radiosurgery

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Andres M. Alvarez-Pinzon, M.D., Ph.D.

2017-12-01

Full Text Available Intestinal type sinonasal adenocarcinomas are a rare malignancy of the nasal cavity and paranasal sinuses ascending in the nasal cavity are particularly unusual. We report an infrequent case of an Intestinal sinonasal adenocarcinoma from the left lateral nasal wall. A 60-year-old Hispanic male complained of complete progressive nasal obstruction and epistaxis for 8 months. A nasal endoscopic exam displayed a prominent enlargement, which remained in connection with the anterior part of left inferior turbinate. Computed tomography revealed a medium-defined, soft tissue dense lesion in the left anterior nasal cavity. Mass biopsy histology confirmed a low grade differentiate Intestinal type sinonasal adenocarcinomas. The patient underwent 8 cycles of chemotherapy including paclitaxel, platinol and fluorouracil. According to the medical records, the patient responded well to the chemotherapy treatment until about six cycles. When a follow up CT scan showed tumor growth, the patient was placed on Doxorubicin but developed toxicity. The main treatment modality is surgical resection with histological clear margins but concerning the low differentiation, low response of chemotherapy, and surgical risk we offered an option with gamma knife radiosurgery. In our case, the patient demonstrated satisfactory relief of symptoms and reported the ability to breathe through the nose. 80% of tumor resolution was observed in 1 month following the CT scan.

Knockdown of UbcH10 Enhances the Chemosensitivity of Dual Drug Resistant Breast Cancer Cells to Epirubicin and Docetaxel

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Cheng Wang

2015-03-01

Full Text Available Breast cancer is one of the most common and lethal cancers in women. As a hub gene involved in a diversity of tumors, the ubiquitin-conjugating enzyme H10 (UbcH10, may also play some roles in the genesis and development of breast cancer. In the current study, we found that the expression of UbcH10 was up-regulated in some breast cancer tissues and five cell lines. We established a dual drug resistant cell line MCF-7/EPB (epirubicin/TXT (docetaxel and a lentiviral system expressing UbcH10 shRNA to investigate the effects of UbcH10 knockdown on the chemosensitivity of MCF-7/EPB/TXT cells to epirubicin and docetaxel. The knockdown of UbcH10 inhibited the proliferation of both MCF-7 and MCF-7/EPB/TXT cells, due to the G1 phase arrest in cell cycle. Furthermore, UbcH10 knockdown increased the sensitivity of MCF-7/EPB/TXT cells to epirubicin and docetaxel and promoted the apoptosis induced by these two drugs. Protein detection showed that, in addition to inhibiting the expression of Ki67 and cyclin D1, UbcH10 RNAi also impaired the increased BCL-2 and MDR-1 expression levels in MCF-7/EPB/TXT cells, which may contribute to abating the drug resistance in the breast cancer cells. Our research in the current study demonstrated that up-regulation of UbcH10 was involved in breast cancer and its knockdown can inhibit the growth of cancer cells and increase the chemosensitivity of the dual drug resistant breast cancer cells to epirubicin and docetaxel, suggesting that UbcH10 may be a promising target for the therapy of breast cancer.

Phosphoproteome and Transcriptome of RA-Responsive and RA-Resistant Breast Cancer Cell Lines.

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Marilyn Carrier

Full Text Available Retinoic acid (RA, the main active vitamin A metabolite, controls multiple biological processes such as cell proliferation and differentiation through genomic programs and kinase cascades activation. Due to these properties, RA has proven anti-cancer capacity. Several breast cancer cells respond to the antiproliferative effects of RA, while others are RA-resistant. However, the overall signaling and transcriptional pathways that are altered in such cells have not been elucidated. Here, in a large-scale analysis of the phosphoproteins and in a genome-wide analysis of the RA-regulated genes, we compared two human breast cancer cell lines, a RA-responsive one, the MCF7 cell line, and a RA-resistant one, the BT474 cell line, which depicts several alterations of the "kinome". Using high-resolution nano-LC-LTQ-Orbitrap mass spectrometry associated to phosphopeptide enrichment, we found that several proteins involved in signaling and in transcription, are differentially phosphorylated before and after RA addition. The paradigm of these proteins is the RA receptor α (RARα, which was phosphorylated in MCF7 cells but not in BT474 cells after RA addition. The panel of the RA-regulated genes was also different. Overall our results indicate that RA resistance might correlate with the deregulation of the phosphoproteome with consequences on gene expression.

The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer

International Nuclear Information System (INIS)

Loh, Yan Ni; Hedditch, Ellen L; Baker, Laura A; Jary, Eve; Ward, Robyn L; Ford, Caroline E

2013-01-01

Acquired resistance to Tamoxifen remains a critical problem in breast cancer patient treatment, yet the underlying causes of resistance have not been fully elucidated. Abberations in the Wnt signalling pathway have been linked to many human cancers, including breast cancer, and appear to be associated with more metastatic and aggressive types of cancer. Here, our aim was to investigate if this key pathway was involved in acquired Tamoxifen resistance, and could be targeted therapeutically. An in vitro model of acquired Tamoxifen resistance (named TamR) was generated by growing the estrogen receptor alpha (ER) positive MCF7 breast cancer cell line in increasing concentrations of Tamoxifen (up to 5 uM). Alterations in the Wnt signalling pathway and epithelial to mesenchymal transition (EMT) in response to Tamoxifen and treatment with the Wnt inhibitor, IWP-2 were measured via quantitative RT-PCR (qPCR) and TOP/FOP Wnt reporter assays. Resistance to Tamoxifen, and effects of IWP-2 treatment were determined by MTT proliferation assays. TamR cells exhibited increased Wnt signalling as measured via the TOP/FOP Wnt luciferase reporter assays. Genes associated with both the β-catenin dependent (AXIN2, MYC, CSNK1A1) and independent arms (ROR2, JUN), as well as general Wnt secretion (PORCN) of the Wnt signalling pathway were upregulated in the TamR cells compared to the parental MCF7 cell line. Treatment of the TamR cell line with human recombinant Wnt3a (rWnt3a) further increased the resistance of both MCF7 and TamR cells to the anti-proliferative effects of Tamoxifen treatment. TamR cells demonstrated increased expression of EMT markers (VIM, TWIST1, SNAI2) and decreased CDH1, which may contribute to their resistance to Tamoxifen. Treatment with the Wnt inhibitor, IWP-2 inhibited cell proliferation and markers of EMT. These data support the role of the Wnt signalling pathway in acquired resistance to Tamoxifen. Further research into the mechanism by which activated Wnt

A gene expression signature of retinoblastoma loss-of-function is a predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients with ER positive early breast cancer.

Science.gov (United States)

Malorni, Luca; Piazza, Silvano; Ciani, Yari; Guarducci, Cristina; Bonechi, Martina; Biagioni, Chiara; Hart, Christopher D; Verardo, Roberto; Di Leo, Angelo; Migliaccio, Ilenia

2016-09-13

Palbociclib is a CDK4/6 inhibitor that received FDA approval for treatment of hormone receptor positive (HR+) HER2 negative (HER2neg) advanced breast cancer. To better personalize patients treatment it is critical to identify subgroups that would mostly benefit from it. We hypothesize that complex alterations of the Retinoblastoma (Rb) pathway might be implicated in resistance to CDK4/6 inhibitors and aim to investigate whether signatures of Rb loss-of-function would identify breast cancer cell lines resistant to palbociclib. We established a gene expression signature of Rb loss-of-function (RBsig) by identifying genes correlated with E2F1 and E2F2 expression in breast cancers within The Cancer Genome Atlas. We assessed the RBsig prognostic role in the METABRIC and in a comprehensive breast cancer meta-dataset. Finally, we analyzed whether RBsig would discriminate palbociclib-sensitive and -resistant breast cancer cells in a large RNA sequencing-based dataset. The RBsig was associated with RB1 genetic status in all tumors (p <7e-32) and in luminal or basal subtypes (p < 7e-11 and p < 0.002, respectively). The RBsig was prognostic in the METABRIC dataset (discovery: HR = 1.93 [1.5-2.4] p = 1.4e-08; validation: HR = 2.01 [1.6-2.5] p = 1.3e-09). Untreated and endocrine treated patients with estrogen receptor positive breast cancer expressing high RBsig had significantly worse recurrence free survival compared to those with low RBsig (HR = 2.37 [1.8 - 3.2] p = 1.87e-08 and HR = 2.62 [1.9- 3.5] p = 8.6e-11, respectively). The RBsig was able to identify palbociclib resistant and sensitive breast cancer cells (ROC AUC = 0,7778). Signatures of RB loss might be helpful in personalizing treatment of patients with HR+/HER2neg breast cancer. Further validation in patients receiving palbociclib is warranted.

Primary breast cancer imaging with technetium-99m sestamibi and its relation with P-glycoprotein overexpression

Energy Technology Data Exchange (ETDEWEB)

Moretti, J.L. [Medicine Nucleaire, CHU Bobigny, Paris (France); Azaloux, H. [Medicine Nucleaire Oncologie, Hopital P. Zobda Quitman, Fort de France (France); Boisseron, D. [Medicine Nucleaire Oncologie, Hopital P. Zobda Quitman, Fort de France (France); Kouyoumdjian, J.C. [Service de Biochemie, Hopital Henri Mondor, Creteil (France); Vilcoq, J. [Service de Cancerologie-Radiotherapie, Inst. Curie, Paris (France)

1996-08-01

The aim of this preliminary study was to evaluate retrospectively sestamibi scintigraphy in relation to the presence of the 170-kDa P-glycoprotein (Pgp), which represents an expression of multidrug resistance in patients with primary breast cancer. Fifteen women (age range 37-76 years) were referred for technetium-99m sestamibi scintigraphy because of suspicious breast lesions detected by mammography and ultrasonography, and subsequently assessed by fine-needle aspiration. Scintigraphy was performed 30 min following the injection of 500 MBq {sup 99m}Tc-sestamibi. Three planar anterior and oblique images were obtained with the patient in the supine position. Excised tumours were assessed for cytosolic CA 15.3, oestrogen (OR) and progesterone (PR) receptors and c-erb B2 neu oncogene. Pathology revealed that only 13 of the 15 patients had malignant tumours. The two benign tumours were sestamibi-negative and Pgp-positive. Sestamibi scintigraphy was positive in 10 of the 13 malignant lesions (including nine of ten infiltrating ductal carcinomas). Two of the three lesions with false-negative scintigraphy were Pgp-negative; in one of these cases histology revealed an invasive lobular carcinoma and in the other, mucinous adenocarcinoma. The third false-negative lesion was a Pgp-positive infiltrating ductal carcinoma which was c-erb B2 neu-negative but CA 15.3-, OR- and PR-positive. This preliminary study confirms that the resistance to chemotherapy which may occur in patients with primary breast cancer can be a cause of negative sestamibi scintigraphy. (orig.)

SPIN1, negatively regulated by miR-148/152, enhances Adriamycin resistance via upregulating drug metabolizing enzymes and transporter in breast cancer.

Science.gov (United States)

Chen, Xu; Wang, Ya-Wen; Gao, Peng

2018-05-09

Spindlin1 (SPIN1), a protein highly expressed in several human cancers, has been correlated with tumorigenesis and development. Alterations of drug metabolizing enzymes and drug transporters are major determinants of chemoresistance in tumor cells. However, whether the metabolizing enzymes and transporters are under the control of SPIN1 in breast cancer chemoresistance has not yet been defined. SPIN1 expression in breast cancer cells and tissues was detected by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Chemosensitivity assays in vitro and in vivo were performed to determine the effect of SPIN1 on Adriamycin resistance. Downstream effectors of SPIN1 were screened by microarray and confirmed by qRT-PCR and Western blot. Luciferase assay and Western blot were used to identify miRNAs regulating SPIN1. We showed that SPIN1 was significantly elevated in drug-resistant breast cancer cell lines and tissues, compared with the chemosensitive ones. SPIN1 enhanced Adriamycin resistance of breast cancer cells in vitro, and downregulation of SPIN1 by miRNA could decrease Adriamycin resistance in vivo. Mechanistically, drug metabolizing enzymes and transporter CYP2C8, UGT2B4, UGT2B17 and ABCB4 were proven to be downstream effectors of SPIN1. Notably, SPIN1 was identified as a direct target of the miR-148/152 family (miR-148a-3p, miR-148b-3p and miR-152-3p). As expected, miR-148a-3p, miR-148b-3p or miR-152-3p could increase Adriamycin sensitivity in breast cancer cells in vitro. Moreover, high expression of SPIN1 or low expression of the miR-148/152 family predicted poorer survival in breast cancer patients. Our results establish that SPIN1, negatively regulated by the miR-148/152 family, enhances Adriamycin resistance in breast cancer via upregulating the expression of drug metabolizing enzymes and drug transporter.

EGFR and KRAS mutation coexistence in lung adenocarcinomas

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Vitor Manuel Leitão de Sousa

2015-04-01

Full Text Available Lung cancer is one of the most common causes of cancer deaths. The development of EGFR targeted therapies, including monoclonal antibodies and tyrosine kinase inhibitors have generated an interest in the molecular characterization of these tumours. KRAS mutations are associated with resistance to EGFR TKIs. EGFR and KRAS mutations have been considered as mutually exclusive. This paper presents three bronchial-pulmonary carcinomas, two adenocarcinomas and one pleomorphic sarcomatoid carcinoma, harboring EGFR and KRAS mutations. Case 1 corresponded to an adenocarcinoma with EGFR exon 21 mutation (L858R and KRAS codon 12 point mutation (G12V; case 2, a  mucinous adenocarcinoma expressed coexistence of EGFR exon 21 mutation (L858R and KRAS codon 12 point mutation (G12V; and case 3 a sarcomatoid carcinoma with EGFR exon 19 deletion – del 9bp and KRAS codon 12 point mutation (G12C - cysteine. Based on our experience and on the literature, we conclude that EGFR and KRAS mutations can indeed coexist in the same bronchial-pulmonary carcinoma, either in the same histological type or in different patterns. The biological implications of this coexistence are still poorly understood mainly because these cases are not frequent or currently searched. It is therefore necessary to study larger series of cases with the two mutations to better understand the biological, clinical and therapeutic implications.

HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

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Babak Nami

2017-04-01

Full Text Available HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60% of patients with HER2+ breast tumor develop de novo resistance to trastuzumab, partially due to the loss of expression of HER2 extracellular domain on their tumor cells. This is due to shedding/cleavage of HER2 by metalloproteinases (ADAMs and MMPs. HER2 shedding results in the accumulation of intracellular carboxyl-terminal HER2 (p95HER2, which is a common phenomenon in trastuzumab-resistant tumors and is suggested as a predictive marker for trastuzumab resistance. Up-regulation of the metalloproteinases is a poor prognosis factor and is commonly seen in mesenchymal-like cancer stem cells that are risen during epithelial to mesenchymal transition (EMT of tumor cells. HER2 cleavage during EMT can explain why secondary metastatic tumors with high percentage of mesenchymal-like cancer stem cells are mostly resistant to trastuzumab but still sensitive to lapatinib. Importantly, many studies report HER2 interaction with oncogenic/stemness signaling pathways including TGF-β/Smad, Wnt/β-catenin, Notch, JAK/STAT and Hedgehog. HER2 overexpression promotes EMT and the emergence of cancer stem cell properties in BC. Increased expression and activation of metalloproteinases during EMT leads to proteolytic cleavage and shedding of HER2 receptor, which downregulates HER2 extracellular domain and eventually increases trastuzumab resistance. Here, we review the hypothesis that a negative feedback loop between HER2 and stemness signaling drives resistance of BC to trastuzumab.

C-Cbl reverses HER2-mediated tamoxifen resistance in human breast cancer cells.

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Li, Wei; Xu, Ling; Che, Xiaofang; Li, Haizhou; Zhang, Ye; Song, Na; Wen, Ti; Hou, Kezuo; Yang, Yi; Zhou, Lu; Xin, Xing; Xu, Lu; Zeng, Xue; Shi, Sha; Liu, Yunpeng; Qu, Xiujuan; Teng, Yuee

2018-05-02

Tamoxifen is a frontline therapy for estrogen receptor (ER)-positive breast cancer in premenopausal women. However, many patients develop resistance to tamoxifen, and the mechanism underlying tamoxifen resistance is not well understood. Here we examined whether ER-c-Src-HER2 complex formation is involved in tamoxifen resistance. MTT and colony formation assays were used to measure cell viability and proliferation. Western blot was used to detect protein expression and protein complex formations were detected by immunoprecipitation and immunofluorescence. SiRNA was used to examine the function of HER2 in of BT474 cells. An in vivo xenograft animal model was established to examine the role of c-Cbl in tumor growth. MTT and colony formation assay showed that BT474 cells are resistant to tamoxifen and T47D cells are sensitive to tamoxifen. Immunoprecipitation experiments revealed ER-c-Src-HER2 complex formation in BT474 cells but not in T47D cells. However, ER-c-Src-HER2 complex formation was detected after overexpressing HER2 in T47D cells and these cells were more resistant to tamoxifen. HER2 knockdown by siRNA in BT474 cells reduced ER-c-Src-HER2 complex formation and reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was also disrupted and tamoxifen resistance was reversed in BT474 cells by the c-Src inhibitor PP2 and HER2 antibody trastuzumab. Nystatin, a lipid raft inhibitor, reduced ER-c-Src-HER2 complex formation and partially reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was disrupted by overexpression of c-Cbl but not by the c-Cbl ubiquitin ligase mutant. In addition, c-Cbl could reverse tamoxifen resistance in BT474 cells, but the ubiquitin ligase mutant had no effect. The effect of c-Cbl was validated in BT474 tumor-bearing nude mice in vivo. Immunofluorescence also revealed ER-c-Src-HER2 complex formation was reduced in tumor tissues of nude mice with c-Cbl overexpression. Our results suggested that c-Cbl can reverse tamoxifen

Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity

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Bruno M. Simões

2015-09-01

Full Text Available Breast cancers (BCs typically express estrogen receptors (ERs but frequently exhibit de novo or acquired resistance to hormonal therapies. Here, we show that short-term treatment with the anti-estrogens tamoxifen or fulvestrant decrease cell proliferation but increase BC stem cell (BCSC activity through JAG1-NOTCH4 receptor activation both in patient-derived samples and xenograft (PDX tumors. In support of this mechanism, we demonstrate that high ALDH1 predicts resistance in women treated with tamoxifen and that a NOTCH4/HES/HEY gene signature predicts for a poor response/prognosis in 2 ER+ patient cohorts. Targeting of NOTCH4 reverses the increase in Notch and BCSC activity induced by anti-estrogens. Importantly, in PDX tumors with acquired tamoxifen resistance, NOTCH4 inhibition reduced BCSC activity. Thus, we establish that BCSC and NOTCH4 activities predict both de novo and acquired tamoxifen resistance and that combining endocrine therapy with targeting JAG1-NOTCH4 overcomes resistance in human breast cancers.

Microenvironment-Mediated Mechanisms of Resistance to HER2 Inhibitors Differ between HER2+ Breast Cancer Subtypes.

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Watson, Spencer S; Dane, Mark; Chin, Koei; Tatarova, Zuzana; Liu, Moqing; Liby, Tiera; Thompson, Wallace; Smith, Rebecca; Nederlof, Michel; Bucher, Elmar; Kilburn, David; Whitman, Matthew; Sudar, Damir; Mills, Gordon B; Heiser, Laura M; Jonas, Oliver; Gray, Joe W; Korkola, James E

2018-03-28

Extrinsic signals are implicated in breast cancer resistance to HER2-targeted tyrosine kinase inhibitors (TKIs). To examine how microenvironmental signals influence resistance, we monitored TKI-treated breast cancer cell lines grown on microenvironment microarrays composed of printed extracellular matrix proteins supplemented with soluble proteins. We tested ∼2,500 combinations of 56 soluble and 46 matrix microenvironmental proteins on basal-like HER2+ (HER2E) or luminal-like HER2+ (L-HER2+) cells treated with the TKIs lapatinib or neratinib. In HER2E cells, hepatocyte growth factor, a ligand for MET, induced resistance that could be reversed with crizotinib, an inhibitor of MET. In L-HER2+ cells, neuregulin1-β1 (NRG1β), a ligand for HER3, induced resistance that could be reversed with pertuzumab, an inhibitor of HER2-HER3 heterodimerization. The subtype-specific responses were also observed in 3D cultures and murine xenografts. These results, along with bioinformatic pathway analysis and siRNA knockdown experiments, suggest different mechanisms of resistance specific to each HER2+ subtype: MET signaling for HER2E and HER2-HER3 heterodimerization for L-HER2+ cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Lynch syndrome-related small intestinal adenocarcinomas.

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Jun, Sun-Young; Lee, Eui-Jin; Kim, Mi-Ju; Chun, Sung Min; Bae, Young Kyung; Hong, Soon Uk; Choi, Jene; Kim, Joon Mee; Jang, Kee-Taek; Kim, Jung Yeon; Kim, Gwang Il; Jung, Soo Jin; Yoon, Ghilsuk; Hong, Seung-Mo

2017-03-28

Lynch syndrome is an autosomal-dominant disorder caused by defective DNA mismatch repair (MMR) genes and is associated with increased risk of malignancies in multiple organs. Small-intestinal adenocarcinomas are common initial manifestations of Lynch syndrome. To define the incidence and characteristics of Lynch syndrome-related small-intestinal adenocarcinomas, meticulous familial and clinical histories were obtained from 195 patients with small-intestinal adenocarcinoma, and MMR protein immunohistochemistry, microsatellite instability, MLH1 methylation, and germline mutational analyses were performed. Lynch syndrome was confirmed in eight patients (4%), all of whom had synchronous/metachronous malignancies without noticeable familial histories. Small-intestinal adenocarcinomas were the first clinical manifestation in 37% (3/8) of Lynch syndrome patients, and second malignancies developed within 5 years in 63% (5/8). The patients with accompanying Lynch syndrome were younger (≤50 years; P=0.04) and more likely to have mucinous adenocarcinomas (P=0.003), and tended to survive longer (P=0.11) than those with sporadic cases. A meticulous patient history taking, MMR protein immunolabeling, and germline MMR gene mutational analysis are important for the diagnosis of Lynch syndrome-related small-intestinal adenocarcinomas. Identifying Lynch syndrome in patients with small-intestinal adenocarcinoma can be beneficial for the early detection and treatment of additional Lynch syndrome-related cancers, especially in patients who are young or have mucinous adenocarcinomas.

Small-molecule synthetic compound norcantharidin reverses multi-drug resistance by regulating Sonic hedgehog signaling in human breast cancer cells.

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Yu-Jen Chen

Full Text Available Multi-drug resistance (MDR, an unfavorable factor compromising treatment efficacy of anticancer drugs, involves upregulated ATP binding cassette (ABC transporters and activated Sonic hedgehog (Shh signaling. By preparing human breast cancer MCF-7 cells resistant to doxorubicin (DOX, we examined the effect and mechanism of norcantharidin (NCTD, a small-molecule synthetic compound, on reversing multidrug resistance. The DOX-prepared MCF-7R cells also possessed resistance to vinorelbine, characteristic of MDR. At suboptimal concentration, NCTD significantly inhibited the viability of DOX-sensitive (MCF-7S and DOX-resistant (MCF-7R cells and reversed the resistance to DOX and vinorelbine. NCTD increased the intracellular accumulation of DOX in MCF-7R cells and suppressed the upregulated the mdr-1 mRNA, P-gp and BCRP protein expression, but not the MRP-1. The role of P-gp was strengthened by partial reversal of the DOX and vinorelbine resistance by cyclosporine A. NCTD treatment suppressed the upregulation of Shh expression and nuclear translocation of Gli-1, a hallmark of Shh signaling activation in the resistant clone. Furthermore, the Shh ligand upregulated the expression of P-gp and attenuated the growth inhibitory effect of NCTD. The knockdown of mdr-1 mRNA had not altered the expression of Shh and Smoothened in both MCF-7S and MCF-7R cells. This indicates that the role of Shh signaling in MDR might be upstream to mdr-1/P-gp, and similar effect was shown in breast cancer MDA-MB-231 and BT-474 cells. This study demonstrated that NCTD may overcome multidrug resistance through inhibiting Shh signaling and expression of its downstream mdr-1/P-gp expression in human breast cancer cells.

Deleterious effects on MDAMB-231 breast adenocarcinoma cell lineage submitted to Ho-166 radioactive seeds at very low activity

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Falcao, Patricia L.; Campos, Tarcisio P.R., E-mail: campos@nuclear.ufmg.br [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Dept. de Engenharia Nuclear; Sarmento, Eduardo V. [Centro de Desenvolvimento de Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil); Cuperschmid, Ethel M. [Universidade Federal de Minas Gerais (CEMEMOR/UFMG), Belo Horizonte, BR (Brazil). Fac. de Medicina. Centro de Memoria da Medicina

2011-07-01

Herein, the deleterious effect of ionizing radiation provided by Ho-166 radioactive seeds at low activity were addressed, based on experimental in vitro assays at the MDA MB231 cell lineage, a breast adenocarcinoma, compared to PBMC - peripheral blood cells. The methodology involves of the MDBMB-231 and PBMC expansion in culture in suitable environment in 30mm well plates and T-25 flasks. Seeds were synthesized with Ho-165 incorporated and characterized previously. Activation was processed at IPR1 reactor at the peripheral table, at 8h exposition. Three groups of seeds were tested: 0,34 mCi, 0,12 mCi activity, and control group. Such seeds were placed on culture and held to a period of 05 half-lives of the radionuclide. The biological responses at these exposure were documented by inverse microscopic photographic in time. Also, MTT essay were performed. A fast response in producing deleterious effects at cancer cell was observed even if for the low activity seeds. Also, a biological response dependent to a radial distance of the seed was observed. At conclusion, viability clonogenic control of MDAMB231 is identified at the exposition to Ho-166 ceramic seeds, even if at low activity of 0,1 to 0,3mCi. (author)

Deleterious effects on MDAMB-231 breast adenocarcinoma cell lineage submitted to Ho-166 radioactive seeds at very low activity

International Nuclear Information System (INIS)

Falcao, Patricia L.; Campos, Tarcisio P.R.; Cuperschmid, Ethel M.

2011-01-01

Herein, the deleterious effect of ionizing radiation provided by Ho-166 radioactive seeds at low activity were addressed, based on experimental in vitro assays at the MDA MB231 cell lineage, a breast adenocarcinoma, compared to PBMC - peripheral blood cells. The methodology involves of the MDBMB-231 and PBMC expansion in culture in suitable environment in 30mm well plates and T-25 flasks. Seeds were synthesized with Ho-165 incorporated and characterized previously. Activation was processed at IPR1 reactor at the peripheral table, at 8h exposition. Three groups of seeds were tested: 0,34 mCi, 0,12 mCi activity, and control group. Such seeds were placed on culture and held to a period of 05 half-lives of the radionuclide. The biological responses at these exposure were documented by inverse microscopic photographic in time. Also, MTT essay were performed. A fast response in producing deleterious effects at cancer cell was observed even if for the low activity seeds. Also, a biological response dependent to a radial distance of the seed was observed. At conclusion, viability clonogenic control of MDAMB231 is identified at the exposition to Ho-166 ceramic seeds, even if at low activity of 0,1 to 0,3mCi. (author)

Cutaneous metastasis in anorectal adenocarcinoma

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Krishnendra Varma

2015-01-01

Full Text Available Cutaneous metastasis in anorectal adenocarcinoma is a rare entity. Here, we report the case of a 40-year-old female who presented with yellowish-brown, irregular, solid, elevated rashes over the pubis with a recent history off palliative colostomy for anorectal adenocarcinoma. Clinically, we suspected metastasis that was proved on biopsy. We report this case due to the rare presenting site (i.e., perineum of a metastatic adenocarcinoma.

Adenocarcinoma of the lung with EGFR gene mutation and subsequent resistance mechanisms exploration: case report

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Xu L

2017-09-01

Full Text Available Li Xu,1,2 Qian Z Wang,1,2 Lin Wu1,2 1Department of the Second Chest Medicine, Hunan Cancer Hospital, Changsha, Hunan, People’s Republic of China; 2Department of the Second Chest Medicine, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China Abstract: The treatment of lung cancer has made paradigm-shift advancements in the past decade with the development of therapies directed at specific genetic alterations, such as epidermal growth factor receptor (EGFR. Here, we present a rare case of lung adenocarcinoma harboring EGFR activating mutation and ALK overexpression. During the EGFR-tyrosine kinase inhibitors treatment, next-generation sequencing revealed phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway amplifications in tumor specimen and subsequent T790M mutation via plasma circulating tumor DNA. In conclusion, this case illustrates the existence of concomitant resistance mechanisms and demonstrates that circulating tumor DNA can reflect tumor heterogeneity. Keywords: epidermal growth factor receptor, PI3K/Akt/mTOR pathway, T790M, next-generation sequencing, circulating tumor DNA

Male breast cancer is rare: an initial presentation may be as an abscess.

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Ventham, N T; Hussien, M I

2010-08-06

Breast cancer in men is rare. Breast cancer presenting initially as an abscess has been described only a handful of times in the literature. We present the first described case of invasive adenocarcinoma presenting as an abscess in a man. An 80-year-old diabetic man presented with symptoms typical of a breast abscess. The abscess failed to respond to percutaneous therapy and excision of breast abscess was performed. Histology revealed an invasive carcinoma. He went on to have a mastectomy. Histology should be obtained from breast abscesses not resolving within 2 months of initial percutaneous therapy. Histology could be obtained by ultrasound-guided fine-needle aspiration (FNA), core or vacuum assisted biopsy, or by formal incision and drainage.

EGFR Mutation Status in Uighur Lung Adenocarcinoma Patients

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Li SHAN

2013-02-01

Full Text Available Background and objective Epidermal growth factor receptor (EGFR, a transmembrane protein, is a member of the tyrosine kinase family. Gefitinib, an EGFR tyrosine-kinase inhibitors, has shown a high response rate in the treatment of lung cancer in patients with EGFR mutation. However, significant differences in EGFR mutations exist among different ethnic groups. The aim of this study is to investigate the prevalence of EGFR mutations in Uighur lung adenocarcinoma patients by using a rapid and sensitive detection method and to analyze EGFR mutation differences compared with Han lung adenocarcinoma patients. Methods We examined lung adenocarcinoma tissues from 138 patients, including 68 Uighur lung adenocarcinoma patients and 70 Han lung adenocarcinoma patients, for EGFR mutations in exons 18, 19, 20, and 21 by using the amplification refractory mutation system (ARMS PCR method. The mutation differences between Uighur and Han lung adenocarcinoma were compared by using the chi-square test method. Results EGFR mutations were detected in 43 (31.2% of the 138 lung adenocarcinoma patients. EGFR mutations were detected in 11 (16.2% of the 68 Uighur lung adenocarcinoma patients and in 32 (45.7% of the 70 Han lung adenocarcinoma patients. Significant differences were observed in the EGFR mutations between Uighur lung adenocarcinoma patients and Han lung adenocarcinoma patients (P<0.001. Conclusion Our results indicate that the EGFR mutation in Uighur lung adenocarcinoma patients (16.2% is significantly lower than that in Han lung adenocarcinoma patients (45.7%.

Trans- and cis-2-phenylindole platinum(II) complexes as cytotoxic agents against human breast adenocarcinoma cell lines

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Tomé, Maria; López, Concepción; González, Asensio; Ozay, Bahadir; Quirante, Josefina; Font-Bardía, Mercè; Calvet, Teresa; Calvis, Carme; Messeguer, Ramon; Baldomá, Laura; Badía, Josefa

2013-09-01

The synthesis and characterization of the new 2-phenylindole derivative: C8H3N-2-C6H5-3NOMe-5OMe (3c) and the trans- and cis-isomers of [Pt(3c)Cl2(DMSO)] complexes (4c and 5c, respectively) are described. The crystal structures of 4c·CH2Cl2 and 5c confirm: (a) the existence of a Pt-Nindole bond, (b) the relative arrangement of the Cl- ligands [trans- (in 4c) or cis- (in 5c)] and (c) the anti-(E) configuration of the oxime. The cytotoxic assessment of C8H3N-2-(C6H4-4‧R1)-3NOMe-5R2 [with R1 = R2 = H (3a); R1 = Cl, R2 = H (3b) and R1 = H, R2 = OMe (3c)] and the geometrical isomers of [Pt(L)Cl2(DMSO)] with L = 3a-3c [trans- (4a-4c) and cis- (5a-5c), respectively] against human breast adenocarcinoma cell lines (MDA-MB231 and MCF-7) is also reported and reveals that all the platinum(II) complexes (except 4a) are more cytotoxic than cisplatin in front of the MCF7 cell line. Electrophoretic DNA migration studies of the synthesized compounds in the absence and in the presence of topoisomerase-I have been performed, in order to get further insights into their mechanism of action.

Involvement of Cox-2 in the metastatic potential of chemotherapy-resistant breast cancer cells

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Kang, Ju-Hee; Song, Ki-Hoon; Jeong, Kyung-Chae; Kim, Sunshin; Choi, Changsun; Lee, Chang Hoon; Oh, Seung Hyun

2011-01-01

A major problem with the use of current chemotherapy regimens for several cancers, including breast cancer, is development of intrinsic or acquired drug resistance, which results in disease recurrence and metastasis. However, the mechanisms underlying this drug resistance are unknown. To study the molecular mechanisms underlying the invasive and metastatic activities of drug-resistant cancer cells, we generated a doxorubicin-resistant MCF-7 breast cancer cell line (MCF-7/DOX). We used MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays, flow cytometry assays, DNA fragmentation assays, Western blot analysis, cell invasion assays, small interfering RNA (siRNA) transfection, reverse transcription-polymerase chain reaction, experimental lung metastasis models, and gelatin and fibrinogen/plasminogen zymography to study the molecular mechanism of metastatic activities in MCF-7/DOX cells. We found that MCF-7/DOX acquired invasive activities. In addition, Western blot analysis showed increased expression of epidermal growth factor receptor (EGFR) and Cox-2 in MCF-7/DOX cells. Inhibition of Cox-2, phosphoinositide 3-kinase (PI3K)/Akt, or mitogen-activated protein kinase (MAPK) pathways effectively inhibited the invasive activities of MCF-7/DOX cells. Gelatin and fibrinogen/plasminogen zymography analysis showed that the enzymatic activities of matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase-type plasminogen activator were markedly higher in MCF-7/DOX cells than in the MCF-7 cells. In vitro invasion assays and mouse models of lung metastasis demonstrated that MCF-7/DOX cells acquired invasive abilities. Using siRNAs and agonists specific for prostaglandin E (EP) receptors, we found that EP1 and EP3 played important roles in the invasiveness of MCF-7/DOX cells. We found that the invasive activity of MCF-7/DOX cells is mediated by Cox-2, which is induced by the EGFR-activated PI3K/Akt and MAPK pathways. In addition, EP1 and EP3 are important in

News in the studies of multidrug resistance of breast cancer cells

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A. A. Stavrovskaya

2015-01-01

Full Text Available Breast cancer (BC is the most common cancer among women in Russia. One of the main treatment methods of BC is systemic chemotherapy. Multidrug resistance of tumor cells (MDR is the important hindrance on the way to successful chemotherapy. The new data concerning molecular mechanisms of MDR will be presented in this review. The recent data concerning some new biological prognostic markers will be also discussed. There are data showing that transporters of ABC family (ABC transporters influence tumor progression not only by MDR induction but also by the influence on the traits of malignancy in tumor cells. The results of the studies of ABC transporters, participation in the processes of accumulation of tumor stem cells under the influence of chemotherapy will be discussed. The problem of the participation of ABC transporters in the phenomenon of influence of PI3K/AKT/PTEN signal transduction pathway on the MDR regulation is discussed. The results of the studies of the role of microRNA deregulation in breast cancer drug resistance as well as studies of some epigenetic mechanisms of MDR regulation will be considered. Protein phosphatase 2A (PP2A, serine/threonine phosphatase, PTK7 (protein tyrosine kinase 7. fascin (an actin bundling cytoskeletal protein multifunctional YB-1 protein will considered as new BC prognostic markers. The perspectives of MDR studies will be discussed as well.

The role of sonography in patients with breast cancer presenting as an axillary mass

International Nuclear Information System (INIS)

Park, Sun Young; Kim, Eun Kyung; Oh, Ki Keun; Lee, Kyong Sik; Park, Byeong Woo

2002-01-01

To compare sonography and mammography in terms of their diagnostic value in breast cancer cases which initially presented as an axillary mass without a palpable mass or other clinical symptoms. Seven patients with enlarged axillary lymph nodes who first presented with no evidence of palpable breast lesions and who underwent both mammography and sonography were enrolled in this study. In six of the seven, the presence of metastatic adenocarcinoma was confirmed preoperatively by axillary needle aspiration biopsy; in four, subsequent sonographically guided breast core biopsy performed after careful examination of the primary site indicated that primary breast cancer was present. In each case, the radiologic findings were evaluated by both breast sonography and mammography. Breast lesions were detected mammographically in four of seven cases (57%); in three of the four, the lesion presented as a mass, and in one as microcalcification. In three of these four detected cases, fatty or scattered fibroglandular breast parenchyma was present; in one, the parenchyma was dense. In the three cases in which lesions were not detected, mammography revealed the presence of heterogeneously dense parenchyma. Breast sonography showed that lesions were present in six of seven cases (86%); in the remaining patient, malignant microcalcification was detected at mammography. Final pathologic examination indicated that all breast lesions except one, which was a ductal carcinoma in situ, with microinvasion, were infiltrating ductal carcinomas whose size ranged from microscopic to greater than 3 cm. At the time of this study, all seven patients were alive and well, having been disease free for up to 61 months after surgery. In women with a palpable axillary mass confirmed as metastatic adenocarcinoma, breast sonography may be a valuable adjunct to mammography

Genome wide single cell analysis of chemotherapy resistant metastatic cells in a case of gastroesophageal adenocarcinoma

International Nuclear Information System (INIS)

Hjortland, Geir Olav; Fodstad, Oystein; Smeland, Sigbjorn; Hovig, Eivind; Meza-Zepeda, Leonardo A; Beiske, Klaus; Ree, Anne H; Tveito, Siri; Hoifodt, Hanne; Bohler, Per J; Hole, Knut H; Myklebost, Ola

2011-01-01

Metastatic progression due to development or enrichment of therapy-resistant tumor cells is eventually lethal. Molecular characterization of such chemotherapy resistant tumor cell clones may identify markers responsible for malignant progression and potential targets for new treatment. Here, in a case of stage IV adenocarcinoma of the gastroesophageal junction, we report the successful genome wide analysis using array comparative genomic hybridization (CGH) of DNA from only fourteen tumor cells using a bead-based single cell selection method from a bone metastasis progressing during chemotherapy. In a case of metastatic adenocarcinoma of the gastroesophageal junction, the progression of bone metastasis was observed during a chemotherapy regimen of epirubicin, oxaliplatin and capecitabine, whereas lung-, liver and lymph node metastases as well as the primary tumor were regressing. A bone marrow aspirate sampled at the site of progressing metastasis in the right iliac bone was performed, and single cell molecular analysis using array-CGH of Epithelial Specific Antigen (ESA)-positive metastatic cells, and revealed two distinct regions of amplification, 12p12.1 and 17q12-q21.2 amplicons, containing the KRAS (12p) and ERBB2 (HER2/NEU) (17q) oncogenes. Further intrapatient tumor heterogeneity of these highlighted gene copy number changes was analyzed by fluorescence in situ hybridization (FISH) in all available primary and metastatic tumor biopsies, and ErbB2 protein expression was investigated by immunohistochemistry. ERBB2 was heterogeneously amplified by FISH analysis in the primary tumor, as well as liver and bone metastasis, but homogenously amplified in biopsy specimens from a progressing bone metastasis after three initial cycles of chemotherapy, indicating a possible enrichment of erbB2 positive tumor cells in the progressing bone marrow metastasis during chemotherapy. A similar amplification profile was detected for wild-type KRAS, although more heterogeneously

Sensitivity of docetaxel-resistant MCF-7 breast cancer cells to microtubule-destabilizing agents including vinca alkaloids and colchicine-site binding agents.

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Richard C Wang

Full Text Available One of the main reasons for disease recurrence in the curative breast cancer treatment setting is the development of drug resistance. Microtubule targeted agents (MTAs are among the most commonly used drugs for the treatment of breaset cancer and therefore overcoming taxane resistance is of primary clinical importance. Our group has previously demonstrated that the microtubule dynamics of docetaxel-resistant MCF-7TXT cells are insensitivity to docetaxel due to the distinct expression profiles of β-tubulin isotypes in addition to the high expression of p-glycoprotein (ABCB1. In the present investigation we examined whether taxane-resistant breast cancer cells are more sensitive to microtubule destabilizing agents including vinca alkaloids and colchicine-site binding agents (CSBAs than the non-resistant cells.Two isogenic MCF-7 breast cancer cell lines were selected for resistance to docetaxel (MCF-7TXT and the wild type parental cell line (MCF-7CC to examine if taxane-resistant breast cancer cells are sensitive to microtubule-destabilizing agents including vinca alkaloids and CSBAs. Cytotoxicity assays, immunoblotting, indirect immunofluorescence and live imaging were used to study drug resistance, apoptosis, mitotic arrest, microtubule formation, and microtubule dynamics.MCF-7TXT cells were demonstrated to be cross resistant to vinca alkaloids, but were more sensitive to treatment with colchicine compared to parental non-resistant MCF-7CC cells. Cytotoxicity assays indicated that the IC50 of MCF-7TXT cell to vinorelbine and vinblastine was more than 6 and 3 times higher, respectively, than that of MCF-7CC cells. By contrast, the IC50 of MCF-7TXT cell for colchincine was 4 times lower than that of MCF-7CC cells. Indirect immunofluorescence showed that all MTAs induced the disorganization of microtubules and the chromatin morphology and interestingly each with a unique pattern. In terms of microtubule and chromain morphology, MCF-7TXT cells were

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

International Nuclear Information System (INIS)

Gradishar, William J

2016-01-01

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

p-Glycoprotein ABCB5 and YB-1 expression plays a role in increased heterogeneity of breast cancer cells: correlations with cell fusion and doxorubicin resistance

International Nuclear Information System (INIS)

Yang, Ji Yeon; Ha, Seon-Ah; Yang, Yun-Sik; Kim, Jin Woo

2010-01-01

Cancer cells recurrently develop into acquired resistance to the administered drugs. The iatrogenic mechanisms of induced chemotherapy-resistance remain elusive and the degree of drug resistance did not exclusively correlate with reductions of drug accumulation, suggesting that drug resistance may involve additional mechanisms. Our aim is to define the potential targets, that makes drug-sensitive MCF-7 breast cancer cells turn to drug-resistant, for the anti-cancer drug development against drug resistant breast cancer cells. Doxorubicin resistant human breast MCF-7 clones were generated. The doxorubicin-induced cell fusion events were examined. Heterokaryons were identified and sorted by FACS. In the development of doxorubicin resistance, cell-fusion associated genes, from the previous results of microarray, were verified using dot blot array and quantitative RT-PCR. The doxorubicin-induced expression patterns of pro-survival and pro-apoptotic genes were validated. YB-1 and ABCB5 were up regulated in the doxorubicin treated MCF-7 cells that resulted in certain degree of genomic instability that accompanied by the drug resistance phenotype. Cell fusion increased diversity within the cell population and doxorubicin resistant MCF-7 cells emerged probably through clonal selection. Most of the drug resistant hybrid cells were anchorage independent. But some of the anchorage dependent MCF-7 cells exhibited several unique morphological appearances suggesting minor population of the fused cells maybe de-differentiated and have progenitor cell like characteristics. Our work provides valuable insight into the drug induced cell fusion event and outcome, and suggests YB-1, GST, ABCB5 and ERK3 could be potential targets for the anti-cancer drug development against drug resistant breast cancer cells. Especially, the ERK-3 serine/threonine kinase is specifically up-regulated in the resistant cells and known to be susceptible to synthetic antagonists

Loss of FBXW7 and accumulation of MCL1 and PLK1 promote paclitaxel resistance in breast cancer.

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Gasca, Jessica; Flores, Maria Luz; Giráldez, Servando; Ruiz-Borrego, Manuel; Tortolero, María; Romero, Francisco; Japón, Miguel A; Sáez, Carmen

2016-08-16

FBXW7 is a component of SCF (complex of SKP1, CUL1 and F-box-protein)-type ubiquitin ligases that targets several oncoproteins for ubiquitination and degradation by the proteasome. FBXW7 regulates cellular apoptosis by targeting MCL1 for ubiquitination. Recently, we identified PLK1 as a new substrate of FBXW7 modulating the intra-S-phase DNA-damage checkpoint. Taxanes are frequently used in breast cancer treatments, but the acquisition of resistance makes these treatments ineffective. We investigated the role of FBXW7 and their substrates MCL1 and PLK1 in regulating the apoptotic response to paclitaxel treatment in breast cancer cells and their expression in breast cancer tissues. Paclitaxel-sensitive MDA-MB-468 and a paclitaxel-resistant MDA-MB-468R subclone were used to study the role of FBXW7 and substrates in paclitaxel-induced apoptosis. Forced expression of FBXW7 or downregulation of MCL1 or PLK1 restored sensitivity to paclitaxel in MDA-MB-468R cells. By contrary, FBXW7-silenced MDA-MB-468 cells became resistant to paclitaxel. The expression of FBXW7 and substrates were studied in 296 invasive carcinomas by immunohistochemistry and disease-free survival was analyzed in a subset of patients treated with paclitaxel. In breast cancer tissues, loss of FBXW7 correlated with adverse prognosis markers and loss of FBXW7 and MCL1 or PLK1 accumulation were associated with diminished disease-free survival in paclitaxel-treated patients. We conclude that FBXW7 regulates the response to paclitaxel by targeting MCL1 and PLK1 in breast cancer cells and thus targeting these substrates may be a valuable adjunct for paclitaxel treatment. Also, FBXW7, MCL1 and PLK1 may be relevant predictive markers of tumor progression and response to paclitaxel treatment.

Inflammatory Markers and Breast Cancer Risk

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2011-07-01

breast cancer [26, 27] or cytologic atypia [28], while another observed elevated IL-6 levels among breast cancer cases with insulin resistance [29...Relation between insulin resistance and serum concentrations of IL-6 and TNF- alpha in overweight or obese women with early stage breast cancer...without oophorectomy, hysterectomy with uni- or bilateral oophorectomy), prior breast biopsy (no, yes), ever been pregnant (no, yes), and

Radiologic and pathological correlation of adenoid cystic carcinoma of the breast; A case report

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Kim, Jung Gyu; Kim, Shin Young; Jung, Hae Yoen; Kim, Sung Yong; Lee, Deuk Young; Park, Sang Hyun [Soonchunhyang University College of Medicine, Cheonan Hospital, Cheonan (Korea, Republic of); Park, Sang Hyun [Dept. of Radiology, Plus Internal Medicine Clinic, Suncheon (Korea, Republic of)

2015-06-15

Adenoid cystic carcinoma (ACC) is a subtype of adenocarcinoma that is usually seen in the salivary glands. It has also been reported in other organs including the breast, skin, tracheobronchial tree, cervix, larynx, and Bartholin gland. ACC in the breast is rare, accounting for less than 0.1% of all breast cancers. Furthermore, the imaging characteristics of ACC of the breast have not been well described in the literature, especially regarding the findings with magnetic resonance imaging (MRI). Here, we report radiologic findings of a rare case of ACC in the breast by mammography, sonography, computed tomography (CT), positron emission tomography/CT, and MRI with pathologic correlation and a review of the literature.

BAG3 Overexpression and Cytoprotective Autophagy Mediate Apoptosis Resistance in Chemoresistant Breast Cancer Cells

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Chandan Kanta Das

2018-03-01

Full Text Available Target-specific treatment modalities are currently not available for triple-negative breast cancer (TNBC, and acquired chemotherapy resistance is a primary obstacle for the treatment of these tumors. Here we employed derivatives of BT-549 and MDA-MB-468 TNBC cell lines that were adapted to grow in the presence of either 5-Fluorouracil, Doxorubicin or Docetaxel in an aim to identify molecular pathways involved in the adaptation to drug-induced cell killing. All six drug-adapted BT-549 and MDA-MB-468 cell lines displayed cross resistance to chemotherapy and decreased apoptosis sensitivity. Expression of the anti-apoptotic co-chaperone BAG3 was notably enhanced in two thirds (4/6 of the six resistant lines simultaneously with higher expression of HSP70 in comparison to parental controls. Doxorubicin-resistant BT-549 (BT-549rDOX20 and 5-Fluorouracil-resistant MDA-MB-468 (MDA-MB-468r5-FU2000 cells were chosen for further analysis with the autophagy inhibitor Bafilomycin A1 and lentiviral depletion of ATG5, indicating that enhanced cytoprotective autophagy partially contributes to increased drug resistance and cell survival. Stable lentiviral BAG3 depletion was associated with a robust down-regulation of Mcl-1, Bcl-2 and Bcl-xL, restoration of drug-induced apoptosis and reduced cell adhesion in these cells, and these death-sensitizing effects could be mimicked with the BAG3/Hsp70 interaction inhibitor YM-1 and by KRIBB11, a selective transcriptional inhibitor of HSF-1. Furthermore, BAG3 depletion was able to revert the EMT-like transcriptional changes observed in BT-549rDOX20 and MDA-MB-468r5-FU2000 cells. In summary, genetic and pharmacological interference with BAG3 is capable to resensitize TNBC cells to treatment, underscoring its relevance for cell death resistance and as a target to overcome therapy resistance of breast cancer.

BAG3 Overexpression and Cytoprotective Autophagy Mediate Apoptosis Resistance in Chemoresistant Breast Cancer Cells.

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Das, Chandan Kanta; Linder, Benedikt; Bonn, Florian; Rothweiler, Florian; Dikic, Ivan; Michaelis, Martin; Cinatl, Jindrich; Mandal, Mahitosh; Kögel, Donat

2018-03-01

Target-specific treatment modalities are currently not available for triple-negative breast cancer (TNBC), and acquired chemotherapy resistance is a primary obstacle for the treatment of these tumors. Here we employed derivatives of BT-549 and MDA-MB-468 TNBC cell lines that were adapted to grow in the presence of either 5-Fluorouracil, Doxorubicin or Docetaxel in an aim to identify molecular pathways involved in the adaptation to drug-induced cell killing. All six drug-adapted BT-549 and MDA-MB-468 cell lines displayed cross resistance to chemotherapy and decreased apoptosis sensitivity. Expression of the anti-apoptotic co-chaperone BAG3 was notably enhanced in two thirds (4/6) of the six resistant lines simultaneously with higher expression of HSP70 in comparison to parental controls. Doxorubicin-resistant BT-549 (BT-549 r DOX 20 ) and 5-Fluorouracil-resistant MDA-MB-468 (MDA-MB-468 r 5-FU 2000 ) cells were chosen for further analysis with the autophagy inhibitor Bafilomycin A1 and lentiviral depletion of ATG5, indicating that enhanced cytoprotective autophagy partially contributes to increased drug resistance and cell survival. Stable lentiviral BAG3 depletion was associated with a robust down-regulation of Mcl-1, Bcl-2 and Bcl-xL, restoration of drug-induced apoptosis and reduced cell adhesion in these cells, and these death-sensitizing effects could be mimicked with the BAG3/Hsp70 interaction inhibitor YM-1 and by KRIBB11, a selective transcriptional inhibitor of HSF-1. Furthermore, BAG3 depletion was able to revert the EMT-like transcriptional changes observed in BT-549 r DOX 20 and MDA-MB-468 r 5-FU 2000 cells. In summary, genetic and pharmacological interference with BAG3 is capable to resensitize TNBC cells to treatment, underscoring its relevance for cell death resistance and as a target to overcome therapy resistance of breast cancer. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Ell3 stimulates proliferation, drug resistance, and cancer stem cell properties of breast cancer cells via a MEK/ERK-dependent signaling pathway

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Ahn, Hee-Jin [Department of Biomedical Science, College of Life Science, CHA University, Seoul (Korea, Republic of); Kim, Gwangil [Department of Pathology, CHA Bundang Medical Center, CHA University, Seoul (Korea, Republic of); Park, Kyung-Soon, E-mail: kspark@cha.ac.kr [Department of Biomedical Science, College of Life Science, CHA University, Seoul (Korea, Republic of)

2013-08-09

Highlights: •Ell3 enhances proliferation and drug resistance of breast cancer cell lines. •Ell3 is related to the cancer stem cell characteristics of breast cancer cell lines. •Ell3 enhances oncogenicity of breast cancer through the ERK1/2 signaling pathway. -- Abstract: Ell3 is a RNA polymerase II transcription elongation factor that is enriched in testis. The C-terminal domain of Ell3 shows strong similarities to that of Ell (eleven−nineteen lysine-rich leukemia gene), which acts as a negative regulator of p53 and regulates cell proliferation and survival. Recent studies in our laboratory showed that Ell3 induces the differentiation of mouse embryonic stem cells by protecting differentiating cells from apoptosis via the promotion of p53 degradation. In this study, we evaluated the function of Ell3 in breast cancer cell lines. MCF-7 cell lines overexpressing Ell3 were used to examine cell proliferation and cancer stem cell properties. Ectopic expression of Ell3 in breast cancer cell lines induces proliferation and 5-FU resistance. In addition, Ell3 expression increases the cancer stem cell population, which is characterized by CD44 (+) or ALDH1 (+) cells. Mammosphere-forming potential and migration ability were also increased upon Ell3 expression in breast cancer cell lines. Through biochemical and molecular biological analyses, we showed that Ell3 regulates proliferation, cancer stem cell properties and drug resistance in breast cancer cell lines partly through the MEK−extracellular signal-regulated kinase signaling pathway. Murine xenograft experiments showed that Ell3 expression promotes tumorigenesis in vivo. These results suggest that Ell3 may play a critical role in promoting oncogenesis in breast cancer by regulating cell proliferation and cancer stem cell properties via the ERK1/2 signaling pathway.

Ell3 stimulates proliferation, drug resistance, and cancer stem cell properties of breast cancer cells via a MEK/ERK-dependent signaling pathway

International Nuclear Information System (INIS)

Ahn, Hee-Jin; Kim, Gwangil; Park, Kyung-Soon

2013-01-01

Highlights: •Ell3 enhances proliferation and drug resistance of breast cancer cell lines. •Ell3 is related to the cancer stem cell characteristics of breast cancer cell lines. •Ell3 enhances oncogenicity of breast cancer through the ERK1/2 signaling pathway. -- Abstract: Ell3 is a RNA polymerase II transcription elongation factor that is enriched in testis. The C-terminal domain of Ell3 shows strong similarities to that of Ell (eleven−nineteen lysine-rich leukemia gene), which acts as a negative regulator of p53 and regulates cell proliferation and survival. Recent studies in our laboratory showed that Ell3 induces the differentiation of mouse embryonic stem cells by protecting differentiating cells from apoptosis via the promotion of p53 degradation. In this study, we evaluated the function of Ell3 in breast cancer cell lines. MCF-7 cell lines overexpressing Ell3 were used to examine cell proliferation and cancer stem cell properties. Ectopic expression of Ell3 in breast cancer cell lines induces proliferation and 5-FU resistance. In addition, Ell3 expression increases the cancer stem cell population, which is characterized by CD44 (+) or ALDH1 (+) cells. Mammosphere-forming potential and migration ability were also increased upon Ell3 expression in breast cancer cell lines. Through biochemical and molecular biological analyses, we showed that Ell3 regulates proliferation, cancer stem cell properties and drug resistance in breast cancer cell lines partly through the MEK−extracellular signal-regulated kinase signaling pathway. Murine xenograft experiments showed that Ell3 expression promotes tumorigenesis in vivo. These results suggest that Ell3 may play a critical role in promoting oncogenesis in breast cancer by regulating cell proliferation and cancer stem cell properties via the ERK1/2 signaling pathway

Niclosamide inhibits epithelial-mesenchymal transition and tumor growth in lapatinib-resistant human epidermal growth factor receptor 2-positive breast cancer.

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Liu, Junjun; Chen, Xiaosong; Ward, Toby; Mao, Yan; Bockhorn, Jessica; Liu, Xiaofei; Wang, Gen; Pegram, Mark; Shen, Kunwei

2016-02-01

Acquired resistance to lapatinib, a human epidermal growth factor receptor 2 kinase inhibitor, remains a clinical problem for women with human epidermal growth factor receptor 2-positive advanced breast cancer, as metastasis is commonly observed in these patients. Niclosamide, an anti-helminthic agent, has recently been shown to exhibit cytotoxicity to tumor cells with stem-like characteristics. This study was designed to identify the mechanisms underlying lapatinib resistance and to determine whether niclosamide inhibits lapatinib resistance by reversing epithelial-mesenchymal transition. Here, two human epidermal growth factor receptor 2-positive breast cancer cell lines, SKBR3 and BT474, were exposed to increasing concentrations of lapatinib to establish lapatinib-resistant cultures. Lapatinib-resistant SKBR3 and BT474 cells exhibited up-regulation of the phenotypic epithelial-mesenchymal transition markers Snail, vimentin and α-smooth muscle actin, accompanied by activation of nuclear factor-кB and Src and a concomitant increase in stem cell marker expression (CD44(high)/CD24(low)), compared to naive lapatinib-sensitive SKBR3 and BT474 cells, respectively. Interestingly, niclosamide reversed epithelial-mesenchymal transition, induced apoptosis and inhibited cell growth by perturbing aberrant signaling pathway activation in lapatinib-resistant human epidermal growth factor receptor 2-positive cells. The ability of niclosamide to alleviate stem-like phenotype development and invasion was confirmed. Collectively, our results demonstrate that lapatinib resistance correlates with epithelial-mesenchymal transition and that niclosamide inhibits lapatinib-resistant cell viability and epithelial-mesenchymal transition. These findings suggest a role of niclosamide or derivatives optimized for more favorable bioavailability not only in reversing lapatinib resistance but also in reducing metastatic potential during the treatment of human epidermal growth factor receptor

Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: a multicenter randomized controlled trial.

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Courneya, Kerry S; Segal, Roanne J; Mackey, John R; Gelmon, Karen; Reid, Robert D; Friedenreich, Christine M; Ladha, Aliya B; Proulx, Caroline; Vallance, Jeffrey K H; Lane, Kirstin; Yasui, Yutaka; McKenzie, Donald C

2007-10-01

Breast cancer chemotherapy may cause unfavorable changes in physical functioning, body composition, psychosocial functioning, and quality of life (QOL). We evaluated the relative merits of aerobic and resistance exercise in blunting these effects. We conducted a multicenter randomized controlled trial in Canada between 2003 and 2005 that randomly assigned 242 breast cancer patients initiating adjuvant chemotherapy to usual care (n = 82), supervised resistance exercise (n = 82), or supervised aerobic exercise (n = 78) for the duration of their chemotherapy (median, 17 weeks; 95% CI, 9 to 24 weeks). Our primary end point was cancer-specific QOL assessed by the Functional Assessment of Cancer Therapy-Anemia scale. Secondary end points were fatigue, psychosocial functioning, physical fitness, body composition, chemotherapy completion rate, and lymphedema. The follow-up assessment rate for our primary end point was 92.1%, and adherence to the supervised exercise was 70.2%. Unadjusted and adjusted mixed-model analyses indicated that aerobic exercise was superior to usual care for improving self-esteem (P = .015), aerobic fitness (P = .006), and percent body fat (adjusted P = .076). Resistance exercise was superior to usual care for improving self-esteem (P = .018), muscular strength (P exercise groups but did not reach statistical significance. Exercise did not cause lymphedema or adverse events. Neither aerobic nor resistance exercise significantly improved cancer-specific QOL in breast cancer patients receiving chemotherapy, but they did improve self-esteem, physical fitness, body composition, and chemotherapy completion rate without causing lymphedema or significant adverse events.

Prospective prediction of resistance to neoadjuvant therapy in patients with locoregional esophageal adenocarcinoma

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Rosen DG

2015-02-01

Full Text Available Daniel G Rosen,1 Weiwei Shan,2 Natalie Lassen,2 Clare Johnson,2 Kristen Oelschlager,2 Yaeli Bierman-Harrar,1 Kenneth A Kesler,3 Derek Maetzold,2 Sunil Badve,3 Robert W Cook,2 Romil Saxena3 1Baylor College of Medicine, Houston TX, USA; 2Castle Biosciences, Incorporated, Friendswood, TX, USA; 3Indiana University, Indianapolis, IN, USA Background: To clinically validate a multianalyte algorithmic immunohistochemistry (IHC assay that has been previously shown to accurately identify patients with locoregional esophageal adenocarcinoma (EC who will exhibit extreme resistance to neoadjuvant chemoradiotherapy. Methods: Archived biopsy specimens of EC were subject to IHC examination of compartmentalized immunoreactivity of nuclear factor kappa B (NF-κB, Sonic Hedgehog (SHH, and GLI family zinc finger 1 (Gli-1, and a labeling index score was assigned to each biomarker. Test prediction was generated by logistic regression predictive modeling, using the labeling index scores for all three analytes from each sample, referring to a validated training set of 167 EC patients. Accuracy of the test was determined by comparing the predicted outcomes with pathologically determined College of American Pathologists tumor response grade. Analytical validity of the test was measured by comparing validation set prediction results obtained in two independent Clinical Laboratory Improvement Amendment-certified laboratories, and by measuring concordance between two trained labeling index readers. Results: Specimens from 64 patients that met specific criteria were collected. No technical failure was encountered during the IHC labeling procedures. The logistic regression algorithm generated an area under the curve of 0.96 and 0.85 for the 64 sample cohort in two independent clinical laboratories, respectively, comparing predictive results with the established training set. Positive predictive values of 88% and 82% were also achieved in each laboratory, respectively. A

Isolated local-regional recurrence following mastectomy for adenocarcinoma of the breast treated with radiation therapy alone or combined with surgery and/or chemotherapy

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Mendenhall, N.P.; Devine, J.W.; Mendenhall, W.M.; Million, R.R.; Bland, K.I.; Copeland, E.M. III

1988-01-01

The results of radiation therapy alone or combined with surgery and/or chemotherapy are reported for 47 patients who presented with local and/or regional recurrence without evidence of distant metastases following initial management of adenocarcinoma of the breast with radical or modified radical mastectomy (43) or simple mastectomy (4). Patients were treated between October 1964 and March 1983 at the University of Florida; all have a 2-year minimum follow-up and 42/47 (89%) have had follow-up for ≥5 years. The overall actuarial local-regional control rates were 80% at 2 years, 68% at 5 years, and 61% at 10 years. The 5-year actuarial local-regional control rates by site and extent of disease were as follows: single chest wall nodule, 92%; multiple chest wall nodules, 49%; regional lymph nodes, 66%; and multiple sites, 64%. The 5- and 10-year actuarial determinate disease-free survival rates for all patients were 41 and 17%, respectively. The 5- and 10-year actuarial survival rates for all patients were 50 and 34%, respectively. 22 refs.; 5 figs.; 5 tabs

Small cell lung cancer transformation from EGFR-mutated lung adenocarcinoma: A case report and literatures review.

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Liu, Yangyang

2018-06-03

Epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have markedly improved the response of non-small cell lung cancer (NSCLC) with EGFR-mutant patients. However, these patients inevitably come cross acquired resistance to EGFR-TKIs. The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) following treatment with EGFR-TKIs is rare, which leads to resistance to EGFR-TKIs. The present case concerns a case of a 38-year-old man presenting with cough and dyspnea. Radical resection was performed and confirmed an EGFR exon 21 L858R lung adenocarcinoma. However, the patient suffered pleural metastasis after successful treatment with surgery and adjuvant treatment. So, erlotinib was administered with 18 months. Because of enlarged pleural nodule, repeat biopsy identified an SCLC and chemotherapy was started. However, despite the brief success of chemotherapy, our patient suffered brain metastasis. Our case emaphsizes both the profile of transformation from NSCLC to SCLC and the importance of repeat biopsy dealing with drug resistance. We also summarize the clinical characteristics, mechanisms, predictors of SCLC transformation, treatment after transformation and other types of transformation to SCLC.

An integrative analysis of cellular contexts, miRNAs and mRNAs reveals network clusters associated with antiestrogen-resistant breast cancer cells

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Nam Seungyoon

2012-12-01

Full Text Available Abstract Background A major goal of the field of systems biology is to translate genome-wide profiling data (e.g., mRNAs, miRNAs into interpretable functional networks. However, employing a systems biology approach to better understand the complexities underlying drug resistance phenotypes in cancer continues to represent a significant challenge to the field. Previously, we derived two drug-resistant breast cancer sublines (tamoxifen- and fulvestrant-resistant cell lines from the MCF7 breast cancer cell line and performed genome-wide mRNA and microRNA profiling to identify differential molecular pathways underlying acquired resistance to these important antiestrogens. In the current study, to further define molecular characteristics of acquired antiestrogen resistance we constructed an “integrative network”. We combined joint miRNA-mRNA expression profiles, cancer contexts, miRNA-target mRNA relationships, and miRNA upstream regulators. In particular, to reduce the probability of false positive connections in the network, experimentally validated, rather than prediction-oriented, databases were utilized to obtain connectivity. Also, to improve biological interpretation, cancer contexts were incorporated into the network connectivity. Results Based on the integrative network, we extracted “substructures” (network clusters representing the drug resistant states (tamoxifen- or fulvestrant-resistance cells compared to drug sensitive state (parental MCF7 cells. We identified un-described network clusters that contribute to antiestrogen resistance consisting of miR-146a, -27a, -145, -21, -155, -15a, -125b, and let-7s, in addition to the previously described miR-221/222. Conclusions By integrating miRNA-related network, gene/miRNA expression and text-mining, the current study provides a computational-based systems biology approach for further investigating the molecular mechanism underlying antiestrogen resistance in breast cancer cells. In

Kiss-1/GPR54 protein expression in breast cancer.

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Papaoiconomou, Eleni; Lymperi, Maria; Petraki, Constantina; Philippou, Anastassios; Msaouel, Pavlos; Michalopoulou, Fani; Kafiri, Georgia; Vassilakos, George; Zografos, Georgios; Koutsilieris, Michael

2014-03-01

Numerous studies have shown that the Kiss-1 gene countervails the metastatic aptitude of several cancer cell lines and solid-tumor neoplasias. However, there still remains ambiguity regarding its role in breast cancer and literature has arisen asserting that Kiss-1 expression may be linked to an aggressive phenotype and malignant progression. Herein, we investigated the protein expression of Kiss-1 and its receptor GPR54 in breast cancer tissues compared to non-cancerous mammary tissues. Paraffin-fixed cancer tissues from 43 women with resected breast adenocarcinomas and 11 specimens derived from women suffering from fibrocystic disease, serving as controls, were immunostained with Kiss-1 and GPR54 antibodies. Kiss-1 and GPR54 protein expression levels were significantly higher in breast cancer compared to fibrocystic tissues (pbreast cancer and fibrocystic disease specimens. Kiss-1/GPR54 expression was found to be significantly higher in breast cancer compared to non-malignant mammary tissues.

Improved Pancreatic Adenocarcinoma Diagnosis in Jaundiced and Non-Jaundiced Pancreatic Adenocarcinoma Patients through the Combination of Routine Clinical Markers Associated to Pancreatic Adenocarcinoma Pathophysiology.

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Ferri, María José; Saez, Marc; Figueras, Joan; Fort, Esther; Sabat, Miriam; López-Ben, Santiago; de Llorens, Rafael; Aleixandre, Rosa Núria; Peracaula, Rosa

2016-01-01

There is still no reliable biomarker for the diagnosis of pancreatic adenocarcinoma. Carbohydrate antigen 19-9 (CA 19-9) is a tumor marker only recommended for pancreatic adenocarcinoma follow-up. One of the clinical problems lies in distinguishing between this cancer and other benign pancreatic diseases such as chronic pancreatitis. In this study we will assess the value of panels of serum molecules related to pancreatic cancer physiopathology to determine whether alone or in combination could help to discriminate between these two pathologies. CA 19-9, carcinoembryonic antigen (CEA), C-reactive protein, albumin, insulin growth factor-1 (IGF-1) and IGF binding protein-3 were measured using routine clinical analyzers in a cohort of 47 pancreatic adenocarcinoma, 20 chronic pancreatitis and 15 healthy controls. The combination of CA 19-9, IGF-1 and albumin resulted in a combined area under the curve (AUC) of 0.959 with 93.6% sensitivity and 95% specificity, much higher than CA 19-9 alone. An algorithm was defined to classify the patients as chronic pancreatitis or pancreatic cancer with the above specificity and sensitivity. In an independent validation group of 20 pancreatic adenocarcinoma and 13 chronic pancreatitis patients, the combination of the four molecules classified correctly all pancreatic adenocarcinoma and 12 out of 13 chronic pancreatitis patients. Although this panel of markers should be validated in larger cohorts, the high sensitivity and specificity values and the convenience to measure these parameters in clinical laboratories shows great promise for improving pancreatic adenocarcinoma diagnosis.

Improved Pancreatic Adenocarcinoma Diagnosis in Jaundiced and Non-Jaundiced Pancreatic Adenocarcinoma Patients through the Combination of Routine Clinical Markers Associated to Pancreatic Adenocarcinoma Pathophysiology.

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María José Ferri

Full Text Available There is still no reliable biomarker for the diagnosis of pancreatic adenocarcinoma. Carbohydrate antigen 19-9 (CA 19-9 is a tumor marker only recommended for pancreatic adenocarcinoma follow-up. One of the clinical problems lies in distinguishing between this cancer and other benign pancreatic diseases such as chronic pancreatitis. In this study we will assess the value of panels of serum molecules related to pancreatic cancer physiopathology to determine whether alone or in combination could help to discriminate between these two pathologies.CA 19-9, carcinoembryonic antigen (CEA, C-reactive protein, albumin, insulin growth factor-1 (IGF-1 and IGF binding protein-3 were measured using routine clinical analyzers in a cohort of 47 pancreatic adenocarcinoma, 20 chronic pancreatitis and 15 healthy controls.The combination of CA 19-9, IGF-1 and albumin resulted in a combined area under the curve (AUC of 0.959 with 93.6% sensitivity and 95% specificity, much higher than CA 19-9 alone. An algorithm was defined to classify the patients as chronic pancreatitis or pancreatic cancer with the above specificity and sensitivity. In an independent validation group of 20 pancreatic adenocarcinoma and 13 chronic pancreatitis patients, the combination of the four molecules classified correctly all pancreatic adenocarcinoma and 12 out of 13 chronic pancreatitis patients.Although this panel of markers should be validated in larger cohorts, the high sensitivity and specificity values and the convenience to measure these parameters in clinical laboratories shows great promise for improving pancreatic adenocarcinoma diagnosis.

Carcinoma of Gall bladder with distant metastasis to breast parenchyma. Report of a case and review of literature

International Nuclear Information System (INIS)

Kumaran, D.; Anamalai, M.; Velu, U.; Julka, P.K.; Nambirajan, A.

2016-01-01

Background: Gall bladder carcinoma is one of the most common cancers in India. Gall bladder cancer with metastasis to the breast is very rare. Herein we intend to report a case of carcinoma gall bladder with breast metastasis and a short review of the literature. Methods: This report describes an interesting and unusual case of gall bladder carcinoma presenting with breast metastasis. Case report: A 38-year lady presented with complaints of right abdominal pain. Bilateral breast examination showed 2 2 cm palpable lump in the upper outer quadrant of the left breast. Contrast-enhanced CT of the abdomen and pelvis showed circumferential thickening of gall bladder with the loss of fat plane with the adjacent liver parenchyma. Biopsy from the breast lump was reported as metastatic adenocarcinoma compatible with primary in the gall bladder. Whole body PET-CT showed gall bladder mass with abdominal and pelvic nodes with metastasis to liver, left breast, C7 vertebral body and left supra-clavicular node. She was diagnosed to have disseminated carcinoma gall bladder with liver, breast and supraclavicular nodal metastasis. She received palliative chemotherapy with gemcitabine and carboplatin and radiotherapy to C7 vertebra. After receiving 3 cycles of chemotherapy, chemotherapy was changed to the second line with single agent capecitabine. In spite of two lines of chemotherapy, she succumbed to disease progression and expired. Conclusion: There are limited examples of gall bladder adenocarcinoma with simultaneous metastasis to breast in the English literature. Our case showed an unusual dissemination of gall bladder cancer

MCAM/CD146 promotes tamoxifen resistance in breast cancer cells through induction of epithelial-mesenchymal transition, decreased ER alpha expression and AKT activation

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Liang, Yuan-Ke; Zeng, De; Xiao, Ying-Sheng; Wu, Yang; Ouyang, Yan-Xiu; Chen, Min; Li, Yao-Chen; Lin, Hao-Yu; Wei, Xiao-Long; Zhang, Yong-Qu; Kruyt, Frank A. E.; Zhang, Guo-Jun

2017-01-01

Tamoxifen resistance presents a prominent clinical challenge in endocrine therapy for hormone sensitive breast cancer. However, the underlying mechanisms that contribute to tamoxifen resistance are not fully understood. In this study, we established a tamoxifen resistant MCF-7 cell line

Connective tissue growth factor confers drug resistance in breast cancer through concomitant up-regulation of Bcl-xL and cIAP1.

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Wang, Ming-Yang; Chen, Pai-Sheng; Prakash, Ekambaranellore; Hsu, Hsing-Chih; Huang, Hsin-Yi; Lin, Ming-Tsan; Chang, King-Jen; Kuo, Min-Liang

2009-04-15

Connective tissue growth factor (CTGF) expression is elevated in advanced breast cancer and promotes metastasis. Chemotherapy response is only transient in most metastatic diseases. In the present study, we examined whether CTGF expression could confer drug resistance in human breast cancer. In breast cancer patients who received neoadjuvant chemotherapy, CTGF expression was inversely associated with chemotherapy response. Overexpression of CTGF in MCF7 cells (MCF7/CTGF) enhanced clonogenic ability, cell viability, and resistance to apoptosis on exposure to doxorubicin and paclitaxel. Reducing the CTGF level in MDA-MB-231 (MDA231) cells by antisense CTGF cDNA (MDA231/AS cells) mitigated this drug resistance capacity. CTGF overexpression resulted in resistance to doxorubicin- and paclitaxel-induced apoptosis by up-regulation of Bcl-xL and cellular inhibitor of apoptosis protein 1 (cIAP1). Knockdown of Bcl-xL or cIAP1 with specific small interfering RNAs abolished the CTGF-mediated resistance to apoptosis induced by the chemotherapeutic agents in MCF7/CTGF cells. Inhibition of extracellular signal-regulated kinase (ERK)-1/2 effectively reversed the resistance to apoptosis as well as the up-regulation of Bcl-xL and cIAP1 in MCF7/CTGF cells. A neutralizing antibody against integrin alpha(v)beta(3) significantly attenuated CTGF-mediated ERK1/2 activation and up-regulation of Bcl-xL and cIAP1, indicating that the integrin alpha(v)beta(3)/ERK1/2 signaling pathway is essential for CTGF functions. The Bcl-xL level also correlated with the CTGF level in breast cancer patients. We also found that a COOH-terminal domain peptide from CTGF could exert activities similar to full-length CTGF, in activation of ERK1/2, up-regulation of Bcl-xL/cIAP1, and resistance to apoptosis. We conclude that CTGF expression could confer resistance to chemotherapeutic agents through augmenting a survival pathway through ERK1/2-dependent Bcl-xL/cIAP1 up-regulation.

Functional ablation of pRb activates Cdk2 and causes antiestrogen resistance in human breast cancer cells.

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Hemant Varma

2007-12-01

Full Text Available Estrogens are required for the proliferation of hormone dependent breast cancer cells, making estrogen receptor (ER positive tumors amenable to endocrine therapies such as antiestrogens. However, resistance to these agents remains a significant cause of treatment failure. We previously demonstrated that inactivation of the retinoblastoma protein (pRb family tumor suppressors causes antiestrogen resistance in MCF-7 cells, a widely studied model of estrogen responsive human breast cancers. In this study, we investigate the mechanism by which pRb inactivation leads to antiestrogen resistance. Cdk4 and cdk2 are two key cell cycle regulators that can phosphorylate and inactivate pRb, therefore we tested whether these kinases are required in cells lacking pRb function. pRb family members were inactivated in MCF-7 cells by expressing polyomavirus large tumor antigen (PyLT, and cdk activity was inhibited using the cdk inhibitors p16(INK4A and p21(Waf1/Cip1. Cdk4 activity was no longer required in cells lacking functional pRb, while cdk2 activity was required for proliferation in both the presence and absence of pRb function. Using inducible PyLT cell lines, we further demonstrated that pRb inactivation leads to increased cyclin A expression, cdk2 activation and proliferation in antiestrogen arrested cells. These results demonstrate that antiestrogens do not inhibit cdk2 activity or proliferation of MCF-7 cells in the absence of pRb family function, and suggest that antiestrogen resistant breast cancer cells resulting from pRb pathway inactivation would be susceptible to therapies that target cdk2.

Cytoplasmic Overexpression of CD95L in Esophageal Adenocarcinoma Cells Overcomes Resistance to CD95-Mediated Apoptosis

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Gregory A. Watson

2011-03-01

Full Text Available Introduction: The CD95/CD95L pathway plays a critical role in tissue homeostasis and immune system regulation; however, the function of this pathway in malignancy remains poorly understood. We hypothesized that CD95L expression in esophageal adenocarcinoma confers advantages to the neoplasm other than immune privilege. Methods: CD95L expression was characterized in immortalized squamous esophagus (HET-1A and Barrett esophagus (BAR-T cells; adenocarcinoma cell lines FLO-1, SEG-1, and BIC-1, and MDA468 (- control; and KFL cells (+ control. Analyses included reverse transcription-polymerase chain reaction, immunoblots of whole cell and secretory vesicle lysates, FACScan analysis, laser scanning confocal microscopy of native proteins and fluorescent constructs, and assessment of apoptosis and ERK1/2 pathways. Results: Cleaved, soluble CD95L is expressed at both the RNA and protein levels in these cell lines derived from esophageal adenocarcinoma and other human tissues. CD95L was neither trafficked to the cell membrane nor secreted into the media or within vesicles, rather the protein seems to be sequestered in the cytoplasm. CD95 and CD95L colocalize by immunofluorescence, but an interaction was not proven by immunoprecipitation. Overexpression of CD95L in the adenocarcinoma cell lines induced robust apoptosis and, under conditions of pan-caspase inhibition, resulted in activation of ERK signaling. Conclusions: CD95L localization in EA cells is inconsistent with the conference of immune privilege and is more consistent with a function that promotes tumor growth through alternative CD95 signaling. Reduced cell surface expression of CD95 affects cell sensitivity to extracellular apoptotic signals more significantly than alterations in downstream modulators of apoptosis.

Integrative analyses of gene expression and DNA methylation profiles in breast cancer cell line models of tamoxifen-resistance indicate a potential role of cells with stem-like properties

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Lin, Xue; Li, Jian; Yin, Guangliang

2013-01-01

Development of resistance to tamoxifen is an important clinical issue in the treatment of breast cancer. Tamoxifen resistance may be the result of acquisition of epigenetic regulation within breast cancer cells, such as DNA methylation, resulting in changed mRNA expression of genes pivotal for es...

Cytomorphologic features of papillary lesions of the male breast: a study of 11 cases.

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Reid-Nicholson, Michelle D; Tong, Guoxia; Cangiarella, Joan F; Moreira, Andre L

2006-08-25

Breast masses occur in men far less commonly than women and are infrequently subjected to fine-needle aspiration (FNA) biopsy. Papillary lesions of the male breast are rare and are comprised of a spectrum of lesions ranging from papillary hyperplasia in gynecomastia to invasive papillary carcinoma. The following study describes the cytomorphology of papillary breast lesions in 11 men. The patients ranged in age from 23 to 78 years old and each presented with an unilateral subareolar or periareolar breast mass that varied in size from 0.5 to 3 cm. Two patients presented with bloody nipple discharge. Archival material (8-year period) from FNA biopsies of papillary lesions of the male breast was reviewed. The reviewed cases were correlated with appropriate clinicopathologic follow-up. The smears had variable cellularity but all showed papillary clusters of mammary epithelial cells with and without fibrovascular cores. Single epithelial cells with a high nuclear-to-cytoplasmic ratio and eccentric nuclei were seen in all smears; however, these were more numerous in cases of adenocarcinoma. Hemosiderin-laden macrophages were present in all cases. Nipple discharge was seen only in the 2 benign lesions. All adenocarcinomas occurred in older men. The only cytologic criteria that differentiated benign from malignant papillary lesions were marked cellularity and the presence of abundant 3-dimensional clusters. To the best of the authors' knowledge, the current series is the largest in the English literature to date that examines the cytomorphologic features of papillary breast lesions in men. Copyright 2006 American Cancer Society.

The cellular uptake mechanism, intracellular transportation, and exocytosis of polyamidoamine dendrimers in multidrug-resistant breast cancer cells.

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Zhang, Jie; Liu, Dan; Zhang, Mengjun; Sun, Yuqi; Zhang, Xiaojun; Guan, Guannan; Zhao, Xiuli; Qiao, Mingxi; Chen, Dawei; Hu, Haiyang

2016-01-01

Polyamidoamine dendrimers, which can deliver drugs and genetic materials to resistant cells, are attracting increased research attention, but their transportation behavior in resistant cells remains unclear. In this paper, we performed a systematic analysis of the cellular uptake, intracellular transportation, and efflux of PAMAM-NH2 dendrimers in multidrug-resistant breast cancer cells (MCF-7/ADR cells) using sensitive breast cancer cells (MCF-7 cells) as the control. We found that the uptake rate of PAMAM-NH2 was much lower and exocytosis of PAMAM-NH2 was much greater in MCF-7/ADR cells than in MCF-7 cells due to the elimination of PAMAM-NH2 from P-glycoprotein and the multidrug resistance-associated protein in MCF-7/ADR cells. Macropinocytosis played a more important role in its uptake in MCF-7/ADR cells than in MCF-7 cells. PAMAM-NH2 aggregated and became more degraded in the lysosomal vesicles of the MCF-7/ADR cells than in those of the MCF-7 cells. The endoplasmic reticulum and Golgi complex were found to participate in the exocytosis rather than endocytosis process of PAMAM-NH2 in both types of cells. Our findings clearly showed the intracellular transportation process of PAMAM-NH2 in MCF-7/ADR cells and provided a guide of using PAMAM-NH2 as a drug and gene vector in resistant cells.

Reciprocal regulation of annexin A2 and EGFR with Her-2 in Her-2 negative and herceptin-resistant breast cancer.

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Praveenkumar K Shetty

Full Text Available Alternative survival pathways are commonly seen to be upregulated upon inhibition of receptor tyrosine kinases (RTK, including Her-2. It is established that treatment with Herceptin leads to selective overexpression and activation of epidermal growth factor receptor (EGFR and Src which further contributes to oncogenesis in Herceptin resistant and triple negative breast cancer (TNBC patients. Here, we show a co-regulated upregulation in the expression of Annexin A2 (AnxA2, a known substrate of Src and one of the regulators of EGFR receptor endocytosis, in Herceptin resistant and Her-2 negative breast cancer. Immunohistochemical expression analysis revealed a reciprocal regulation between Her-2 and AnxA2 in breast cancer clinical samples as well as in cell lines as confirmed by protein and RNA analysis. The siRNA and Herceptin mediated downregulation/inhibition of Her-2 in Her-2 amplified cells induced AnxA2 expression and membrane translocation. In this study we report a possible involvement of AnxA2 in maintaining constitutively activated EGFR downstream signaling intermediates and hence in cell proliferation, migration and viability. This effect was consistent in Herceptin resistant JIMT-1 cells as well as in Her-2 negative breast cancer. The siRNA mediated AnxA2 downregulation leads to increased apoptosis, decreased cell viability and migration. Our studies further indicate the role of AnxA2 in EGFR-Src membrane bound signaling complex and ligand induced activation of downstream signaling pathways. Targeting this AnxA2 dependent positive regulation of EGFR signaling cascade may be of therapeutic value in Her-2 negative breast cancer.

Lapatinib Resistance in Breast Cancer Cells Is Accompanied by Phosphorylation-Mediated Reprogramming of Glycolysis.

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Ruprecht, Benjamin; Zaal, Esther A; Zecha, Jana; Wu, Wei; Berkers, Celia R; Kuster, Bernhard; Lemeer, Simone

2017-04-15

HER2/ERBB2-overexpressing breast cancers targeted effectively by the small-molecule kinase inhibitor lapatinib frequently acquire resistance to this drug. In this study, we employed explorative mass spectrometry to profile proteome, kinome, and phosphoproteome changes in an established model of lapatinib resistance to systematically investigate initial inhibitor response and subsequent reprogramming in resistance. The resulting dataset, which collectively contains quantitative data for >7,800 proteins, >300 protein kinases, and >15,000 phosphopeptides, enabled deep insight into signaling recovery and molecular reprogramming upon resistance. Our data-driven approach confirmed previously described mechanisms of resistance (e.g., AXL overexpression and PIK3 reactivation), revealed novel pharmacologically actionable targets, and confirmed the expectation of significant heterogeneity in molecular resistance drivers inducing distinct phenotypic changes. Furthermore, our approach identified an extensive and exclusively phosphorylation-mediated reprogramming of glycolytic activity, supported additionally by widespread changes of corresponding metabolites and an increased sensitivity towards glycolysis inhibition. Collectively, our multi-omic analysis offers deeper perspectives on cancer drug resistance and suggests new biomarkers and treatment options for lapatinib-resistant cancers. Cancer Res; 77(8); 1842-53. ©2017 AACR . ©2017 American Association for Cancer Research.

AIB1 is required for the acquisition of epithelial growth factor receptor-mediated tamoxifen resistance in breast cancer cells

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Zhao Wenhui; Zhang Qingyuan; Kang Xinmei; Jin Shi; Lou Changjie

2009-01-01

Acquired resistance to tamoxifen has become a serious obstacle in breast cancer treatment. The underlying mechanism responsible for this condition has not been completely elucidated. In this study, a tamoxifen-resistant (Tam-R) MCF-7 breast cancer cell line was developed to mimic the occurrence of acquired tamoxifen resistance as seen in clinical practice. Increased expression levels of HER1, HER2 and the estrogen receptor (ER)-AIB1 complex were found in tamoxifen-resistant cells. EGF stimulation and gefitinib inhibition experiments further demonstrated that HER1/HER2 signaling and AIB1 were involved in the proliferation of cells that had acquired Tam resistance. However, when AIB1 was silenced with AIB1-siRNA in Tam-R cells, the cell growth stimulated by the HER1/HER2 signaling pathway was significantly reduced, and the cells were again found to be inhibited by tamoxifen. These results suggest that the AIB1 protein could be a limiting factor in the HER1/HER2-mediated hormone-independent growth of Tam-R cells. Thus, AIB1 may be a new therapeutic target, and the removal of AIB1 may decrease the crosstalk between ER and the HER1/HER2 pathway, resulting in the restoration of tamoxifen sensitivity in tamoxifen-resistant cells.

Histologic transformation from adenocarcinoma to both small cell lung cancer and squamous cell carcinoma after treatment with gefitinib: A case report.

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Yao, Yufeng; Zhu, Zhouyu; Wu, Yimin; Chai, Ying

2018-05-01

In the past decade, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) treatment had been an important therapy for treating advanced EGFR-mutated lung cancer patients. However, a large number of these patients with EGFR-TKIs treatment always acquired resistance to these drugs in one year. The histologic transformation is an important resistance mechanism. Here we reported a 41-year-old man with EGFR-mutated lung adenocarcinoma and he showed histologic transformation to both small-cell lung cancer (SCLC) and squamous cell carcinoma (SCC) after treatment of gefitinib. A case of EGFR-mutated lung cancer. Medical thoracoscopy examination was performed and the patient was diagnosed as a EGFR-mutated lung adenocarcinoma. Then gefitinib was administered orally at a dose of 250 mg daily. The patient received treatment with chemotherapy (etoposide 0.1 g day 2-5 +  cis-platinum 30 mg day 2-4) after acquiring resistance to gefitinib. The patient died in April 2017 that survived for 32 months from lung cancer was found for the first time. To the best of our knowledge, it is the first case of EGFR-mutated lung adenocarcinoma transforming to both SCLC and SCC which was treated with and responded to gefitinib.

Pancreatic adenocarcinoma upregulated factor (PAUF) confers resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNA receptor-mediated signaling

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Kaowinn, Sirichat; Cho, Il-Rae; Moon, Jeong; Jun, Seung Won; Kim, Chang Seok [BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-736 (Korea, Republic of); Kang, Ho Young [Department of Microbiology, Pusan National University, Busan 609-736 (Korea, Republic of); Kim, Manbok [Department of Medical Science, Dankook University College of Medicine, Cheonan 330-714 (Korea, Republic of); Koh, Sang Seok [Department of Biological Sciences, Dong-A University, Busan 604-714 (Korea, Republic of); Chung, Young-Hwa, E-mail: younghc@pusan.ac.kr [BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-736 (Korea, Republic of)

2015-04-03

Pancreatic adenocarcinoma upregulated factor (PAUF), a novel oncogene, plays a crucial role in the development of pancreatic cancer, including its metastasis and proliferation. Therefore, PAUF-expressing pancreatic cancer cells could be important targets for oncolytic virus-mediated treatment. Panc-1 cells expressing PAUF (Panc-PAUF) showed relative resistance to parvovirus H-1 infection compared with Panc-1 cells expressing an empty vector (Panc-Vec). Of interest, expression of type I IFN-α receptor (IFNAR) was higher in Panc-PAUF cells than in Panc-Vec cells. Increased expression of IFNAR in turn increased the activation of Stat1 and Tyk2 in Panc-PAUF cells compared with that in Panc-Vec cells. Suppression of Tyk2 and Stat1, which are important downstream molecules for IFN-α signaling, sensitized pancreatic cancer cells to parvovirus H-1-mediated apoptosis. Further, constitutive suppression of PAUF sensitized Bxpc3 pancreatic cancer cells to parvovirus H-1 infection. Taken together, these results suggested that PAUF conferred resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNAR-mediated signaling. - Highlights: • PAUF confers resistance against oncolytic parvovirus H-1 infection. • PAUF enhances the expression of IFNAR in Panc-1 cells. • Increased activation of Tyk2 or Stat1 by PAUF provides resistance to parvovirus H-1-mediated apoptosis. • Constitutive inhibition of PAUF enhances parvovirus H-1-mediated oncolysis of Bxpc3 pancreatic cancer cells.

Pancreatic adenocarcinoma upregulated factor (PAUF) confers resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNA receptor-mediated signaling

International Nuclear Information System (INIS)

Kaowinn, Sirichat; Cho, Il-Rae; Moon, Jeong; Jun, Seung Won; Kim, Chang Seok; Kang, Ho Young; Kim, Manbok; Koh, Sang Seok; Chung, Young-Hwa

2015-01-01

Pancreatic adenocarcinoma upregulated factor (PAUF), a novel oncogene, plays a crucial role in the development of pancreatic cancer, including its metastasis and proliferation. Therefore, PAUF-expressing pancreatic cancer cells could be important targets for oncolytic virus-mediated treatment. Panc-1 cells expressing PAUF (Panc-PAUF) showed relative resistance to parvovirus H-1 infection compared with Panc-1 cells expressing an empty vector (Panc-Vec). Of interest, expression of type I IFN-α receptor (IFNAR) was higher in Panc-PAUF cells than in Panc-Vec cells. Increased expression of IFNAR in turn increased the activation of Stat1 and Tyk2 in Panc-PAUF cells compared with that in Panc-Vec cells. Suppression of Tyk2 and Stat1, which are important downstream molecules for IFN-α signaling, sensitized pancreatic cancer cells to parvovirus H-1-mediated apoptosis. Further, constitutive suppression of PAUF sensitized Bxpc3 pancreatic cancer cells to parvovirus H-1 infection. Taken together, these results suggested that PAUF conferred resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNAR-mediated signaling. - Highlights: • PAUF confers resistance against oncolytic parvovirus H-1 infection. • PAUF enhances the expression of IFNAR in Panc-1 cells. • Increased activation of Tyk2 or Stat1 by PAUF provides resistance to parvovirus H-1-mediated apoptosis. • Constitutive inhibition of PAUF enhances parvovirus H-1-mediated oncolysis of Bxpc3 pancreatic cancer cells

Integrating molecular mechanisms and clinical evidence in the management of trastuzumab resistant or refractory HER-2⁺ metastatic breast cancer.

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Wong, Hilda; Leung, Roland; Kwong, Ava; Chiu, Joanne; Liang, Raymond; Swanton, Charles; Yau, Thomas

2011-01-01

Human epidermal growth factor receptor (HER)-2(+) breast cancer is a distinct molecular and clinical entity, the prognosis of which is improved by trastuzumab. However, primary resistance to trastuzumab is observed in >50% of patients with HER-2(+) advanced breast cancer, and the majority of patients who initially respond to treatment eventually develop disease progression. To facilitate crosstrial comparisons and the understanding of resistance mechanisms, we propose a unifying definition of trastuzumab resistance as progression at first radiological reassessment at 8-12 weeks or within 3 months after first-line trastuzumab in the metastatic setting or new recurrences diagnosed during or within 12 months after adjuvant trastuzumab. In contrast, we define trastuzumab-refractory breast cancer as disease progression after two or more lines of trastuzumab-containing regimens that initially achieved disease response or stabilization at first radiological assessment. We review mechanisms of trastuzumab resistance mediated by p95HER-2 overexpression, phosphoinositide 3-kinase pathway activation, and signaling pathway activation driven by HER-3, epidermal growth factor receptor, and insulin-like growth factor 1 receptor. We distinguish in vitro from in vivo evidence, highlighting that most data describing trastuzumab resistance are derived from preclinical studies or small retrospective patient cohorts, and discuss targeted therapeutic approaches to overcome resistance. Prospective analysis through clinical trials with robust tissue collection procedures, prior to and following acquisition of resistance, integrated with next-generation tumor genome sequencing technologies, is identified as a priority area for development. The identification of predictive biomarkers is of paramount importance to optimize health economic costs and enhance stratification of anti-HER-2 targeted therapies.

Development of liposomal pemetrexed for enhanced therapy against multidrug resistance mediated by ABCC5 in breast cancer

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Bai F

2018-03-01

Full Text Available Fang Bai,1–3,* You Yin,4,* Ting Chen,1,* Jihui Chen,1 Meixin Ge,2 Yunshu Lu,2 Fangyuan Xie,5 Jian Zhang,1 Kejin Wu,3 Yan Liu1,6 1Department of Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 2Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 3Department of Breast Surgery, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, 4Department of Neurology, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, 5Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 6Department of Pharmacy, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, People’s Republic of China *These authors contributed equally to this work Purpose: Breast cancer is the most common cancer among women. Pemetrexed, a new generation antifolate drug, is one of the primary treatments for breast cancer. However, multidrug resistance (MDR in breast cancer greatly hampers the therapeutic efficacy of chemotherapies such as pemetrexed. Nanomedicine is emerging as a promising alternative technique to overcome cancer MDR. Thus, pemetrexed-loaded d-alpha tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS liposomes (liposomal pemetrexed were developed as a strategy to overcome MDR to pemetrexed in breast cancer. Materials and methods: Liposomal pemetrexed was developed using the calcium acetate gradient method. The cytotoxic effects, apoptosis-inducing activity, in vivo distribution, and antitumor activity of liposomal pemetrexed were investigated. Results: Liposomal pemetrexed was small in size (160.77 nm, with a small polydispersity of <0.1. The encapsulation efficacy of liposomal pemetrexed was 63.5%, which is rather high for water-soluble drugs in liposomes. The IC50 of liposomal pemetrexed following treatment with MDR breast cancer cells (MCF-7 cells overexpressing ABCC5

DNA origami as a carrier for circumvention of drug resistance.

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Jiang, Qiao; Song, Chen; Nangreave, Jeanette; Liu, Xiaowei; Lin, Lin; Qiu, Dengli; Wang, Zhen-Gang; Zou, Guozhang; Liang, Xingjie; Yan, Hao; Ding, Baoquan

2012-08-15

Although a multitude of promising anti-cancer drugs have been developed over the past 50 years, effective delivery of the drugs to diseased cells remains a challenge. Recently, nanoparticles have been used as drug delivery vehicles due to their high delivery efficiencies and the possibility to circumvent cellular drug resistance. However, the lack of biocompatibility and inability to engineer spatially addressable surfaces for multi-functional activity remains an obstacle to their widespread use. Here we present a novel drug carrier system based on self-assembled, spatially addressable DNA origami nanostructures that confronts these limitations. Doxorubicin, a well-known anti-cancer drug, was non-covalently attached to DNA origami nanostructures through intercalation. A high level of drug loading efficiency was achieved, and the complex exhibited prominent cytotoxicity not only to regular human breast adenocarcinoma cancer cells (MCF 7), but more importantly to doxorubicin-resistant cancer cells, inducing a remarkable reversal of phenotype resistance. With the DNA origami drug delivery vehicles, the cellular internalization of doxorubicin was increased, which contributed to the significant enhancement of cell-killing activity to doxorubicin-resistant MCF 7 cells. Presumably, the activity of doxorubicin-loaded DNA origami inhibits lysosomal acidification, resulting in cellular redistribution of the drug to action sites. Our results suggest that DNA origami has immense potential as an efficient, biocompatible drug carrier and delivery vehicle in the treatment of cancer.

MR imaging-guided sonography followed by fine-needle aspiration cytology in occult carcinoma of the breast

NARCIS (Netherlands)

A.I.M. Obdeijn (Inge-Marie); Brouwers-Kuyper, E.M.; M.M.A. Tilanus-Linthorst (Madeleine); T. Wiggers (Theo); M. Oudkerk (Matthijs)

2000-01-01

markdownabstractOBJECTIVE. In patients with axillary metastases as clinical evidence of possible occult breast cancer, a combined approach of MR imaging, sonography, and aspiration biopsy cytology was evaluated. SUBJECTS AND METHODS. Thirty-one women with metastatic adenocarcinoma in their

Long-term follow-up of advanced bladder adenocarcinoma

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Karen Korkes

2009-12-01

Full Text Available Objective: to evaluate patients treated with primary bladder adenocarcinoma at our institution. Methods: A review of 30 patients diagnosed with bladder adenocarcinoma at a single institution from 1994 of 2005 was undertaken. Cases of primary bladder adenocarcinoma were retrospectively evaluated. Rresults: Out of 490 patients with bladder carcinoma, 30 had bladder adenocarcinoma: 22 metastatic tumors, eight (1.6% primary adenocarcinoma. Of these, three (0.6% were primary non-urachal and five (1.0% were urachal adenocarcinoma. All patients were men with mean age of 55.8 years (range 37-83. Dysuria and hematuria were the main symptoms reported. Of the total, four patients had cancer-related mortality. Cconclusion: Primary bladder adenocarcinoma is a rare neoplasm, observed in 1.6% patients with bladder malignancies. Late diagnosis limits therapeutic possibilities. Partial cystectomy seems to have unsatisfactory results and radical cystectomy, although remains as the gold standard, have no proven efficacy. New methods of adjuvant treatment must be studied to improve treatment outcomes, as high mortality is observed despite treatment.

Chemoradiation for adenocarcinoma of the anus

International Nuclear Information System (INIS)

Papagikos, Michael; Crane, Christopher H.; Skibber, John; Janjan, Nora A.; Feig, Barry; Rodriguez-Bigas, Miguel A.; Hung, Arthur; Wolff, Robert A.; Delclos, Marc; Lin, Edward; Cleary, Karen

2003-01-01

Purpose: To assess the efficacy and limitations of definitive chemoradiation for adenocarcinoma of the anal canal and to propose a treatment strategy that addresses the limitations of treatment. Methods and Materials: Between 1976 and 1998, 16 patients with localized adenocarcinoma of the anal canal were treated with radiotherapy with or without chemotherapy with curative intent. Available histologic slides were reviewed for evidence of primary adenocarcinoma of anal duct origin. The treatment results for these patients were compared with those of a group of patients with epidermoid histologic features who were all treated with definitive chemoradiation (55 Gy with concurrent 5-fluorouracil and cisplatin, n=92) between 1989 and 1998. The hospital records were reviewed for all patients. Patients with epidermoid carcinoma presented with more advanced primary tumors (42% vs. 19% Stage T3 or greater). All adenocarcinoma patients were treated with radiotherapy (median dose 55 Gy): 11 received concurrent 5-fluorouracil-based chemotherapy and 5 received radiotherapy alone. The initial surgical procedures included abdominoperineal resection, excisional biopsies (n=5), and local excision (n=1). Abdominoperineal resection was performed as salvage therapy after local recurrence in 5 patients. The Kaplan-Meier method was used to calculate 5-year actuarial pelvic control, distant disease control, disease-free survival, and overall survival. The median follow-up was 45 months (range 5-196) for patients with adenocarcinoma and 44 months (range 9-115) for patients with epidermoid histologic features. Results: Both local and distant recurrence rates were significantly greater in the adenocarcinoma patients. Of 16 patients with adenocarcinoma, 7 (5-year actuarial rate 54%) had recurrence at the primary site compared with 16 (5-year actuarial rate 18%) of 92 patients with epidermoid histologic features (p=0.004). Distant disease developed in more patients with adenocarcinoma (5-year

ABRAXAS (FAM175A) and Breast Cancer Susceptibility: No Evidence of Association in the Breast Cancer Family Registry.

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Renault, Anne-Laure; Lesueur, Fabienne; Coulombe, Yan; Gobeil, Stéphane; Soucy, Penny; Hamdi, Yosr; Desjardins, Sylvie; Le Calvez-Kelm, Florence; Vallée, Maxime; Voegele, Catherine; Hopper, John L; Andrulis, Irene L; Southey, Melissa C; John, Esther M; Masson, Jean-Yves; Tavtigian, Sean V; Simard, Jacques

2016-01-01

Approximately half of the familial aggregation of breast cancer remains unexplained. This proportion is less for early-onset disease where familial aggregation is greater, suggesting that other susceptibility genes remain to be discovered. The majority of known breast cancer susceptibility genes are involved in the DNA double-strand break repair pathway. ABRAXAS is involved in this pathway and mutations in this gene impair BRCA1 recruitment to DNA damage foci and increase cell sensitivity to ionizing radiation. Moreover, a recurrent germline mutation was reported in Finnish high-risk breast cancer families. To determine if ABRAXAS could be a breast cancer susceptibility gene in other populations, we conducted a population-based case-control mutation screening study of the coding exons and exon/intron boundaries of ABRAXAS in the Breast Cancer Family Registry. In addition to the common variant p.Asp373Asn, sixteen distinct rare variants were identified. Although no significant difference in allele frequencies between cases and controls was observed for the identified variants, two variants, p.Gly39Val and p.Thr141Ile, were shown to diminish phosphorylation of gamma-H2AX in MCF7 human breast adenocarcinoma cells, an important biomarker of DNA double-strand breaks. Overall, likely damaging or neutral variants were evenly represented among cases and controls suggesting that rare variants in ABRAXAS may explain only a small proportion of hereditary breast cancer.

Ajwa Date (Phoenix dactylifera L. Extract Inhibits Human Breast Adenocarcinoma (MCF7 Cells In Vitro by Inducing Apoptosis and Cell Cycle Arrest.

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Fazal Khan

Full Text Available Phoenix dactylifera L (Date palm is a native plant of the Kingdom of Saudi Arabia (KSA and other Middle Eastern countries. Ajwa date has been described in the traditional and alternative medicine to provide several health benefits including anticholesteremic, antioxidant, hepatoprotective and anticancer effects, but most remains to be scientifically validated. Herein, we evaluated the anticancer effects of the Methanolic Extract of Ajwa Date (MEAD on human breast adenocarcinoma (MCF7 cells in vitro.MCF7 cells were treated with various concentrations (5, 10, 15, 20 and 25 mg/ml of MEAD for 24, 48 and 72 h and changes in cell morphology, cell cycle, apoptosis related protein and gene expression were studied.Phase contrast microscopy showed various morphological changes such as cell shrinkage, vacuolation, blebbing and fragmentation. MTT (2-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide assay demonstrated statistically significant dose-dependent inhibitions of MCF7 cell proliferation from 35% to 95%. Annexin V-FITC and TUNEL assays showed positive staining for apoptosis of MCF7 cells treated with MEAD (15 mg and 25 mg for 48 h. Flow cytometric analyses of MCF7 cells with MEAD (15 mg/ml and 20 mg/ml for 24 h demonstrated cell cycle arrest at 'S' phase; increased p53, Bax protein expression; caspase 3activation and decreased the mitochondrial membrane potential (MMP. Quantitative real time PCR (qRT-PCR analysis showed up-regulation of p53, Bax, Fas, and FasL and down-regulation of Bcl-2.MEAD inhibited MCF7 cells in vitro by the inducing cell cycle arrest and apoptosis. Our results indicate the anticancer effects of Ajwa dates, which therefore may be used as an adjunct therapy with conventional chemotherapeutics to achieve a synergistic effect against breast cancer.

Mitochondrial thiol modification by a targeted electrophile inhibits metabolism in breast adenocarcinoma cells by inhibiting enzyme activity and protein levels

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M. Ryan Smith

2016-08-01

Full Text Available Many cancer cells follow an aberrant metabolic program to maintain energy for rapid cell proliferation. Metabolic reprogramming often involves the upregulation of glutaminolysis to generate reducing equivalents for the electron transport chain and amino acids for protein synthesis. Critical enzymes involved in metabolism possess a reactive thiolate group, which can be modified by certain oxidants. In the current study, we show that modification of mitochondrial protein thiols by a model compound, iodobutyl triphenylphosphonium (IBTP, decreased mitochondrial metabolism and ATP in MDA-MB 231 (MB231 breast adenocarcinoma cells up to 6 days after an initial 24 h treatment. Mitochondrial thiol modification also depressed oxygen consumption rates (OCR in a dose-dependent manner to a greater extent than a non-thiol modifying analog, suggesting that thiol reactivity is an important factor in the inhibition of cancer cell metabolism. In non-tumorigenic MCF-10A cells, IBTP also decreased OCR; however the extracellular acidification rate was significantly increased at all but the highest concentration (10 µM of IBTP indicating that thiol modification can have significantly different effects on bioenergetics in tumorigenic versus non-tumorigenic cells. ATP and other adenonucleotide levels were also decreased by thiol modification up to 6 days post-treatment, indicating a decreased overall energetic state in MB231 cells. Cellular proliferation of MB231 cells was also inhibited up to 6 days post-treatment with little change to cell viability. Targeted metabolomic analyses revealed that thiol modification caused depletion of both Krebs cycle and glutaminolysis intermediates. Further experiments revealed that the activity of the Krebs cycle enzyme, aconitase, was attenuated in response to thiol modification. Additionally, the inhibition of glutaminolysis corresponded to decreased glutaminase C (GAC protein levels, although other protein levels were

Administration of the optimized β-Lapachone-poloxamer-cyclodextrin ternary system induces apoptosis, DNA damage and reduces tumor growth in a human breast adenocarcinoma xenograft mouse model.

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Seoane, Samuel; Díaz-Rodríguez, Patricia; Sendon-Lago, Juan; Gallego, Rosalia; Pérez-Fernández, Román; Landin, Mariana

2013-08-01

β-Lapachone (β-Lap) is a 1,2-orthonaphthoquinone that selectively induces cell death in human cancer cells through NAD(P)H:quinone oxidoreductase-1 (NQO1). NQO1 is overexpressed in a variety of tumors, as compared to normal adjacent tissue. However, the low solubility and non-specific distribution of β-Lap limit its suitability for clinical assays. We formulated β-Lap in an optimal random methylated-β-cyclodextrin/poloxamer 407 mixture (i.e., β-Lap ternary system) and, using human breast adenocarcinoma MCF-7 cells and immunodeficient mice, performed in vitro and in vivo evaluation of its anti-tumor effects on proliferation, cell cycle, apoptosis, DNA damage, and tumor growth. This ternary system is fluid at room temperature, gels over 29 °C, and provides a significant amount of drug, thus facilitating intratumoral delivery, in situ gelation, and the formation of a depot for time-release. Administration of β-Lap ternary system to MCF-7 cells induces an increase in apoptosis and DNA damage, while producing no changes in cell cycle. Moreover, in a mouse xenograft tumor model, intratumoral injection of the system significantly reduces tumor volume, while increasing apoptosis and DNA damage without visible toxicity to liver or kidney. These anti-tumoral effects and lack of visible toxicity make this system a promising new therapeutic agent for breast cancer treatment. Copyright © 2013 Elsevier B.V. All rights reserved.

Outcomes with single agent LIPO-DOX in platinum-resistant ovarian and fallopian tube cancers and primary peritoneal adenocarcinoma - Chiang Mai University Hospital experience.

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Suprasert, Prapaporn; Manopunya, Manatsawee; Cheewakriangkrai, Chalong

2014-01-01

Single pegylated liposomal doxorubicin (PLD) is commonly used as a salvage treatment in platinum-resistant ovarian cancer, fallopian tube cancer and primary peritoneal adenocarcinoma (PPA) with a satisfactory outcome. However, the data for second generation PLD administered in this setting are still limited. We conducted a retrospective study to evaluate the outcome of patients who received single-agent second generation PLD (LIPO-DOX) after the development of clinical platinum resistance. The study period was between March 2008 and March 2013. LIPO-DOX was administered intravenously 40 mg/m2 every 28 days until disease progression, but for not more than six cycles. The response rate was evaluated using the Gynecologic Cancer Intergroup (GCIG) criteria while the toxicity was evaluated according to WHO criteria. Twenty-nine patients met the inclusion criteria in the study period with an overall response rate of 13.8%. The median progression free survival and overall survival were three and eleven months, respectively. With the total of 96 cycles of chemotherapy, the patients developed grades 3 and 4 hematologic toxicity as follows: anemia, 0%, leukopenia, 9.6%, neutropenia, 32.3% and thrombocytopenia, 0%. In conclusion, the single agent second generation PLD demonstrated modest efficacy in patients with platinum-resistant ovarian cancer, fallopian tube cancer and PPA without serious toxicity.

A kinase inhibitor screen identifies Mcl-1 and Aurora kinase A as novel treatment targets in antiestrogen-resistant breast cancer cells

DEFF Research Database (Denmark)

Thrane, S; Pedersen, A M; Thomsen, M B H

2015-01-01

Antiestrogen resistance is a major problem in breast cancer treatment. Therefore, the search for new therapeutic targets and biomarkers for antiestrogen resistance is crucial. In this study, we performed a kinase inhibitor screen on antiestrogen responsive MCF-7 cells and a panel of MCF-7-derived...

Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions

NARCIS (Netherlands)

Breedveld, Pauline; Zelcer, Noam; Pluim, Dick; Sönmezer, Ozgür; Tibben, Matthijs M.; Beijnen, Jos H.; Schinkel, Alfred H.; van Tellingen, Olaf; Borst, Piet; Schellens, Jan H. M.

2004-01-01

The antifolate drug methotrexate (MTX) is transported by breast cancer resistance protein (BCRP; ABCG2) and multidrug resistance-associated protein1-4 (MRP1-4; ABCC1-4). In cancer patients, coadministration of benzimidazoles and MTX can result in profound MTX-induced toxicity coinciding with an

Fine-needle aspiration of gray zone lesions of the breast: fibroadenoma versus ductal carcinoma.

Science.gov (United States)

Jing, Xin; Normolle, Daniel; Michael, Claire W

2013-09-01

While breast lesions have characteristic cytological features, some lesions, particularly adenocarcinoma and fibroadenoma, may present with overlapping features causing erroneous diagnoses. The current study aimed to define significant cytomorphologic features predictive of fibroadenoma and adenocarcinoma, respectively. Further, we intended to evaluate the predictive characteristics for differentiation between gray zone lesions and to identify root causes contributing to misdiagnoses. First, direct smears prepared from 14 histology-confirmed fibroadenomas and 14 adenocarcinomas were reviewed and characteristics of commonly encountered morphologic features were assessed. We then retrospectively and blindly reviewed nine cytohistologic discrepant cases using the significant characteristic as a guideline, in order to assess whether these discrepant cases could be correctly categorized. Morphologic characteristics predictive of fibroadenoma included moderate cellularity, large, folded cellular sheets/aggregates, staghorn projections, smooth and round borders, monolayers, honeycomb arrangement, smaller nuclear size, and background bipolar cells. Predictive characteristics of adenocarcinoma included high cellularity, loose cohesive sheets/aggregates, pointed projections, irregular borders, larger nuclear size, irregular nuclear membrane, prominent nucleoli, and single atypical epithelial cells. Retrospective, blind review correctly re-classified seven out of nine cytohistologic discrepant cases, including five false negative cases and two false positive cases. Root causes contributing to the misdiagnoses were large branching sheets of carcinoma mimicking folded sheets of fibroadenoma; fibroblasts mimicking myoepithelial cells; apocrine cells mimicking carcinoma cells; and not recognizing the loose myxoid matrix presenting as soap bubbles in fibroadenoma. In conclusion, this study identified significant characteristics that can assist in achieving accurate diagnosis in a

Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas

NARCIS (Netherlands)

Liu, Yang; Sethi, Nilay S; Hinoue, Toshinori; Schneider, Barbara G; Cherniack, Andrew D; Sanchez-Vega, Francisco; Seoane, Jose A; Farshidfar, Farshad; Bowlby, Reanne; Islam, Mirazul; Kim, Jaegil; Chatila, Walid; Akbani, Rehan; Kanchi, Rupa S; Rabkin, Charles S; Willis, Joseph E; Wang, Kenneth K; McCall, Shannon J; Mishra, Lopa; Ojesina, Akinyemi I; Bullman, Susan; Pedamallu, Chandra Sekhar; Lazar, Alexander J; Sakai, Ryo; Thorsson, Vésteinn; Bass, Adam J; Laird, Peter W; de Krijger, RR

2018-01-01

We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for

EGF receptor-targeted synthetic double-stranded RNA eliminates glioblastoma, breast cancer, and adenocarcinoma tumors in mice.

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Alexei Shir

2006-01-01

Full Text Available BACKGROUND: Glioblastoma multiforme (GBM is the most lethal form of brain cancer. With the available treatments, survival does not exceed 12-14 mo from the time of diagnosis. We describe a novel strategy to selectively induce the death of glioblastoma cells and other cancer cells that over-express the EGF receptor. Using a non-viral delivery vector that homes to the EGF receptor, we target synthetic anti-proliferative dsRNA (polyinosine-cytosine [poly IC], a strong activator of apoptosis, selectively to cancer cells. METHODS AND FINDINGS: Poly IC was delivered by means of a non-viral vector: 25kDa polyethylenimine-polyethyleneglycol-EGF (PEI25-PEG-EGF. EGFR-targeted poly IC induced rapid apoptosis in the target cells in vitro and in vivo. Expression of several cytokines and "bystander killing" of untransfected tumor cells was detected in vitro and in vivo. Intra-tumoral delivery of the EGFR-targeted poly IC induced the complete regression of pre-established intracranial tumors in nude mice, with no obvious adverse toxic effects on normal brain tissue. A year after treatment completion the treated mice remain cancer-free and healthy. Similarly, non-viral delivery of poly IC completely eliminated pre-established breast cancer and adenocarcinoma xenografts derived from EGFR over-expressing cancer cell lines, suggesting that the strategy is applicable to other EGFR-over-expressing tumors. CONCLUSION: The strategy described has yielded an effective treatment of EGFR over-expressing GBM in an animal model. If this strategy is translated successfully to the clinical setting, it may actually offer help to GBM patients. Moreover the elimination of two additional EGFR over-expressing cancers in vivo suggests that in principle this strategy can be applied to treat other tumors that over-express EGFR.

Poly(ADP-ribose polymerase 1 (PARP1 overexpression in human breast cancer stem cells and resistance to olaparib.

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Marine Gilabert

Full Text Available BACKGROUND: Breast cancer stem cells (BCSCs have been recognized as playing a major role in various aspects of breast cancer biology. To identify specific biomarkers of BCSCs, we have performed comparative proteomics of BCSC-enriched and mature cancer cell populations from the human breast cancer cell line (BCL, BrCA-MZ-01. METHODS: ALDEFLUOR assay was used to sort BCSC-enriched (ALDH+ and mature cancer (ALDH- cell populations. Total proteins were extracted from both fractions and subjected to 2-Dimensional Difference In-Gel Electrophoresis (2-D DIGE. Differentially-expressed spots were excised and proteins were gel-extracted, digested and identified using MALDI-TOF MS. RESULTS: 2-D DIGE identified poly(ADP-ribose polymerase 1 (PARP1 as overexpressed in ALDH+ cells from BrCA-MZ-01. This observation was confirmed by western blot and extended to four additional human BCLs. ALDH+ cells from BRCA1-mutated HCC1937, which had the highest level of PARP1 overexpression, displayed resistance to olaparib, a specific PARP1 inhibitor. CONCLUSION: An unbiased proteomic approach identified PARP1 as upregulated in ALDH+, BCSC-enriched cells from various human BCLs, which may contribute to clinical resistance to PARP inhibitors.

β-Elemene Reverses Chemoresistance of Breast Cancer Cells by Reducing Resistance Transmission via Exosomes

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Jun Zhang

2015-07-01

Full Text Available Background: Currently, exosomes that act as mediators of intercellular communication are being researched extensively. Our previous studies confirmed that these exosomes contain microRNAs (miRNAs that could alter chemo-susceptibility, which is partly attributed to the successful intercellular transfer of multidrug resistance (MDR-specific miRNAs. We also confirmed that β-elemene could influence MDR-related miRNA expression and regulate the expression of the target genes PTEN and Pgp, which may lead to the reversal of the chemoresistant breast cancer (BCA cells. We are the first to report these findings, and we propose the following logical hypothesis: β-elemene can mediate MDR-related miRNA expression in cells, thereby affecting the exosome contents, reducing chemoresistance transmission via exosomes, and reversing the drug resistance of breast cancer cells. Methods: MTT-cytotoxic, miRNA microarray, real-time quantitative PCR, Dual Luciferase Activity Assay, and Western blot analysis were performed to investigate the impact of β-elemene on the expression of chemoresistance specific miRNA and PTEN as well as Pgp in chemoresistant BCA exosomes. Results: Drug resistance can be reversed by β-elemene related to exosomes. There were 104 differentially expressed miRNAs in the exosomes of two chemoresistant BCA cells: adriacin (Adr - resistant MCF-7 cells (MCF-7/Adr and docetaxel (Doc - resistant MCF-7 cells (MCF-7/Doc that underwent treatment. Of these, 31 miRNAs were correlated with the constant changes in the MDR. The expression of miR-34a and miR-452 can lead to changes in the characteristics of two chemoresistant BCA exosomes: MCF-7/Adr exosomes (A/exo and MCF-7/Doc exosomes (D/exo. The PTEN expression affected by β-elemene was significantly increased, and the Pgp expression affected by β-elemene was significantly decreased in both cells and exosomes. β-elemene induced a significant increase in the apoptosis rate in both MCF-7/Doc and MCF-7

Breast cancers radiation-resistance: key role of the cancer stem cells marker CD24

International Nuclear Information System (INIS)

Bensimon, Julie

2013-01-01

This work focuses on the characterization of radiation-resistant breast cancer cells, responsible for relapse after radiotherapy. The 'Cancer Stem Cells' (CSC) theory describes a radiation-resistant cellular sub-population, with enhanced capacity to induce tumors and proliferate. In this work, we show that only the CSC marker CD24-/low defines a radiation resistant cell population, able to transmit the 'memory' of irradiation, expressed as long term genomic instability in the progeny of irradiated cells. We show that CD24 is not only a marker, but is an actor of radiation-response. So, CD24 expression controls cell proliferation in vitro and in vivo, and ROS level before and after irradiation. As a result, CD24-/low cells display enhanced radiation-resistance and genomic stability. For the first time, our results attribute a role to CD24-/low CSCs in the transmission of genomic instability. Moreover, by providing informations on tumor intrinsic radiation-sensitivity, CD24- marker could help to design new radiotherapy protocols. (author)

Involvement of CUL4A in Regulation of Multidrug Resistance to P-gp Substrate Drugs in Breast Cancer Cells

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Yunshan Wang

2013-12-01

Full Text Available CUL4A encodes a core component of a cullin-based E3 ubiquitin ligase complex that regulates many critical processes such as cell cycle progression, DNA replication, DNA repair and chromatin remodeling by targeting a variety of proteins for ubiquitination and degradation. In the research described in this report we aimed to clarify whether CUL4A participates in multiple drug resistance (MDR in breast cancer cells. We first transfected vectors carrying CUL4A and specific shCUL4A into breast cancer cells and corresponding Adr cells respectively. Using reverse transcription polymerase chain reactions and western blots, we found that overexpression of CUL4A in MCF7 and MDA-MB-468 cells up-regulated MDR1/P-gp expression on both the transcription and protein levels, which conferred multidrug resistance to P-gp substrate drugs, as determined by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assays. On the other hand, silencing CUL4A in MCF7/Adr and MDA-MB-468/Adr cells led to the opposite effect. Moreover, ERK1/2 in CUL4A-overexpressing cells was highly activated and after treatment with PD98059, an ERK1/2-specific inhibitor, CUL4A-induced expression of MDR1/P-gp was decreased significantly. Lastly, immunohistochemistry in breast cancer tissues showed that P-gp expression had a positive correlation with the expression of CUL4A and ERK1/2. Thus, these results implied that CUL4A and ERK1/2 participated in multi-drug resistance in breast cancer through regulation of MDR1/P-gp expression.

Interaction of CDCP1 with HER2 Enhances HER2-Driven Tumorigenesis and Promotes Trastuzumab Resistance in Breast Cancer

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Abdullah Alajati

2015-04-01

Full Text Available Understanding the molecular pathways that contribute to the aggressive behavior of HER2-positive breast cancers may aid in the development of novel therapeutic interventions. Here, we show that CDCP1 and HER2 are frequently co-overexpressed in metastatic breast tumors and associated with poor patient prognosis. HER2 and CDCP1 co-overexpression leads to increased transformation ability, cell migration, and tumor formation in vivo, and enhanced HER2 activation and downstream signaling in different breast cancer cell lines. Mechanistically, we demonstrate that CDCP1 binds to HER2 through its intracellular domain, thereby increasing HER2 interaction with the non-receptor tyrosine kinase c-SRC (SRC, leading to trastuzumab resistance. Taken together, our findings establish that CDCP1 is a modulator of HER2 signaling and a biomarker for the stratification of breast cancer patients with poor prognosis. Our results also provide a rationale for therapeutic targeting of CDCP1 in HER2-positive breast cancer patients.

Bisphenol A activates EGFR and ERK promoting proliferation, tumor spheroid formation and resistance to EGFR pathway inhibition in estrogen receptor negative inflammatory breast cancer cells

Science.gov (United States)

Background: Inflammatory breast cancer (IBC) is a distinct and the deadliest breast cancer variant, which shows a rapid rate of progression and acquired therapeutic resistance. Epidemiological studies suggest that chemical exposure in the environment and consumer products can aff...

Association of ABCB1, β tubulin I, and III with multidrug resistance of MCF7/DOC subline from breast cancer cell line MCF7.

Science.gov (United States)

Li, Wentao; Zhai, Baoping; Zhi, Hui; Li, Yuhong; Jia, Linjiao; Ding, Chao; Zhang, Bin; You, Wei

2014-09-01

Docetaxel is a first-line chemotherapeutic agent for treating advanced breast cancer. The development of chemoresistance or multidrug resistance (MDR), however, results in breast cancer chemotherapy failure. This study aims to explore the molecular mechanisms underlying docetaxel-resistance in treatment of breast cancer. The docetaxel-resistant subline MCF7/DOC, derived from the parental sensitive breast cancer cell line MCF7, was established by intermittent exposure to moderate concentrations of docetaxel, followed by examination of its phenotypes. The MCF7/DOC subline showed cross resistance against paclitaxel, doxorubicin, methotrexate, and 5-Fu. Compared to the parental MCF7, MCF7/DOC cells were enlarged with heterogeneous sizes and a cobblestone and polygonal appearance. They were arrested at G2/M phase and proliferated slowly. The colony formation potential of MCF7/DOC in soft agar was significantly increased. MCF7/DOC cells showed reduced intracellular accumulation and increased efflux of rhodamine 123. The mRNA expression level of adenosine triphosphate binding cassette (ABC) transporter family, i.e., ABCB1, ABCC1, ABCC2, ABCG2, and β tubulin isotypes were characterized by quantitative PCR. High-level expression of ABCB1, βI, and βIII tubulin mRNA in MCF7/DOC was detected. Downregulation of ABCB1, βI, and βIII tubulin mediated by three combined siRNAs resulted in stronger growth inhibition of MCF7/DOC than inhibition of the expression of individual genes. ABCB1, βI, and βIII tubulin might contribute to the MDR of MCF7/DOC and be potential therapeutic targets for overcoming MDR of breast cancer.

Ground-glass nodule on thin-section CT: Differentiation among adenocarcinoma in situ, minimally invasive adenocarcinoma and lepidic predominant invasive adenocarcinoma

International Nuclear Information System (INIS)

Lee, Man Ho; Ryu, Dae Shick; Kim, Do Young; Ahn, Jae Hong; Choi, Soo Jung; Gang, Gil Hyeon; Yoo, Dong Gon; Shin, Dong Rock

2015-01-01

To investigate different computed tomography (CT) features among adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic predominant invasive adenocarcinoma (LPA) that appeared as ground-glass nodules (GGN). We also analyzed different CT findings between Group A (AIS and MIA) and Group B (LPA). We evaluated 19 AIS, 4 MIA, and 9 LPA images that were histologically confirmed and manifested as GGN on thin-section CT scans. CT scans were assessed for lesion characteristics: size, shape, solid portion, internal air density, marginal irregularity and pleural tag. CT findings of Group A and Group B were analyzed using the Kruskal-Wallis test or Fisher's exact test. A significant statistical difference was seen between AIS and LPA for lesion characteristics (p < 0.05). No significant difference was observed between AIS and MIA. Round or polygonal shape with smooth margin was significantly associated with Group A, and complex shape with marginal irregularity was associated with Group B. Group A (AIS and MIA) could be distinguished from Group B (LPA) by smaller lesion size, round or polygonal shape, smaller solid portion and smooth margin

Ground-glass nodule on thin-section CT: Differentiation among adenocarcinoma in situ, minimally invasive adenocarcinoma and lepidic predominant invasive adenocarcinoma

Energy Technology Data Exchange (ETDEWEB)

Lee, Man Ho; Ryu, Dae Shick; Kim, Do Young; Ahn, Jae Hong; Choi, Soo Jung; Gang, Gil Hyeon; Yoo, Dong Gon; Shin, Dong Rock [Gangneung Asan Hospital, College of Medicine, University of Ulsan, Gangneung (Korea, Republic of)

2015-12-15

To investigate different computed tomography (CT) features among adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic predominant invasive adenocarcinoma (LPA) that appeared as ground-glass nodules (GGN). We also analyzed different CT findings between Group A (AIS and MIA) and Group B (LPA). We evaluated 19 AIS, 4 MIA, and 9 LPA images that were histologically confirmed and manifested as GGN on thin-section CT scans. CT scans were assessed for lesion characteristics: size, shape, solid portion, internal air density, marginal irregularity and pleural tag. CT findings of Group A and Group B were analyzed using the Kruskal-Wallis test or Fisher's exact test. A significant statistical difference was seen between AIS and LPA for lesion characteristics (p < 0.05). No significant difference was observed between AIS and MIA. Round or polygonal shape with smooth margin was significantly associated with Group A, and complex shape with marginal irregularity was associated with Group B. Group A (AIS and MIA) could be distinguished from Group B (LPA) by smaller lesion size, round or polygonal shape, smaller solid portion and smooth margin.

Adenocarcinoma of urinary bladder: A report of two patients

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Nitu Kumari

2015-01-01

Full Text Available Adenocarcinoma of the bladder is a rare tumor. Primary and metastatic adenocarcinomas of urinary bladder are morphologically similar, but histogenetically different. We present two cases, a signet ring cell adenocarcinoma with follow-up and another of glandular adenocarcinoma of urinary bladder. Pathological evaluation and immunohistochemical panel of eight markers (E-cadherin, CK20, CK7, CDX2, estrogen receptor (ER, gross cystic disease fluid protein 15 (GCDFP15, 34bE12, and prostate specific antigen (PSA provides a diagnostic confirmation of primary adenocarcinoma with the positive expression of E-cadherin and CK20 in case 1 and metastatic adenocarcinoma of prostate with profile of E-cadherin+, CK20-, GCDFP15+, 34bE12+, and PSA+ in case 2.

Adenocarcinoma of urinary bladder: A report of two patients.

Science.gov (United States)

Kumari, Nitu; Vasudeva, Pawan; Kumar, Anup; Agrawal, Usha

2015-01-01

Adenocarcinoma of the bladder is a rare tumor. Primary and metastatic adenocarcinomas of urinary bladder are morphologically similar, but histogenetically different. We present two cases, a signet ring cell adenocarcinoma with follow-up and another of glandular adenocarcinoma of urinary bladder. Pathological evaluation and immunohistochemical panel of eight markers (E-cadherin, CK20, CK7, CDX2, estrogen receptor (ER), gross cystic disease fluid protein 15 (GCDFP15), 34bE12, and prostate specific antigen (PSA) provides a diagnostic confirmation of primary adenocarcinoma with the positive expression of E-cadherin and CK20 in case 1 and metastatic adenocarcinoma of prostate with profile of E-cadherin+, CK20-, GCDFP15+, 34bE12+, and PSA+ in case 2.

Comparison of glycoprotein expression between ovarian and colon adenocarcinomas

DEFF Research Database (Denmark)

Multhaupt, H A; Arenas-Elliott, C P; Warhol, M J

1999-01-01

, carcinoembryonic antigen, and cytokeratins 7 and 20 to detect tumor-associated glycoproteins and keratin proteins in ovarian and colonic carcinomas. RESULTS: CA125, carcinoembryonic antigen, and cytokeratins 7 and 20 can distinguish between colonic and serous or endometrioid adenocarcinomas of the ovary in both...... primary and metastatic lesions. Mucinous ovarian adenocarcinomas differed in that they express carcinoembryonic antigen and cytokeratins 7 and 20 and weakly express CA125. The other glycoprotein antigens were equally expressed by ovarian and colonic adenocarcinomas and therefore were of no use...... in distinguishing between these 2 entities. CONCLUSION: A panel of monoclonal antibodies against cytokeratins 7 and 20 antigens, CA125, and carcinoembryonic antigen is useful in differentiating serous and endometrioid adenocarcinomas of the ovary from colonic adenocarcinomas. Mucinous ovarian adenocarcinomas cannot...

Laparoscopic Diagnosis of Adenocarcinoma of the Appendix Mimicking Serous Papillary Adenocarcinoma of the Peritoneum

OpenAIRE

Yoshimura, Mayumi; Terai, Yoshito; Konishi, Hiromi; Tanaka, Yoshimichi; Tanaka, Tomohito; Sasaki, Hiroshi; Ohmichi, Masahide

2013-01-01

Primary carcinoma of the vermiform appendix is a rare disease with few clinical symptoms. Accordingly, preoperative diagnosis of appendiceal cancer is challenging because of the lack of specific symptoms. We herein report a case of appendicular adenocarcinoma found unexpectedly during laparoscopic surgery in a 69-year-old Japanese female patient diagnosed with serous papillary adenocarcinoma, in order to determine whether optimal cytoreduction could successfully be achieved at the time of pri...

Follistatin is a novel biomarker for lung adenocarcinoma in humans.

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Fangfang Chen

Full Text Available Follistatin (FST, a single chain glycoprotein, is originally isolated from follicular fluid of ovary. Previous studies have revealed that serum FST served as a biomarker for pregnancy and ovarian mucinous tumor. However, whether FST can serve as a biomarker for diagnosis in lung adenocarcinoma of humans remains unclear.The study population consisted of 80 patients with lung adenocarcinoma, 40 patients with ovarian adenocarcinoma and 80 healthy subjects. Serum FST levels in patients and healthy subjects were measured using ELISA. The results showed that the positive ratio of serum FST levels was 51.3% (41/80, which was comparable to the sensitivity of FST in 40 patients with ovarian adenocarcinoma (60%, 24/40 using the 95th confidence interval for the healthy subject group as the cut-off value. FST expressions in lung adenocarcinoma were examined by immunohistochemical staining, we found that lung adenocarcinoma could produce FST and there was positive correlation between the level of FST expression and the differential degree of lung adenocarcinoma. Furthermore, the results showed that primary cultured lung adenocarcinoma cells could secrete FST, while cells derived from non-tumor lung tissues almost did not produce FST. In addition, the results of CCK8 assay and flow cytometry showed that using anti-FST monoclonal antibody to neutralize endogenous FST significantly augmented activin A-induced lung adenocarcinoma cells apoptosis.These data indicate that lung adenocarcinoma cells can secret FST into serum, which may be beneficial to the survival of adenocarcinoma cells by neutralizing activin A action. Thus, FST can serve as a promising biomarker for diagnosis of lung adenocarcinoma and a useful biotherapy target for lung adenocarcinoma.

Association of visceral adiposity with oesophageal and junctional adenocarcinomas.

LENUS (Irish Health Repository)

Beddy, P

2012-02-01

BACKGROUND: Obesity is associated with an increased incidence of oesophageal and oesophagogastric junction adenocarcinoma, in particular Siewert types I and II. This study compared abdominal fat composition in patients with oesophageal\\/junctional adenocarcinoma with that in patients with oesophageal squamous cell carcinoma and gastric adenocarcinoma, and in controls. METHOD: In total, 194 patients (110 with oesophageal\\/junctional adenocarcinoma, 38 with gastric adenocarcinoma and 46 with oesophageal squamous cell carcinoma) and 90 matched control subjects were recruited. The abdominal fat area was assessed using computed tomography (CT), and the total fat area (TFA), visceral fat area (VFA) and subcutaneous fat area (SFA) were calculated. RESULTS: Patients with oesophageal\\/junctional adenocarcinoma had significantly higher TFA and VFA values compared with controls (both P < 0.001), patients with gastric adenocarcinoma (P = 0.013 and P = 0.006 respectively) and patients with oesophageal squamous cell carcinoma (both P < 0.001). For junctional tumours, the highest TFA and VFA values were seen in patients with Siewert type I tumours (respectively P = 0.041 and P = 0.033 versus type III; P = 0.332 and P = 0.152 versus type II). CONCLUSION: Patients with oesophageal\\/junctional adenocarcinoma, in particular oesophageal and Siewert type I junctional tumours, have greater CT-defined visceral adiposity than patients with gastric adenocarcinoma or oesophageal squamous cell carcinoma, or controls.

Enhancement of viability of radiosensitive (PBMC and resistant (MDA-MB-231 clones in low-dose-rate cobalt-60 radiation therapy

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Patrícia Lima Falcão

2015-06-01

Full Text Available Abstract Objective: In the present study, the authors investigated the in vitro behavior of radio-resistant breast adenocarcinoma (MDA-MB-231 cells line and radiosensitive peripheral blood mononuclear cells (PBMC, as a function of different radiation doses, dose rates and postirradiation time kinetics, with a view to the interest of clinical radiotherapy. Materials and Methods: The cells were irradiated with Co-60, at 2 and 10 Gy and two different exposure rates, 339.56 cGy.min–1 and the other corresponding to one fourth of the standard dose rates, present over a 10-year period of cobalt therapy. Post-irradiation sampling was performed at pre-established kinetics of 24, 48 and 72 hours. The optical density response in viability assay was evaluated and a morphological analysis was performed. Results: Radiosensitive PBMC showed decrease in viability at 2 Gy, and a more significant decrease at 10 Gy for both dose rates. MDAMB- 231 cells presented viability decrease only at higher dose and dose rate. The results showed MDA-MB-231 clone expansion at low dose rate after 48–72 hours post-radiation. Conclusion: Low dose rate shows a possible potential clinical impact involving decrease in management of radio-resistant and radiosensitive tumor cell lines in cobalt therapy for breast cancer.

Appendiceal goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid are genetically distinct from primary colorectal-type adenocarcinoma of the appendix

DEFF Research Database (Denmark)

Jesinghaus, Moritz; Konukiewitz, Björn; Foersch, Sebastian

2018-01-01

The appendix gives rise to goblet cell carcinoids, which represent special carcinomas with distinct biological and histological features. Their genetic background and molecular relationship to colorectal adenocarcinoma is largely unknown. We therefore performed a next-generation sequencing analysis...... a morphomolecular entity, histologically and genetically distinct from appendiceal colorectal-type adenocarcinomas and its colorectal counterparts. Altered Wnt-signaling associated genes, apart from APC, may act as potential drivers of these neoplasms. The absence of KRAS/NRAS mutations might render some....../adenocarcinoma ex-goblet cell carcinoid (n=2, respectively). Mutations in colorectal cancer-related genes (eg, TP53, KRAS, APC) were rare to absent in both, goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid, but frequent in primary colorectal-type adenocarcinomas of the appendix. Additional large...

Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer.

Science.gov (United States)

Haricharan, Svasti; Punturi, Nindo; Singh, Purba; Holloway, Kimberly R; Anurag, Meenakshi; Schmelz, Jacob; Schmidt, Cheryl; Lei, Jonathan T; Suman, Vera; Hunt, Kelly; Olson, John A; Hoog, Jeremy; Li, Shunqiang; Huang, Shixia; Edwards, Dean P; Kavuri, Shyam M; Bainbridge, Matthew N; Ma, Cynthia X; Ellis, Matthew J

2017-10-01

Significant endocrine therapy-resistant tumor proliferation is present in ≥20% of estrogen receptor-positive (ER + ) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair (MMR) complex ( MLH1/3 , PMS1/2 ), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER + breast cancer abrogates CHK2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness. Consequently, CDK4/6 inhibitors (CDK4/6i) remain effective in MutL-defective ER + breast cancer cells. These observations are supported by data from a clinical trial where a CDK4/6i was found to strongly inhibit aromatase inhibitor-resistant proliferation of MutL-defective tumors. These data suggest that diagnostic markers of MutL deficiency could be used to direct adjuvant CDK4/6i to a population of patients with breast cancer who exhibit marked resistance to the current standard of care. Significance: MutL deficiency in a subset of ER + primary tumors explains why CDK4/6 inhibition is effective against some de novo endocrine therapy-resistant tumors. Therefore, markers of MutL dysregulation could guide CDK4/6 inhibitor use in the adjuvant setting, where the risk benefit ratio for untargeted therapeutic intervention is narrow. Cancer Discov; 7(10); 1168-83. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1047 . ©2017 American Association for Cancer Research.

Laparoscopic diagnosis of adenocarcinoma of the appendix mimicking serous papillary adenocarcinoma of the peritoneum.

Science.gov (United States)

Yoshimura, Mayumi; Terai, Yoshito; Konishi, Hiromi; Tanaka, Yoshimichi; Tanaka, Tomohito; Sasaki, Hiroshi; Ohmichi, Masahide

2013-01-01

Primary carcinoma of the vermiform appendix is a rare disease with few clinical symptoms. Accordingly, preoperative diagnosis of appendiceal cancer is challenging because of the lack of specific symptoms. We herein report a case of appendicular adenocarcinoma found unexpectedly during laparoscopic surgery in a 69-year-old Japanese female patient diagnosed with serous papillary adenocarcinoma, in order to determine whether optimal cytoreduction could successfully be achieved at the time of primary surgery. We performed diagnostic laparoscopic surgery in order to make a correct diagnosis based on the histological tissue. The vermiform appendix was found to contain a tumor measuring 1.5 cm wide and 4.5 cm long. Laparoscopic appendectomy, partial omentectomy, and partial resection of the lesion in the peritoneum were performed. The histological diagnosis was mucinous adenocarcinoma of the vermiform appendix, and the stage was T4NxM1. The patient received adjuvant chemotherapy with mFOLFOX 6 (5FU, leucovorin, and oxaliplatin). She achieved stable disease and was alive with disease eleven months after surgery. We therefore recommend that gynecologists should not rule out the possibility of appendiceal cancer, even in cases with preoperative findings similar to those of serous papillary adenocarcinoma of the peritoneum with peritoneal disseminated tumors.

Discordance of Mutation Statuses of Epidermal Growth Factor Receptor and K-ras between Primary Adenocarcinoma of Lung and Brain Metastasis

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Kun-Ming Rau

2016-04-01

Full Text Available Mutations on epidermal growth factor receptor (EGFR of adenocarcinomas of lung have been found to be associated with increased sensitivity to EGFR tyrosine kinase inhibitors and K-ras mutations may correlate with primary resistance. We aimed to explore the discordant mutation statuses of EGFR and K-ras between primary tumors and matched brain metastases in adenocarcinomas of lung. We used a sensitive Scorpion ARMS method to analyze EGFR mutation, and Sanger sequencing followed by allele-specific real-time polymerase chain reaction to analyze K-ras mutation. Forty-nine paired tissues with both primary adenocarcinoma of lung and matched brain metastasis were collected. Thirteen patients (26.5% were discordant for the status of EGFR between primary and metastatic sites. K-ras gene could be checked in paired specimens from 33 patients, thirteen patients (39.6% were discordant for the status of K-ras. In primary lung adenocarcinoma, there were 14 patients of mutant EGFR had mutant K-ras synchronously. This study revealed that the status of EGFR mutation in lung adenocarcinomas is relatively consistent between primary and metastatic sites compared to K-ras mutation. However, there are still a few cases of adenocarcinoma of lung showing discordance for the status of EGFR mutation. Repeated analysis of EGFR mutation is highly recommended if tissue from metastatic or recurrent site is available for the evaluation of target therapy.

Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism

Science.gov (United States)

Goodman, C R; Sato, T; Peck, A R; Girondo, M A; Yang, N; Liu, C; Yanac, A F; Kovatich, A J; Hooke, J A; Shriver, C D; Mitchell, E P; Hyslop, T; Rui, H

2016-01-01

Therapy resistance remains a major problem in estrogen receptor-α (ERα)-positive breast cancer. A subgroup of ERα-positive breast cancer is characterized by mosaic presence of a minor population of ERα-negative cancer cells expressing the basal cytokeratin-5 (CK5). These CK5-positive cells are therapy resistant and have increased tumor-initiating potential. Although a series of reports document induction of the CK5-positive cells by progestins, it is unknown if other 3-ketosteroids share this ability. We now report that glucocorticoids and mineralocorticoids effectively expand the CK5-positive cell population. CK5-positive cells induced by 3-ketosteroids lacked ERα and progesterone receptors, expressed stem cell marker, CD44, and displayed increased clonogenicity in soft agar and broad drug-resistance in vitro and in vivo. Upregulation of CK5-positive cells by 3-ketosteroids required induction of the transcriptional repressor BCL6 based on suppression of BCL6 by two independent BCL6 small hairpin RNAs or by prolactin. Prolactin also suppressed 3-ketosteroid induction of CK5+ cells in T47D xenografts in vivo. Survival analysis with recursive partitioning in node-negative ERα-positive breast cancer using quantitative CK5 and BCL6 mRNA or protein expression data identified patients at high or low risk for tumor recurrence in two independent patient cohorts. The data provide a mechanism by which common pathophysiological or pharmacologic elevations in glucocorticoids or other 3-ketosteroids may adversely affect patients with mixed ERα+/CK5+ breast cancer. The observations further suggest a cooperative diagnostic utility of CK5 and BCL6 expression levels and justify exploring efficacy of inhibitors of BCL6 and 3-ketosteroid receptors for a subset of ERα-positive breast cancers. PMID:26096934

HER2 amplification, overexpression and score criteria in esophageal adenocarcinoma

Science.gov (United States)

Hu, Yingchuan; Bandla, Santhoshi; Godfrey, Tony E.; Tan, Dongfeng; Luketich, James D.; Pennathur, Arjun; Qiu, Xing; Hicks, David G.; Peters, Jeffrey; Zhou, Zhongren

2011-01-01

The HER2 oncogene was recently reported to be amplified and overexpressed in esophageal adenocarcinoma. However, the relationship of HER2 amplification in esophageal adenocarcinoma with prognosis has not been well defined. The scoring systems for clinically evaluating HER2 in esophageal adenocarcinoma are not established. The aims of the study were to establish a HER2 scoring system and comprehensively investigate HER2 amplification and overexpression in esophageal adenocarcinoma and its precursor lesion. Using a tissue microarray, containing 116 cases of esophageal adenocarcinoma, 34 cases of BE, 18 cases of low grade dysplasia and 15 cases of high grade dysplasia, HER2 amplification and overexpression were analyzed by HercepTest and CISH methods. The amplification frequency in an independent series of 116 esophageal adenocarcinoma samples was also analyzed using Affymetrix SNP 6.0 microarrays. In our studies, we have found that HER2 amplification does not associate with poor prognosis in total 232 esophageal adenocarcinoma patients by CISH and high density microarrays. We further confirm the similar frequency of HER2 amplification by CISH (18.10%; 21/116) and SNP 6.0 microarrays (16.4%, 19/116) in esophageal adenocarcinoma. HER2 protein overexpression was observed in 12.1 % (14/116) of esophageal adenocarcinoma and 6.67% (1/15) of HGD. No HER2 amplification or overexpression was identified in BE or LGD. All HER2 protein overexpression cases showed HER2 gene amplification. Gene amplification was found to be more frequent by CISH than protein overexpression in esophageal adenocarcinoma (18.10% vs 12.9%). A modified two-step model for esophageal adenocarcinoma HER-2 testing is recommend for clinical esophageal adenocarcinoma HER-2 trial. PMID:21460800

The Role of Interferon Regulatory Factor-1 (IRF1) in Overcoming Antiestrogen Resistance in the Treatment of Breast Cancer

International Nuclear Information System (INIS)

Schwartz, J.L.; Shajahan, A.N.; Clarke, R.

2011-01-01

Resistance to endocrine therapy is common among breast cancer patients with estrogen receptor alpha-positive (ER+) tumors and limits the success of this therapeutic strategy. While the mechanisms that regulate endocrine responsiveness and cell fate are not fully understood, interferon regulatory factor-1 (IRF1) is strongly implicated as a key regulatory node in the underlying signaling network. IRF1 is a tumor suppressor that mediates cell fate by facilitating apoptosis and can do so with or without functional p53. Expression of IRF1 is down regulated in endocrine-resistant breast cancer cells, protecting these cells from IRF1-induced inhibition of proliferation and/or induction of cell death. Nonetheless, when IRF1 expression is induced following IFN treatment, antiestrogen sensitivity is restored by a process that includes the inhibition of pro survival BCL2 family members and caspase activation. These data suggest that a combination of endocrine therapy and compounds that effectively induce IRF1 expression may be useful for the treatment of many ER+ breast cancers. By understanding IRF1 signaling in the context of endocrine responsiveness, we may be able to develop novel therapeutic strategies and better predict how patients will respond to endocrine therapy

CT findings of adenocarcinoma of the lung

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Jeon, T. J.; Kim, S. J.; Lee, D. Y.; Ahn, C. M [Yonsei Univ. College of Medicine, Seoul (Korea, Republic of)

1996-03-01

To evaluate CT findings of primary adenocarcinoma of the lung and to assess distant metastasis at the time of diagnosis. CT findings of 150 patients with adenocarcinoma, confirmed by histopathologic methods, were classified as central or peripheral lesion and pattern analysis of typical findings noted in this cancer was carried out. Intra and extrathoracic metastases of adenocarcinoma were also investigated. Of 150 cases of adenocarcinoma of the lung, 121 were found to be of the peripheral type and 29 were of the central type. These peripheral lesions comprised 105 nodules, 11 consolidations, four cavities and one linear lesion, while the central lesions consisted of 19 cases of atelectasis and tens of branchial wall thickening. lung to lung(nine cases), lymphangitic(five cases), and pleural metastasis(16 cases) were presented as intrathoracic metastasis, while bone(17), brain,(six), liver(two) and adrenal metastasis(one case)were presented as extrathoracic metastasis. The most common radiologic finding of adenocarcinoma is a peripheral single mass or nodule but consolidation, cavity or tubular lesions, as well as atelectasis or bronchial wall thickening alone can be presented as unusual findings of adenocarcinoma. As a consequence, it is in many cases difficult to differentially diagnose. Distant metastasis was also noted in many cases of early T-stage lesion, so to successfully manage the patient, careful evaluation of the metastasis is essential.

CT findings of adenocarcinoma of the lung

International Nuclear Information System (INIS)

Jeon, T. J.; Kim, S. J.; Lee, D. Y.; Ahn, C. M

1996-01-01

To evaluate CT findings of primary adenocarcinoma of the lung and to assess distant metastasis at the time of diagnosis. CT findings of 150 patients with adenocarcinoma, confirmed by histopathologic methods, were classified as central or peripheral lesion and pattern analysis of typical findings noted in this cancer was carried out. Intra and extrathoracic metastases of adenocarcinoma were also investigated. Of 150 cases of adenocarcinoma of the lung, 121 were found to be of the peripheral type and 29 were of the central type. These peripheral lesions comprised 105 nodules, 11 consolidations, four cavities and one linear lesion, while the central lesions consisted of 19 cases of atelectasis and tens of branchial wall thickening. lung to lung(nine cases), lymphangitic(five cases), and pleural metastasis(16 cases) were presented as intrathoracic metastasis, while bone(17), brain,(six), liver(two) and adrenal metastasis(one case)were presented as extrathoracic metastasis. The most common radiologic finding of adenocarcinoma is a peripheral single mass or nodule but consolidation, cavity or tubular lesions, as well as atelectasis or bronchial wall thickening alone can be presented as unusual findings of adenocarcinoma. As a consequence, it is in many cases difficult to differentially diagnose. Distant metastasis was also noted in many cases of early T-stage lesion, so to successfully manage the patient, careful evaluation of the metastasis is essential

Nrf2 and Keap1 Abnormalities in 104 Lung Adenocarcinoma Cases and Association with Clinicopathologic Features

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Yu XIAO

2018-03-01

Full Text Available Background and objective There are significantly interindividual variations of the expression level of nuclear factor erythroid-2-related factor 2 (Nrf2 and/or Kelch-like ECH-associated protein 1 (Keap1 in our previous studies. It has been proven that Nrf2 or Keap1 is related to resistance of chemotherapeutic drugs and/or epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs. However, the expression of Nrf2 and Keap1 in lung adenocarcinoma patients with different “driver gene” is not clear. The aim of this study is to investigate the protein expression level of Nrf2 and Keap1 in lung adenocarcinoma and to elucidate the correlation between Nrf2 or Keap1 expression and the status of EGFR gene mutation and to determine the effects of Nrf2 and Keap1 on the patients. Methods Immunohistochemical analysis of Nrf2 and Keap1 in tumor specimens was performed in a total of 104 lung adenocarcinoma patients with the status of EGFR gene mutations or EGFR wide-type. Results The Nrf2 positive rate was 71.2% and Keap1 high expression rate was 34.6% in 104 patients. The Nrf2 positive rate significantly correlated with gender, stage and status of EGFR gene mutation (P0.05. The high expression of Keap1 was not significantly correlated with gender, age, smoking, differentiation, subtype of lung adenocarcinoma and status of EGFR gene mutation (P>0.05. The progression -free survival (PFS and overall survival (OS of the patients treated by EGFR-TKIs were significantly correlated with the expression level of Nrf2, but not with Keap1. The PFS and OS of the patients with Nrf2 high expression were significantly shorter than the patients with low/negative expression (P<0.05. Furthermore, Nrf2 high expression was the independent predictive factor for EGFR-TKIs induced PFS and OS (P<0.05. Conclusion The Nrf2 positive rate significantly correlated with the status of EGFR gene mutation in lung adenocarcinoma. The Nrf2 high expression significantly

High CDK6 protects cells from fulvestrant-mediated apoptosis and is a predictor of resistance to fulvestrant in estrogen receptor-positive metastatic breast cancer

DEFF Research Database (Denmark)

Alves, Carla Maria Lourenco; Elias, Daniel; Lyng, Maria B

2016-01-01

expression impaired fulvestrant-resistant cell growth and induced apoptosis. Treatment with palbociclib re-sensitized fulvestrant-resistant cells to fulvestrant through alteration of retinoblastoma protein phosphorylation. High CDK6 levels in metastatic samples from two independent cohorts of breast cancer...

Adenocarcinoma of the esophagus and Barrett's esophagus

DEFF Research Database (Denmark)

Bytzer, P; Christensen, P B; Damkier, P

1999-01-01

often by endoscopy. A previous diagnosis of Barrett's esophagus was found in only 1.3% of the cancer patients. CONCLUSIONS: The rate of esophageal adenocarcinoma in Denmark has increased eightfold over a 20-yr period, and this increase is not explained by changes in classification or diagnostic routines....... More than 98% of esophageal adenocarcinomas were found in patients who could not have entered endoscopic surveillance, as Barrett's esophagus had not been diagnosed before the cancer diagnosis. Endoscopic surveillance to detect dysplasia may be an option for the individual patient with Barrett......OBJECTIVE: We described incidence rates of esophageal adenocarcinoma in Denmark in a 20-yr period and determined the proportion of patients diagnosed with esophageal adenocarcinoma who had a previous diagnosis of Barrett's esophagus, making them potential candidates for endoscopic surveillance...

Influence Of Smoking Habit On Age At Diagnosis Of Breast Cancer

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Rajaei Mehrdad

2015-09-01

Full Text Available No studies have yet investigated the influence of smoking on age at diagnosis of breast cancer. Therefore, the present study was carried out. This study consisted of 605 females with pathologically confirmed primary adenocarcinoma of the breast and 438 healthy females matched by age. Among our participants, 86 (14.2% patients and 62 (14.1% control subjects, respectively, were smokers. Based on a Cox regression model, evidence suggested that smoking status influenced the age at diagnosis of breast cancer (HR=0.78, 95% CI: 0.62-0.99, P=0.040. After stratification of the patients according to their menopausal status, the same results were obtained. The present study indicated that non-smokers have a lower age at diagnosis in comparison with patients who smoke.

TMPRSS2-ERG gene fusions are infrequent in prostatic ductal adenocarcinomas.

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Lotan, Tamara L; Toubaji, Antoun; Albadine, Roula; Latour, Mathieu; Herawi, Mehsati; Meeker, Alan K; DeMarzo, Angelo M; Platz, Elizabeth A; Epstein, Jonathan I; Netto, George J

2009-03-01

Ductal adenocarcinoma of the prostate is an unusual subtype that may be associated with a more aggressive clinical course, and is less responsive to conventional therapies than the more common prostatic acinar adenocarcinoma. However, given its frequent association with an acinar component at prostatectomy, some have challenged the concept of prostatic ductal adenocarcinoma as a distinct clinicopathologic entity. We studied the occurrence of the TMPRSS2-ERG gene fusion, in 40 surgically resected ductal adenocarcinoma cases, and in their associated acinar component using fluorescence in situ hybridization. A group of 38 'pure' acinar adenocarcinoma cases matched with the ductal adenocarcinoma group for pathological grade and stage was studied as a control. Compared with the matched acinar adenocarcinoma cases, the TMPRSS2-ERG gene fusion was significantly less frequently observed in ductal adenocarcinoma (45 vs 11% of cases, P=0.002, Fisher's exact test). Here, of the ductal adenocarcinoma cases with the gene fusion, 75% were fused through deletion, and the remaining case was fused through translocation. The TMPRSS2-ERG gene fusion was also rare in the acinar component of mixed ductal-acinar tumors when compared with the pure acinar adenocarcinoma controls (5 vs 45%, P=0.001, Fisher's exact test). In 95% of the ductal adenocarcinoma cases in which a concurrent acinar component was analyzed, there was concordance for presence/absence of the TMPRSS2-ERG gene fusion between the different histologic subtypes. In the control group of pure acinar adenocarcinoma cases, 59% were fused through deletion and 41% were fused through translocation. The presence of the TMPRSS2-ERG gene fusion in some cases of prostatic ductal adenocarcinoma supports the concept that ductal adenocarcinoma and acinar adenocarcinoma may be related genetically. However, the significantly lower rate of the gene fusion in pure ductal adenocarcinoma cases underscores the fact that genetic and biologic

Prognostic value of the 99mTc-Isonitrile washout rate in neoadjuvant chemotherapy in patients with locally advanced breast cancer

International Nuclear Information System (INIS)

Silva, N. Jr.; Anselmi, C.E.; Foppa, M.; Batista, L.; Grobocopatel, D.; Hunsche, A.; Fernandes, D.; Berdichevski, E.; Madke, R.; Baptista, I.; Martini, J.; Obando, A.

2004-01-01

Full text: Neoadjuvant chemotherapy is the pre-surgical treatment of choice in patients with locally advanced breast tumor for better disease control and breast conservation. Resistance to chemotherapy may be seen in about 18%-51% of the cancers. The term multi drug resistance (MDR) is commonly used to indicate the expression of the transmembrane glycoprotein (P-glycoprotein). This protein removes some very important chemotherapeutic drugs from inside the cell and is responsible for the clinical manifestation of the MDR. The knowledge of MDR before the initiation of chemotherapy can help choosing the best treatment. 99mTc-Isonitrile is a radiotracer largely used in nuclear medicine. It enters cells, is identified by the P-glycoprotein as a substrate and is, therefore, expelled from the neoplastic cell. Various studies have demonstrated direct correlation between the 99mTc-Isonitrile efflux, P-glycoprotein expression and MDR. On the other hand, 99mTc-Isonitrile retention in the tumor suggests chemosensitivity. The objective of this study was to monitor the response to neoadjuvant chemotherapy in breast cancer by the use of 99mTc-Sestamibi scintimammography and its washout rate in a pilot study. Five patients with locally advanced breast cancer were subjected to neoadjuvant chemotherapy. Inclusion criteria were locally advanced tumor, biopsy results, no distant metastasis, and completion of the whole chemotherapy protocol. Exclusion criteria were any previous cancer treatment or other primary tumor. All the patients underwent 99mTc-Sestamibi scintimammography before and after completion of the chemotherapy protocol. For scintimammography, 740MBq of radiotracer was injected in the arm contra lateral to the side of lesion. Planar images were acquired at 10 and 240 minutes, in anterior supine position as well as in both lateral projections in prone position. Regions of interest of same size were drawn over the tumor and in the contra lateral breast to correct for

Randomized controlled trial to evaluate the effects of progressive resistance training compared to progressive muscle relaxation in breast cancer patients undergoing adjuvant radiotherapy: the BEST study

International Nuclear Information System (INIS)

Potthoff, Karin; Steindorf, Karen; Schmidt, Martina E; Wiskemann, Joachim; Hof, Holger; Klassen, Oliver; Habermann, Nina; Beckhove, Philipp; Debus, Juergen; Ulrich, Cornelia M

2013-01-01

Cancer-related fatigue (CRF) is one of the most common and distressing side effects of cancer and its treatment. During and after radiotherapy breast cancer patients often suffer from CRF which frequently impairs quality of life (QoL). Despite the high prevalence of CRF in breast cancer patients and the severe impact on the physical and emotional well-being, effective treatment methods are scarce. Physical activity for breast cancer patients has been reported to decrease fatigue, to improve emotional well-being and to increase physical strength. The pathophysiological and molecular mechanisms of CRF and the molecular-biologic changes induced by exercise, however, are poorly understood. In the BEST trial we aim to assess the effects of resistance training on fatigue, QoL and physical fitness as well as on molecular, immunological and inflammatory changes in breast cancer patients during adjuvant radiotherapy. The BEST study is a prospective randomized, controlled intervention trial investigating the effects of a 12-week supervised progressive resistance training compared to a 12-week supervised muscle relaxation training in 160 patients with breast cancer undergoing adjuvant radiotherapy. To determine the effect of exercise itself beyond potential psychosocial group effects, patients in the control group perform a group-based progressive muscle relaxation training. Main inclusion criterion is histologically confirmed breast cancer stage I-III after lumpectomy or mastectomy with indication for adjuvant radiotherapy. Main exclusion criteria are acute infectious diseases, severe neurological, musculosceletal or cardiorespiratory disorders. The primary endpoint is cancer-related fatigue; secondary endpoints include immunological and inflammatory parameters analyzed in peripheral blood, saliva and urine. In addition, QoL, depression, physical performance and cognitive capacity will be assessed. The BEST study is the first randomized controlled trial comparing progressive

The breast cancer resistance protein transporter ABCG2 is expressed in the human kidney proximal tubule apical membrane.

NARCIS (Netherlands)

Huls, M.; Brown, C.D.; Windass, A.S.; Sayer, R.; Heuvel, J.J.M.W. van den; Heemskerk, S.; Russel, F.G.M.; Masereeuw, R.

2008-01-01

The Breast Cancer Resistance Protein (BCRP/ABCG2) is a transporter restricting absorption and enhancing excretion of many compounds including anticancer drugs. This transporter is highly expressed in many tissues; however, in human kidney, only the mRNA was found in contrast to the mouse kidney,

Autophagy Protects from Trastuzumab-Induced Cytotoxicity in HER2 Overexpressing Breast Tumor Spheroids.

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Cristina E Rodríguez

Full Text Available Multicellular tumor spheroids represent a 3D in vitro model that mimics solid tumor essential properties including assembly and development of extracellular matrix and nutrient, oxygen and proliferation gradients. In the present study, we analyze the impact of 3D spatial organization of HER2-overexpressing breast cancer cells on the response to Trastuzumab. We cultured human mammary adenocarcinoma cell lines as spheroids with the hanging drop method and we observed a gradient of proliferating, quiescent, hypoxic, apoptotic and autophagic cells towards the inner core. This 3D organization decreased Trastuzumab sensitivity of HER2 over-expressing cells compared to monolayer cell cultures. We did not observe apoptosis induced by Trastuzumab but found cell arrest in G0/G1 phase. Moreover, the treatment downregulated the basal apoptosis only found in tumor spheroids, by eliciting protective autophagy. We were able to increase sensitivity to Trastuzumab by autophagy inhibition, thus exposing the interaction between apoptosis and autophagy. We confirmed this result by developing a resistant cell line that was more sensitive to autophagy inhibition than the parental BT474 cells. In summary, the development of Trastuzumab resistance relies on the balance between death and survival mechanisms, characteristic of 3D cell organization. We propose the use of spheroids to further improve the understanding of Trastuzumab antitumor activity and overcome resistance.

Estrogen receptor positive breast tumors resist chemotherapy by the overexpression of P53 in Cancer Stem Cells

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Fatma Ashour

2018-06-01

Full Text Available Background and Objectives: Breast cancer (BC is classified according to estrogen receptor (ER status into ER+ and ER− tumors. ER+ tumors have a worse response to chemotherapy compared to ER− tumors. BCL-2, TP53, BAX and NF-ΚB are involved in drug resistance in the ER+ tumors. Recently it was shown that Cancer Stem Cells (CSCs play an important role in drug resistance. In this study we tested the hypothesis that CSCs of the ER+ tumors resist drug through the overexpression of BCL-2, TP53, BAX and NF-ΚB. Methods: CSCs were isolated by anoikis resistance assay from MCF7 (ER+ and MDA-MB-231 (ER− cell lines. Isolated CSCs were treated with doxorubicin (DOX and the mRNA expression levels of BCL-2, TP53, BAX and NFKB were investigated by quantitative real time PCR (qPCR with and without treatment. Results: BCL-2, BAX and NF-ΚB showed decreased expression in MCF7 bulk cancer cells after DOX treatment whereas only BCL-2 and BAX showed decreased expression in MDA-MB-231 bulk cancer cells. Interestingly TP53 was the only gene showed a considerable increase in its expression in CSCs of the ER+ MCF7 cell line compared to bulk cancer cells. Moreover, TP53 was the only gene showing exceptionally higher level of expression in MCF7-CSCs compared to MDA-MB-231-CSCs. Conclusion: Our results suggest that CSCs in the ER+ cells escape the effect of DOX treatment by the elevation of p53 expression. Keywords: Breast cancer, Cancer Stem Cells, Drug resistance, Estrogen receptors

Trastuzumab Resistance: Role for Notch Signaling

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Kinnari Mehta

2009-01-01

Full Text Available Epidermal growth factor receptor-2 (ErbB-2/HER2 is a potent breast oncogene that has been shown to be amplified in 20% of breast cancers. Overexpression of ErbB-2 predicts for aggressive tumor behavior, resistance to some cytotoxic and antihormonal therapies, and poor overall survival. Trastuzumab, the humanized, monoclonal antibody directed against ErbB-2 has shown tremendous efficacy and improved overall survival for women when combined with a taxane-based chemotherapy. However, resistance to trastuzumab remains a major concern, most notably in women with metastatic breast cancer. Numerous mechanisms that include overexpression of alternate receptor tyrosine kinases and/or loss of critical tumor suppressors have been proposed in the last several years to elucidate trastuzumab resistance. Here we review the many possible mechanisms of action that could contribute to resistance, and novel therapies to prevent or reverse the resistant phenotype. Moreover, we provide a critical role for Notch signaling cross-talk with overlapping or new signaling networks in trastuzumab-resistant breast.

Synchronous uterine adenocarcinoma and leiomyosarcoma – a case study

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Kamila Dudzik

2017-04-01

Full Text Available Synchronous gynecological cancers are rarely described. Those cases account for approximately up to 6% of female genital tract malignancies. The presence of synchronous endometrial adenocarcinoma and gynecological tract neoplasia is rare – the most commonly described is synchronous adenocarcinoma and endometrial ovarian cancer (accounting for 15-20% of ovarian neoplasia and 5% of endometrial cancers. Concomitant uterine carcinosarcoma and ovarian cancer, or endometrial adenocarcinoma are extremely rare. Up till now, only 3 cases of synchronous adenocarcinoma and leiomyosarcoma were described. In the present study a case of 60-year-old woman diagnosed with synchronous endometrial adenocarcinoma and leiomyosarcoma uteri is described. As the preoperative evaluation revealed endometrial adenocarcinoma G2 with intermediate-risk of lymph node metastasis and synchronous leiomyosarcoma G3, total hysterectomy with bilateral salpingo-oophorectomy and systemic lymphadenectomy was performed showing no lymphatic involvement. In the postoperative evaluation the patient was qualified to adenocarcinoma low recurrence-risk group (adenocarcinoma G1 with no LVSI, FIGO IA – no further radiotherapy was required. However, as synchronous leiomyosarcoma G3 was diagnosed, we decided to refer the patient for adjuvant chemotherapy. Contemporary recommendation on the diagnosis and treatment of uterine carcinomas, especially uterine leiomyosarcomas, is also described in this paper. The presented case showed that diagnosis and treatment of women with uterine tumors should be individualized as in the same case an extremely rare cancer type can be present which, consequently, changes the treatment regimen and prognosis.

Primary Rectal Adenocarcinoma Metastasizing to Bilateral Breast - a Rare Case Demonstrated by {sup 18}F-FDG PET/CT

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Soundararajan, Ramya; Arora, Saurabh; Das, Chandan Jyoti; Roy, Maitrayee; Kumar, Rakesh; Bal, Chandrasekhar [All India Institute of Medical Sciences, New Delhi (India)

2016-06-15

A 22-year-old female presented with multiple painless bilateral breast masses for the past 2 months. On Further questioning she had hematochezia and constipation for three months. On digital rectal examination, thickening of rectal mucosa at 5 cm from the anal verge was found. On physical examination, multiple firm, non-tender, nodular lesions were found in bilateral breasts. Metastatic breast disease from extra mammary primaries is uncommon and it constitutes 0.5 - 6% of all breast malignancies. melanomas, lymphomas, leukemias, ands sarcomas are the most common malignancies causing breast metastases. Infrequently, carcinomas of the lung, stomach, ovary, liver, tonsil, pleura, pancreas, cervix, perineum, endometrium, bladder, carcinoid tumors and renal cell carcinomas can cause metastatic breast disease. Metastatic breast disease from colorectal cancer is characterised by disseminated metastatic disease and a poor prognosis. In this case, It was essential to distinguish between metastatic breast disease primary breast carcinoma to plan appropriate management. Because of its rare incidence and high index of clinical suspicion, appropriate radiological investigations and histopathology is essential for accurate diagnosis. {sup 18}F-FDG PET/CT, being a whole-body metabolic functional imaging modality, helped us determine the extent of the primary and metastatic disease. In view of disseminated metastases, the bilateral breast disease was also considered as metastatic involvement, Which was proven by histopathology.

Comprehensive profiling of DNA repair defects in breast cancer identifies a novel class of endocrine therapy resistance drivers.

Science.gov (United States)

Anurag, Meenakshi; Punturi, Nindo; Hoog, Jeremy; Bainbridge, Matthew N; Ellis, Matthew J; Haricharan, Svasti

2018-05-23

This study was undertaken to conduct a comprehensive investigation of the role of DNA damage repair (DDR) defects in poor outcome ER+ disease. Expression and mutational status of DDR genes in ER+ breast tumors were correlated with proliferative response in neoadjuvant aromatase inhibitor therapy trials (discovery data set), with outcomes in METABRIC, TCGA and Loi data sets (validation data sets), and in patient derived xenografts. A causal relationship between candidate DDR genes and endocrine treatment response, and the underlying mechanism, was then tested in ER+ breast cancer cell lines. Correlations between loss of expression of three genes: CETN2 (p<0.001) and ERCC1 (p=0.01) from the nucleotide excision repair (NER) and NEIL2 (p=0.04) from the base excision repair (BER) pathways were associated with endocrine treatment resistance in discovery data sets, and subsequently validated in independent patient cohorts. Complementary mutation analysis supported associations between mutations in NER and BER pathways and reduced endocrine treatment response. A causal role for CETN2, NEIL2 and ERCC1 loss in intrinsic endocrine resistance was experimentally validated in ER+ breast cancer cell lines, and in ER+ patient-derived xenograft models. Loss of CETN2, NEIL2 or ERCC1 induced endocrine treatment response by dysregulating G1/S transition, and therefore, increased sensitivity to CDK4/6 inhibitors. A combined DDR signature score was developed that predicted poor outcome in multiple patient cohorts. This report identifies DDR defects as a new class of endocrine treatment resistance drivers and indicates new avenues for predicting efficacy of CDK4/6 inhibition in the adjuvant treatment setting. Copyright ©2018, American Association for Cancer Research.

Label-free recognition of drug resistance via impedimetric screening of breast cancer cells.

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Bilge Eker

Full Text Available We present a novel study on label-free recognition and distinction of drug resistant breast cancer cells (MCF-7 DOX from their parental cells (MCF-7 WT via impedimetric measurements. Drug resistant cells exhibited significant differences in their dielectric properties compared to wild-type cells, exerting much higher extracellular resistance (Rextra . Immunostaining revealed that MCF-7 DOX cells gained a much denser F-actin network upon acquiring drug resistance indicating that remodeling of actin cytoskeleton is probably the reason behind higher Rextra , providing stronger cell architecture. Moreover, having exposed both cell types to doxorubicin, we were able to distinguish these two phenotypes based on their substantially different drug response. Interestingly, impedimetric measurements identified a concentration-dependent and reversible increase in cell stiffness in the presence of low non-lethal drug doses. Combined with a profound frequency analysis, these findings enabled distinguishing distinct cellular responses during drug exposure within four concentration ranges without using any labeling. Overall, this study highlights the possibility to differentiate drug resistant phenotypes from their parental cells and to assess their drug response by using microelectrodes, offering direct, real-time and noninvasive measurements of cell dependent parameters under drug exposure, hence providing a promising step for personalized medicine applications such as evaluation of the disease progress and optimization of the drug treatment of a patient during chemotherapy.

Identification of the Interaction between P-Glycoprotein and Anxa2 in Multidrug-resistant Human Breast Cancer Cells

International Nuclear Information System (INIS)

Zhang, Hai-chang; Zhang, Fei; Wu, Bing; Han, Jing-hua; Ji, Wei; Zhou, Yan; Niu, Rui-fang

2012-01-01

To explore the interaction of Anxa2 with P-Glycoprotein (P-gp) in the migration and invasion of the multidrug-resistant (MDR) human breast cancer cell line MCF-7/ADR. A pair of short hairpin RNA (shRNA) targeting P-gp was transfected into MCF-7/ADR cells, and monoclonal cell strains were screened. The expression of P-gp was detected by Western blot. Transwell chambers were used to observe the cell migration capacity and invasion ability. The interaction between P-gp and Anxa2 was examined by immunoprecipitation and immunofluorescence confocal microscopy analyses. P-gp expression was significantly knocked down, and there were notable decreasing trends in the migration and invasion capability of MDR breast cancer cells (P<0.05). There was a close interaction between Anxa2 and P-gp. MCF-7/ADR is an MDR human breast cancer cell line with high migration and invasion abilities. The knockdown of P-gp notably impaired the migration and invasion abilities of the tumor cells. The interaction of Anxa2 with P-pg may play an important role in the enhanced invasiveness of MDR human breast cancer cells

Alterations in mRNA profiles of trastuzumab‑resistant Her‑2‑positive breast cancer.

Science.gov (United States)

Zhao, Bin; Zhao, Yang; Sun, Yan; Niu, Haitao; Sheng, Long; Huang, Dongfang; Li, Li

2018-05-07

Breast cancer is one of the most common malignancies in women. Neoadjuvant trastuzumab therapy improves the prognosis of certain Her‑2‑positive breast cancer patients, however around two‑thirds of patients with Her‑2‑positive breast cancer do not benefit from Her‑2‑targeted therapy. To investigate the key mechanisms in trastuzumab resistance, potential biomarkers for neoadjuvant trastuzumab sensitivity were investigated using the gene expression omnibus (GEO) database for mRNA microarray data of Her‑2‑positive breast cancer patients who received neoadjuvant trastuzumab therapy. GEO profiles of 22 patients with a complete response and 48 patients with a partial response were identified in the GSE22358, GSE62327 and GSE66305 datasets. A total of 2,376, 1,000 and 1,152 differentially expressed genes in GSE22358, GSE62327 and GSE66305 datasets were demonstrated, respectively, utilizing GEO2R software. Furthermore, enriched gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways were analyzed using the Database for Annotation, Visualization and Integrated Discovery software. Subsequently, a protein‑protein interaction network was established using STRING software. The results demonstrated that low sex‑determining region Y‑box 11 and high Bcl‑2 expression may be employed as markers for neoadjuvant trastuzumab therapy for Her‑2‑positive breast cancer. More importantly, phosphoinositide 3‑kinase/Akt and angiogenesis pathways, which are known to be the key targets of trastuzumab, were activated at a lower level in the partial response patients, while the Wnt and estrogen receptor signaling pathways were activated in these patients. Therefore, combination therapy of trastuzumab and anti‑Wnt or hormone therapy may be a promising treatment modality and should be tested in further studies.

Adenocarcinoma primário de duodeno

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Hamilton Petry de Souza

Full Text Available Primary adenocarcinoma of the duodenum is an extremely rare disease, and represents only 0.35 % of all gastrointestinal malignies. Early detection of the disease is dificult because doesn't have pathognomonic simptoms. The Whipple procedure is the optimal method of treatment. The authors relate one case of a adenocarcinoma of the duodenum in a 65- year-old white female with a history of abdominal pain for a six-month period, associated with postprandial fullness, vomiting and weight loss. Endoscopy showed a elevated tumor in the second part of the duodenum, with partial obstruction of the lumen. Histological study of endoscopic biopsies reveled a moderare differentiated adenocarcinoma of the duodenum. The treatment was surgical. The authors comment on the more important aspects of this pathology.

Hormone resistance in two MCF-7 breast cancer cell lines is associated with reduced mTOR signaling, decreased glycolysis and increased sensitivity to cytotoxic drugs

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Euphemia Yee Leung

2014-09-01

Full Text Available The mTOR pathway is a key regulator of multiple cellular signaling pathways and is a potential target for therapy. We have previously developed two hormone-resistant sub-lines of the MCF-7 human breast cancer line, designated TamC3 and TamR3, which were characterized by reduced mTOR signaling, reduced cell volume and resistance to mTOR inhibition. Here we show that these lines exhibit increased sensitivity to carboplatin, oxaliplatin, 5-fluorouracil, camptothecin, doxorubicin, paclitaxel, docetaxel and hydrogen peroxide. The mechanisms underlying these changes have not yet been characterized but may include a shift from glycolysis to mitochondrial respiration. If this phenotype is found in clinical hormone-resistant breast cancers, conventional cytotoxic therapy may be a preferred option for treatment.

HDAC2 and HDAC5 Up-Regulations Modulate Survivin and miR-125a-5p Expressions and Promote Hormone Therapy Resistance in Estrogen Receptor Positive Breast Cancer Cells

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Wen-Tsung Huang

2017-12-01

Full Text Available Intrinsic or acquired resistance to hormone therapy is frequently reported in estrogen receptor positive (ER+ breast cancer patients. Even though dysregulations of histone deacetylases (HDACs are known to promote cancer cells survival, the role of different HDACs in the induction of hormone therapy resistance in ER+ breast cancer remains unclear. Survivin is a well-known pro-tumor survival molecule and miR-125a-5p is a recently discovered tumor suppressor. In this study, we found that ER+, hormone-independent, tamoxifen-resistant MCF7-TamC3 cells exhibit increased expression of HDAC2, HDAC5, and survivin, but show decreased expression of miR-125a-5p, as compared to the parental tamoxifen-sensitive MCF7 breast cancer cells. Molecular down-regulations of HDAC2, HDAC5, and survivin, and ectopic over-expression of miR-125a-5p, increased the sensitivity of MCF7-TamC3 cells to estrogen deprivation and restored the sensitivity to tamoxifen. The same treatments also further increased the sensitivity to estrogen-deprivation in the ER+ hormone-dependent ZR-75-1 breast cancer cells in vitro. Kaplan–Meier analysis and receiver operating characteristic curve analysis of expression cohorts of breast tumor showed that high HDAC2 and survivin, and low miR-125a-5p, expression levels correlate with poor relapse-free survival in endocrine therapy and tamoxifen-treated ER+ breast cancer patients. Further molecular analysis revealed that HDAC2 and HDAC5 positively modulates the expression of survivin, and negatively regulates the expression miR-125a-5p, in ER+ MCF7, MCF7-TamC3, and ZR-75-1 breast cancer cells. These findings indicate that dysregulations of HDAC2 and HDAC5 promote the development of hormone independency and tamoxifen resistance in ERC breast cancer cells in part through expression regulation of survivin and miR-125a-5p.

Different histological status of gastritis in superficial adenocarcinoma of the esophagogastric junction.

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Yamada, Masayoshi; Kushima, Ryoji; Oda, Ichiro; Mojtahed, Kaveh; Nonaka, Satoru; Suzuki, Haruhisa; Yoshinaga, Shigetaka; Matsubara, Akiko; Taniguchi, Hirokazu; Sekine, Shigeki; Saito, Yutaka; Shimoda, Tadakazu

2014-01-01

Although many gastric cancers arise in chronic gastritis, the association between adenocarcinoma of the esophagogastric junction and the status of background gastritis remains unclear. We aim to investigate the histological status of gastritis in the background fundic gland mucosa of adenocarcinoma of the esophagogastric junction. The present study included 121 consecutive patients with superficial adenocarcinoma of the esophagogastric junction obtained by surgical and/or endoscopic resection. We re-evaluated the histogenesis of adenocarcinoma of the esophagogastric junction, including the background fundic gland mucosa using the Updated Sydney System. The prevalence of histologic atrophic gastric mucosa with gastritis (positive gastritis), non-atrophic gastric mucosa without gastritis (negative gastritis) and Barrett's adenocarcinoma was examined. Histologic-positive gastritis was found in 67 (55%) of all patients, in 24 (38%) of 63 Barrett's adenocarcinoma patients and in 43 (74%) of 58 non-Barrett's adenocarcinoma patients (P gastritis patients `and younger age in non-Barrett's adenocarcinoma without gastritis patients were shown. There were no differences in clinicopathological features related to the gastritis status in Barrett's adenocarcinoma patients. Reflux esophagitis was observed in most (81%) of all patients, and 32 (74%) of the non-Barrett's adenocarcinoma with gastritis patients. In the 67 positive gastritis patients, the mean Updated Sydney System scores of glandular atrophy and intestinal metaplasia were 1.45 and 1.10, respectively, and these scores were higher in the non-Barrett's adenocarcinoma patients than in the Barrett's adenocarcinoma patients. This study suggests that about half of the patients with adenocarcinoma of the esophagogastric junction harbor histological gastritis. Adenocarcinoma of the esophagogastric junction is considered to be a heterogeneous entity, including Barrett's esophagus-related, positive gastritis-related, and

Male occult triple-negative breast cancer with dermatomyositis: a case report and review of the literature

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Zhang L

2017-11-01

Full Text Available Le Zhang,1 Chenghua Zhang,2 Zhaoying Yang,1 Miao He,3 Lijuan Zhang,1 Shereen Ezzat,4 Xi Liang5 1Department of Breast Surgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China; 2Endoscopy Department, Jilin Cancer Hospital, Changchun, Jilin,China; 3Department of Anesthesia, The Second Hospital of Jilin University, Changchun, Jilin, China; 4Ontario Cancer Institute and The Endocrine Oncology Site Group, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada; 5Department of Breast Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China Abstract: Occult breast cancer is defined by the presence of axillary metastases without an identifiable primary breast tumor. Here, we report a rare case of a male occult breast cancer with dermatomyositis. We performed a modified radical mastectomy consisting of whole breast mastectomy and axillary lymph node dissection. Immunohistochemistry and fluorescent in situ hybridization analyses demonstrated an adenocarcinoma likely of breast origin, which was an occult triple-negative breast cancer. Interestingly, the patient’s previously noted periorbital dermatomyositis resolved promptly following surgical excision. Keywords: male breast cancer, occult breast cancer, triple-negative breast cancer, dermato­myositis 

Foetal antigen 2 (FA2) in the stromal reaction induced by breast carcinoma

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Rasmussen, H B; Teisner, B; Andersen, J A

1992-01-01

An indirect immunoperoxidase technique was used to examine the distribution of foetal antigen 2 (FA2), a recently described basement membrane (BM)-associated antigen, in invasive breast carcinoma (n = 34), fibroadenoma (n = 5) and normal breast tissue (n = 5), and to compare its distribution...... with that of laminin and collagen type IV. In normal breast tissue, FA2 was detected in the intralobular stroma as a broad band around acini and ducts, but was not present in the interlobular stroma. In areas of carcinoma in situ, FA2 was present diffusely around and in close contact with the glandular elements......, the staining being more intense than that found around normal glandular structures. Two distinct patterns of FA2 distribution were found in adenocarcinomas of the breast. In the fibroblast reaction type, fibroblast staining dominated, whilst in the stromal reaction type, intense and extensive staining...

Comparison the treatment effects between simultaneous dual frequency and single frequency irradiation of ultrasound in a murine model of breast adenocarcinoma

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Mahboobeh Alamolhoda

2010-12-01

Full Text Available Introduction: Transient cavitations induced by low frequency irradiation of ultrasound can be used to treat tumors. Previous studies in in-vitro experiments have shown that induced cavitation by dual or multiple frequencies of ultrasound is greater than induced cavitation by single frequency irradiation. In this study, we compared and evaluated the treatment effects of dual frequency irradiation of ultrasound (1 MHz and 150 kHz and single frequency irradiation in in-vivo experiments on breast adenocarcinoma tumors. Material and Method: In this study, the tumor-bearing mice were divided into 5 groups: control, sham, treated group for 30 min with 150 kHz frequency in continuous mode, another group with 1 MHz frequency in pulse mode, and treated group with combined dual frequency ultrasound (150 kHz in continuous mode and 1 MHz in 80% pulse mode. To evaluate the effects of ultrasound irradiation on tumor growth delay, the volumes of the tumors were investigated for 30 days. Tumor growth delay parameters including relative volume, inhibition ratio percentage and the required times for the tumor volume to reach to two (T2 and five (T5 times its initial volume were calculated. Results: The results showed that the treated groups with single frequency irradiation of 150 kHz continuous mode and 1 MHz pulse mode and combined dual frequency had statistically significant differences in tumor relative volume percentage during the period of 3 to 24 days after treatment (p

Mouse models of estrogen receptor-positive breast cancer

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Shakur Mohibi

2011-01-01

Full Text Available Breast cancer is the most frequent malignancy and second leading cause of cancer-related deaths among women. Despite advances in genetic and biochemical analyses, the incidence of breast cancer and its associated mortality remain very high. About 60 - 70% of breast cancers are Estrogen Receptor alpha (ER-α positive and are dependent on estrogen for growth. Selective estrogen receptor modulators (SERMs have therefore provided an effective targeted therapy to treat ER-α positive breast cancer patients. Unfortunately, development of resistance to endocrine therapy is frequent and leads to cancer recurrence. Our understanding of molecular mechanisms involved in the development of ER-α positive tumors and their resistance to ER antagonists is currently limited due to lack of experimental models of ER-α positive breast cancer. In most mouse models of breast cancer, the tumors that form are typically ER-negative and independent of estrogen for their growth. However, in recent years more attention has been given to develop mouse models that develop different subtypes of breast cancers, including ER-positive tumors. In this review, we discuss the currently available mouse models that develop ER-α positive mammary tumors and their potential use to elucidate the molecular mechanisms of ER-α positive breast cancer development and endocrine resistance.

The effects of conjugated linoleic acids on breast cancer: A systematic review

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Arman Arab

2016-01-01

Full Text Available Recently prevention strategies for breast cancer are focused on lifestyle modification such as diet. Some dietary factors such as Conjugated linoleic acid (CLA can lower the risk of breast cancer, metastasis and some factors concerning this malignancy. Many studies have been established in this field, but their results are inconsistent. Therefore, we evaluated this association based on systematic review among published scientific literature. We performed an electronic search using PubMed, Cochrane, Scopus, Google Scholar and Persian database (Iran Medex, magiran to identify relevant studies. We summarized the findings of 8 papers in this review. Although, three cohort studies were not overall identified a protective effect of CLA dietary intake or CLA content in breast tissue on breast cancer incidence, metastasis and death, one of them showed an inverse association after adjusting for age. Also, among case-control studies a weak inverse association between breast cancer risk and CLA dietary intake and serum levels among post-menopausal women was reported. Besides, a clinical trial showed that some indicator of breast tumor decreased after CLA administration among women with breast adenocarcinoma. Lacking published evidence suggested inconsistent results. So, further well-designed studies are required, particularly in considering the main breast cancer risk factors.

Primary urachal adenocarcinoma: A case report

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I. Ziouziou

2014-06-01

Full Text Available Primary urachal adenocarcinoma is an aggressive rare cancer that often presents at advanced stages with poor prognosis. We report this case of a 52-year-old patient with a stage-I (Mayo Clinic primary urachal adenocarcinoma with good outcomes after surgery in a 2-year follow-up period. We analyze epidemiological, clinical and therapeutic features of this disease in the literature review.

Resistance to discontinuing breast cancer screening in older women: A qualitative study.

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Housten, Ashley J; Pappadis, Monique R; Krishnan, Shilpa; Weller, Susan C; Giordano, Sharon H; Bevers, Therese B; Volk, Robert J; Hoover, Diana S

2018-06-01

Screening mammography is associated with reduced breast cancer-specific mortality; however, among older women, evidence suggests that the potential harms of screening may outweigh the benefits. We used a qualitative approach to examine the willingness of older women from different racial/ethnic groups to discontinue breast cancer screening. Women ≥70 years of age who reported having a screening mammogram in the past 3 years and/or reported that they intended to continue screening in the future were recruited for in-depth interviews. Participants who intended to continue screening were asked to describe how the following hypothetical scenarios would impact a decision to discontinue screening: health concerns or limited life expectancy, a physician's recommendation to discontinue, reluctance to undergo treatment, and recommendations from experts or governmental panels to stop screening. Semi-structured, face-to-face interviews were audio-recorded. Data coding and analysis followed inductive and deductive approaches. Regardless of the scenario, participants (n = 29) expressed a strong intention to continue screening. Based on the hypothetical physician recommendations, intentions to continue screening appeared to remain strong. They did not envision a change in their health status that would lead them to discontinue screening and were skeptical of expert/government recommendations. There were no differences observed according to age, race/ethnicity, or education. Among older women who planned to continue screening, intentions to continue breast cancer screening appear to be highly resilient and resistant to recommendations from physicians or expert/government panels. Copyright © 2018 John Wiley & Sons, Ltd.

TMPRSS2-ERG gene fusion status in minute (minimal) prostatic adenocarcinoma.

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Albadine, Roula; Latour, Mathieu; Toubaji, Antoun; Haffner, Michael; Isaacs, William B; A Platz, Elizabeth; Meeker, Alan K; Demarzo, Angelo M; Epstein, Jonathan I; Netto, George J

2009-11-01

Minute prostatic adenocarcinomas are considered to be of insufficient virulence. Given recent suggestions of TMPRSS2-ERG gene fusion association with aggressive prostatic adenocarcinoma, we evaluated the incidence of TMPRSS2-ERG fusion in minute prostatic adenocarcinomas. A total of 45 consecutive prostatectomies with minute adenocarcinoma were used for tissue microarray construction. A total of 63 consecutive non-minimal, Gleason Score 6 tumors, from a separate PSA Era prostatectomy tissue microarray, were used for comparison. FISH was carried out using ERG break-apart probes. Tumors were assessed for fusion by deletion (Edel) or split (Esplit), duplicated fusions and low-level copy number gain in normal ERG gene locus. Minute adenocarcinomas: Fusion was evaluable in 32/45 tumors (71%). Fifteen out of 32 (47%) tumors were positive for fusion. Six (19%) were of the Edel class and 7 (22%) were classified as combined Edel+Esplit. Non-minute adenocarcinomas (pT2): Fusion was identified in 20/30 tumors (67%). Four (13%) were of Edel class and 5 (17%) were combined Edel+Esplit. Duplicated fusions were encountered in 5 (16%) tumors. Non-minute adenocarcinomas (pT3): Fusion was identified in 19/33 (58%). Fusion was due to a deletion in 6 (18%) tumors. Seven tumors (21%) were classified as combined Edel+Esplit. One tumor showed Esplit alone. Duplicated fusions were encountered in 3 (9%) cases. The incidence of duplicated fusions was higher in non-minute adenocarcinomas (13 vs 0%; P=0.03). A trend for higher incidence of low-level copy number gain in normal ERG gene locus without fusion was noted in non-minute adenocarcinomas (10 vs 0%; P=0.07). We found a TMPRSS2-ERG fusion rate of 47% in minute adenocarcinomas. The latter is not significantly different from that of grade matched non-minute adenocarcinomas. The incidence of duplicated fusion was higher in non-minute adenocarcinomas. Our finding of comparable rate of TMPRSS2-ERG fusion in minute adenocarcinomas may argue

Cryptolepine, isolated from Sida acuta, sensitizes human gastric adenocarcinoma cells to TRAIL-induced apoptosis.

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Ahmed, Firoj; Toume, Kazufumi; Ohtsuki, Takashi; Rahman, Mahmudur; Sadhu, Samir Kumar; Ishibashi, Masami

2011-01-01

Bioassay guided separation of Sida acuta whole plants led to the isolation of an alkaloid, cryptolepine (1), along with two kaempferol glycosides (2-3). Compound 1 showed strong activity in overcoming TRAIL-resistance in human gastric adenocarcinoma (AGS) cells at 1.25, 2.5 and 5 μm. Combined treatment of 1 and TRAIL sensitized AGS cells to TRAIL-induced apoptosis at the aforementioned concentrations. Copyright © 2010 John Wiley & Sons, Ltd.

A report of three cases with thrombotic thrombocytopenic purpura (TTP) secondary to an occult gastric adenocarcinoma

International Nuclear Information System (INIS)

Forat, Y.M.; Hashemian, Z.; Nazmieh, H.; Ghadimi, H.R.

2009-01-01

Thrombotic thrombocytopenic purpura (TTP) is a disseminated form of thrombotic microangiopathy with clinical findings consisting of fever, microangiopathic hemolytic anemia (MAHA), thrombocytopenia, fluctuating neurologic impairment and renal dysfunction. However, Microangiopathic hemolytic anemia has been described in association with disseminated malignancies, most commonly adenocarcinoma of the breast or stomach. We present three patients with microangiopathic anemia in whom metastatic cancer was finally diagnosed; however, they died of refractory hemolytic anemia in the end. The occurrence of microangiopathic hemolytic anemia and thrombocytopenia in patients with disseminated malignant in gastric adenocarsinoma is well documented. Therefore, the diagnosis of tumor-associated TTP should be considered in unresponsive TTP patient treated with plasmapheresis. (author)

Sunitinib significantly suppresses the proliferation, migration, apoptosis resistance, tumor angiogenesis and growth of triple-negative breast cancers but increases breast cancer stem cells.

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Chinchar, Edmund; Makey, Kristina L; Gibson, John; Chen, Fang; Cole, Shelby A; Megason, Gail C; Vijayakumar, Srinivassan; Miele, Lucio; Gu, Jian-Wei

2014-01-01

The majority of triple-negative breast cancers (TNBCs) are basal-like breast cancers. However there is no reported study on anti-tumor effects of sunitinib in xenografts of basal-like TNBC (MDA-MB-468) cells. In the present study, MDA-MB-231, MDA-MB-468, MCF-7 cells were cultured using RPMI 1640 media with 10% FBS. Vascular endothelia growth factor (VEGF) protein levels were detected using ELISA (R & D Systams). MDA-MB-468 cells were exposed to sunitinib for 18 hours for measuring proliferation (3H-thymidine incorporation), migration (BD Invasion Chamber), and apoptosis (ApopTag and ApoScreen Anuexin V Kit). The effect of sunitinib on Notch-1 expression was determined by Western blot in cultured MDA-MB-468 cells. 10(6) MDA-MB-468 cells were inoculated into the left fourth mammary gland fat pad in athymic nude-foxn1 mice. When the tumor volume reached 100 mm(3), sunitinib was given by gavage at 80 mg/kg/2 days for 4 weeks. Tumor angiogenesis was determined by CD31 immunohistochemistry. Breast cancer stem cells (CSCs) isolated from the tumors were determined by flow cytometry analysis using CD44(+)/CD24(-) or low. ELISA indicated that VEGF was much more highly expressed in MDA-MB-468 cells than MDA-MB-231 and MCF-7 cells. Sunitinib significantly inhibited the proliferation, invasion, and apoptosis resistance in cultured basal like breast cancer cells. Sunitinib significantly increased the expression of Notch-1 protein in cultured MDA-MB-468 or MDA-MB-231 cells. The xenograft models showed that oral sunitinib significantly reduced the tumor volume of TNBCs in association with the inhibition of tumor angiogeneisis, but increased breast CSCs. These findings support the hypothesis that the possibility should be considered of sunitinib increasing breast CSCs though it inhibits TNBC tumor angiogenesis and growth/progression, and that effects of sunitinib on Notch expression and hypoxia may increase breast cancer stem cells. This work provides the groundwork for an

Radiation response of drug-resistant variants of a human breast cancer cell line

International Nuclear Information System (INIS)

Lehnert, S.; Greene, D.; Batist, G.

1989-01-01

The radiation response of drug-resistant variants of the human tumor breast cancer cell line MCF-7 has been investigated. Two sublines, one resistant to adriamycin (ADRR) and the other to melphalan (MLNR), have been selected by exposure to stepwise increasing concentrations of the respective drugs. ADRR cells are 200-fold resistant to adriamycin and cross-resistant to a number of other drugs and are characterized by the presence of elevated levels of selenium-dependent glutathione peroxidase and glutathione-S-transferase. MLNR cells are fourfold resistant to melphalan and cross-resistant to some other drugs. The only mechanism of drug resistance established for MLNR cells to date is an enhancement of DNA excision repair processes. While the spectrum of drug resistance and the underlying mechanisms differ for the two sublines, their response to radiation is qualitatively similar. Radiation survival curves for ADRR and MLNR cells differ from that for wild-type cells in a complex manner with, for the linear-quadratic model, a decrease in the size of alpha and an increase in the size of beta. There is a concomitant decrease in the size of the alpha/beta ratio which is greater for ADRR cells than for MLNR cells. Analysis of results using the multitarget model gave values of D0 of 1.48, 1.43, and 1.67 Gy for MCF-7 cells are not a consequence of cell kinetic differences between these sublines. Results of split-dose experiments indicated that for both drug-resistant sublines the extent of sublethal damage repair reflected the width of the shoulder on the single-dose survival curve. For MCF-7 cells in the stationary phase of growth, the drug-resistant sublines did not show cross-resistance to radiation; however, delayed subculture following irradiation of stationary-phase cultures increased survival to a greater extent for ADRR and MLNR cells than for wild-type cells

Ureteric stricture secondary to unusual extension of prostatic adenocarcinoma.

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Chalasani, Venu; Macek, Petr; O'Neill, Gordon F; Barret, Wade

2010-02-01

This article describes an unusual finding in a patient who presented with an adenocarcinoma of the prostate and right hydronephrosis. A 68-year-old male presented with right hydronephrosis and a PSA of 96. DRE was consistent with cT3 carcinoma. Cystoscopy showed an exophytic superficial transitional cell carcinoma (TCC) of the bladder and a transrectal biopsy of the prostate confirmed adenocarcinoma Gleason score 4+3. Staging investigations (CT pelvis and bone scan) were negative; androgen deprivation therapy was therefore initiated for the prostatic adenocarcinoma. Upper tract imaging showed multiple filling defects in the proximal ureter. Ureteroscopy showed a stricture at the level of the iliac vessels. With a working diagnosis of upper tract TCC, right open nephroureterectomy was performed. Final histology showed prostatic adenocarcinoma infiltrating the adventitia of the entire ureter up to the level of the renal pelvis. A rare cause of ureteric stricture, contiguous spread of prostatic adenocarcinoma, should be considered in the differential diagnosis of patients presenting with upper tract obstruction and a known history of prostatic adenocarcinoma. Androgen deprivation therapy for several months did not seem to cause resolution of the tumor in the periureteric, ureteric and perihilar tissues.

TIMP-1 increases expression and phosphorylation of proteins associated with drug resistance in breast cancer cells

DEFF Research Database (Denmark)

Hekmat, Omid; Munk, Stephanie; Fogh, Louise

2013-01-01

may explain the resistance phenotype to topoisomerase inhibitors that was observed in cells with high TIMP-1 levels. Pathway analysis showed an enrichment of proteins from functional categories such as apoptosis, cell cycle, DNA repair, transcription factors, drug targets and proteins associated......Tissue inhibitor of metalloproteinase 1 (TIMP-1) is a protein with a potential biological role in drug resistance. To elucidate the unknown molecular mechanisms underlying the association between high TIMP-1 levels and increased chemotherapy resistance, we employed SILAC-based quantitative mass...... spectrometry to analyze global proteome and phosphoproteome differences of MCF-7 breast cancer cells expressing high or low levels of TIMP-1. In TIMP-1 high expressing cells, 312 proteins and 452 phosphorylation sites were up-regulated. Among these were the cancer drug targets topoisomerase 1, 2A and 2B, which...

Laparoscopic distal pancreatectomy for adenocarcinoma: safe and reasonable?

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Postlewait, Lauren M.

2015-01-01

As a result of technological advances during the past two decades, surgeons now use minimally invasive surgery (MIS) approaches to pancreatic resection more frequently, yet the role of these approaches for pancreatic ductal adenocarcinoma resections remains uncertain, given the aggressive nature of this malignancy. Although there are no controlled trials comparing MIS technique to open surgical technique, laparoscopic distal pancreatectomy for pancreatic adenocarcinoma is performed with increasing frequency. Data from retrospective studies suggest that perioperative complication profiles between open and laparoscopic distal pancreatectomy are similar, with perhaps lower blood loss and fewer wound infections in the MIS group. Concerning oncologic outcomes, there appear to be no differences in the rate of achieving negative margins or in the number of lymph nodes (LNs) resected when compared to open surgery. There are limited recurrence and survival data on laparoscopic compared to open distal pancreatectomy for pancreatic adenocarcinoma, but in the few studies that assess long term outcomes, recurrence rates and survival outcomes appear similar. Recent studies show that though laparoscopic distal pancreatectomy entails a greater operative cost, the associated shorter length of hospital stay leads to decreased overall cost compared to open procedures. Multiple new technologies are emerging to improve resection of pancreatic cancer. Robotic pancreatectomy is feasible, but there are limited data on robotic resection of pancreatic adenocarcinoma, and outcomes appear similar to laparoscopic approaches. Additionally fluorescence-guided surgery represents a new technology on the horizon that could improve oncologic outcomes after resection of pancreatic adenocarcinoma, though published data thus far are limited to animal models. Overall, MIS distal pancreatectomy appears to be a safe and reasonable approach to treating selected patients with pancreatic ductal

Compartmental modelling of the pharmacokinetics of a breast cancer resistance protein.

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Grandjean, Thomas R B; Chappell, Mike J; Yates, James T W; Jones, Kevin; Wood, Gemma; Coleman, Tanya

2011-11-01

A mathematical model for the pharmacokinetics of Hoechst 33342 following administration into a culture medium containing a population of transfected cells (HEK293 hBCRP) with a potent breast cancer resistance protein inhibitor, Fumitremorgin C (FTC), present is described. FTC is reported to almost completely annul resistance mediated by BCRP in vitro. This non-linear compartmental model has seven macroscopic sub-units, with 14 rate parameters. It describes the relationship between the concentration of Hoechst 33342 and FTC, initially spiked in the medium, and the observed change in fluorescence due to Hoechst 33342 binding to DNA. Structural identifiability analysis has been performed using two methods, one based on the similarity transformation/exhaustive modelling approach and the other based on the differential algebra approach. The analyses demonstrated that all models derived are uniquely identifiable for the experiments/observations available. A kinetic modelling software package, namely FACSIMILE (MPCA Software, UK), was used for parameter fitting and to obtain numerical solutions for the system equations. Model fits gave very good agreement with in vitro data provided by AstraZeneca across a variety of experimental scenarios. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Metastatic prostate adenocarcinoma penis: Case report

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Pablo Santiago Caicedo

2014-08-01

Full Text Available Objective: Describe a case report of a patient with prostatic adenocarcinoma metastatic to penis due to shortage reports of similar cases to perform a literature review. Methods: We identified a case of a patient with prostatic adenocarcinoma, who during de the course of a cystoscopy at Hospital Universitario San Jose (Third-level Public Hospital in Popayan, Colombia a suspicious nodule of malignancy was observed in the penis. We described the clinical case in order to proceed to a literature search for the discussion. Results: 72-year-old patient diagnosed with prostatic adenocarcinoma Gleason Score 4+5=9, treated with bilateral orchiectomy and a suspicious nodule of malignancy incidentally observed in the penis, currently undergoing palliative care with Karnofsky score of 30 points. Conclusion: cutaneous metastases are rare; indicate longstanding disease and poor prognosis.

Interaction of insulin-like growth factor-I and insulin resistance-related genetic variants with lifestyle factors on postmenopausal breast cancer risk.

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Jung, Su Yon; Ho, Gloria; Rohan, Thomas; Strickler, Howard; Bea, Jennifer; Papp, Jeanette; Sobel, Eric; Zhang, Zuo-Feng; Crandall, Carolyn

2017-07-01

Genetic variants and traits in metabolic signaling pathways may interact with obesity, physical activity, and exogenous estrogen (E), influencing postmenopausal breast cancer risk, but these inter-related pathways are incompletely understood. We used 75 single-nucleotide polymorphisms (SNPs) in genes related to insulin-like growth factor-I (IGF-I)/insulin resistance (IR) traits and signaling pathways, and data from 1003 postmenopausal women in Women's Health Initiative Observation ancillary studies. Stratifying via obesity and lifestyle modifiers, we assessed the role of IGF-I/IR traits (fasting IGF-I, IGF-binding protein 3, insulin, glucose, and homeostatic model assessment-insulin resistance) in breast cancer risk as a mediator or influencing factor. Seven SNPs in IGF-I and INS genes were associated with breast cancer risk. These associations differed between non-obese/active and obese/inactive women and between exogenous E non-users and users. The mediation effects of IGF-I/IR traits on the relationship between these SNPs and cancer differed between strata, but only roughly 35% of the cancer risk due to the SNPs was mediated by traits. Similarly, carriers of 20 SNPs in PIK3R1, AKT1/2, and MAPK1 genes (signaling pathways-genetic variants) had different associations with breast cancer between strata, and the proportion of the SNP-cancer relationship explained by traits varied 45-50% between the strata. Our findings suggest that IGF-I/IR genetic variants interact with obesity and lifestyle factors, altering cancer risk partially through pathways other than IGF-I/IR traits. Unraveling gene-phenotype-lifestyle interactions will provide data on potential genetic targets in clinical trials for cancer prevention and intervention strategies to reduce breast cancer risk.

Efficacy of S-1 plus nedaplatin compared to standard second-line chemotherapy in EGFR-negative lung adenocarcinoma after failure of first-line chemotherapy.

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Tang, Yu; Wang, Wei; Teng, Xiu-Zhi; Shi, Lin

2014-09-01

For patients with advanced non-small cell lung adenocarcinoma that fail to respond to first-line chemotherapy and that do not involve epidermal growth factor receptor (EGFR) mutations, previous empirical analysis showed that a single second-line chemotherapy agent may be inadequate for the control of further tumor development. This study examines the combination of S-1 drugs and nedaplatin that has no cross-resistance to first-line treatments; 179 cases of IIIb-IV stage non-small-cell lung adenocarcinoma that failed to respond to first-line chemotherapy were included, and these subjects did not have mutated EGFRs. In the present study, S-1 plus nedaplatin chemotherapy was better than standard second-line chemotherapy options in the treatment of advanced lung adenocarcinoma that did not involve EGFR mutations and that failed to respond to first-line chemotherapy. Additionally, the combination of S-1 and nedaplatin seemed to be well tolerated, making this chemotherapy technique a potentially strong candidate for the treatment of advanced non-small-cell lung adenocarcinoma.

Clinical studies on gastric cancer and breast cancer among A-bomb survivors

Energy Technology Data Exchange (ETDEWEB)

Yamagata, S; Ohya, M; Nagusa, Y; Harada, T; Tani, T [Hiroshima Univ. (Japan). Research Inst. for Nuclear Medicine and Biology

1977-04-01

Fifty-five cases of gastric cancer and 14 cases of breast cancer among A-Bomb survivors, which had been treated at Dept. of Surgery, Research Institute for Nuclear Medicine and Biology of Hiroshima Univ., were discussed. Both gastric cancer and breast cancer were recognized more in A-Bomb survivors of advanced age. Particularly, the number of gastric cancer in A-Bomb survivors of over 65-year old was about double the number of unexposed persons. Ratio of male to female in A-Bomb survivors with gastric cancer was 1.6:1, and the ratio of female was higher as compared to the ratio in unexposed persons (2.6:1). Gastric cancer of stage III and IV in A-Bomb survivors was 54.5%, and advanced cancer was comparatively few in A-Bomb survivors as compared to in unexposed persons (78.2%). Similarly, comparatively early stage breast cancer of stage I and II was recognized more in A-Bomb survivors. Particularly, T/sub 1/ and T/sub 2/ in which tumor was small in size showed very high percentage of 92.9% in A-Bomb survivors. In gastric cancer in A-Bomb survivors, poorly differentiated adenocarcinoma showed the highest percentage of 34.5%. However, there was no significant difference according to the exposure conditions. As to histological type of breast cancer, medullary tubular adenocarcinoma abounds mostly in both A-Bomb survivors (71.4%) and unexposed persons (75.9%). As the influence of operation, anemia was recognized before operation strongly in A-Bomb survivors with gastric cancer of over 65-year old. After the operation, transient rise of GOT and GPT was recognized in A-Bomb survivors of advanced age with gastric cancer. However, there was no difference in postoperative complications between A-Bomb survivors and unexposed persons.

Mucin 1-specific immunotherapy in a mouse model of spontaneous breast cancer.

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Mukherjee, Pinku; Madsen, Cathy S; Ginardi, Amelia R; Tinder, Teresa L; Jacobs, Fred; Parker, Joanne; Agrawal, Babita; Longenecker, B Michael; Gendler, Sandra J

2003-01-01

Human mucin 1 (MUC1) is an epithelial mucin glycoprotein that is overexpressed in 90% of all adenocarcinomas including breast, lung, pancreas, prostate, stomach, colon, and ovary. MUC1 is a target for immune intervention, because, in patients with solid adenocarcinomas, low-level cellular and humoral immune responses to MUC1 have been observed, which are not sufficiently strong to eradicate the growing tumor. The hypothesis for this study is that enhancing MUC1-specific immunity will result in antitumor immunity. To test this, the authors have developed a clinically relevant breast cancer model that demonstrates peripheral and central tolerance to MUC1 and develops spontaneous tumors of the mammary gland. In these mice, the authors tested a vaccine formulation comprised of liposomal-MUC1 lipopeptide and human recombinant interleukin-2. Results indicate that when compared with untreated mice, immunized mice develop T cells that express intracellular IFN-gamma, are reactive with MHC class I H-2Db/MUC1 tetramer, and are cytotoxic against MUC1-expressing tumor cells in vitro. The presence of MUC1-specific CTL did not translate into a clinical response as measured by time of tumor onset, tumor burden, and survival. The authors demonstrate that some of the immune-evasion mechanisms used by the tumor cells include downregulation of MHC-class I molecule, expression of TGF-beta2, and decrease in IFN-gamma -expressing effector T cells as tumors progress. Finally, utilizing an injectable breast cancer model, the authors show that targeting a single tumor antigen may not be an effective antitumor treatment, but that immunization with dendritic cells fed with whole tumor lysate is effective in breaking tolerance and protecting mice from subsequent tumor challenge. A physiologically relevant spontaneous breast cancer model has been developed to test improved immunotherapeutic approaches.

Expression of inwardly rectifying potassium channels (GIRKs) and beta-adrenergic regulation of breast cancer cell lines

International Nuclear Information System (INIS)

Plummer, Howard K III; Yu, Qiang; Cakir, Yavuz; Schuller, Hildegard M

2004-01-01

Previous research has indicated that at various organ sites there is a subset of adenocarcinomas that is regulated by beta-adrenergic and arachidonic acid-mediated signal transduction pathways. We wished to determine if this regulation exists in breast adenocarcinomas. Expression of mRNA that encodes a G-protein coupled inwardly rectifying potassium channel (GIRK1) has been shown in tissue samples from approximately 40% of primary human breast cancers. Previously, GIRK channels have been associated with beta-adrenergic signaling. Breast cancer cell lines were screened for GIRK channels by RT-PCR. Cell cultures of breast cancer cells were treated with beta-adrenergic agonists and antagonists, and changes in gene expression were determined by both relative competitive and real time PCR. Potassium flux was determined by flow cytometry and cell signaling was determined by western blotting. Breast cancer cell lines MCF-7, MDA-MB-361 MDA-MB 453, and ZR-75-1 expressed mRNA for the GIRK1 channel, while MDA-MB-468 and MDA-MB-435S did not. GIRK4 was expressed in all six breast cancer cell lines, and GIRK2 was expressed in all but ZR-75-1 and MDA-MB-435. Exposure of MDA-MB-453 cells for 6 days to the beta-blocker propranolol (1 μM) increased the GIRK1 mRNA levels and decreased beta 2 -adrenergic mRNA levels, while treatment for 30 minutes daily for 7 days had no effect. Exposure to a beta-adrenergic agonist and antagonist for 24 hours had no effect on gene expression. The beta adrenergic agonist, formoterol hemifumarate, led to increases in K + flux into MDA-MB-453 cells, and this increase was inhibited by the GIRK channel inhibitor clozapine. The tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a high affinity agonist for beta-adrenergic receptors stimulated activation of Erk 1/2 in MDA-MB-453 cells. Our data suggests β-adrenergic receptors and GIRK channels may play a role in breast cancer

Necl 4 and RNase 5 Are Important Biomarkers for Gastric and Colon Adenocarcinomas.

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Sayar, İlyas; Gökçe, Aysun; Demirtas, Levent; Eken, Hüseyin; Çimen, Ferda Keskin; Çimen, Orhan

2017-05-31

BACKGROUND There is a need to identify new prognostic factors that may be used in addition to the known risk factors in gastrointestinal adenocarcinomas. In this study, we aimed to determine the expression of Necl 4 and RNase 5 biomarkers in gastric and colon adenocarcinomas, as well as the prognostic efficacy of these biomarkers in gastric and colon adenocarcinomas. MATERIAL AND METHODS Ninety-two cases resected due to stomach and colon adenocarcinoma were included in the study. The expression of Necl 4 and RNase 5 biomarkers was evaluated by immunohistochemical staining of the stomach and colon normal mucosa and adenocarcinoma areas. RESULTS In colon adenocarcinomas, there was a significant association between Necl 4 and lymphovascular invasion, vascular invasion, and perineural invasion (p<0.05). There was a significant association between RNase 5 and histological differentiation in colon adenocarcinomas (p<0.05). There was no association between RNase 5 and Necl 4 in gastric or colon adenocarcinomas. CONCLUSIONS Necl 4 may have prognostic value in colon adenocarcinomas, but it is difficult to ascertain in gastric adenocarcinomas.

Experiment list: SRX099869 [Chip-atlas[Archive

Lifescience Database Archive (English)

Full Text Available of Extraction=Pleura|Tissue Diagnosis=Adenocarcinoma 30024170,98.2,3.9,1267 GSM808758: MCF7 INPUT source_name=breast adenocarcinoma... cells || cell type=breast adenocarcinoma cells || cell line=MCF7 || antibody=INPUT h

Mucinous adenocarcinoma of posterior urethra. Report of a case.

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Yvgenia, Rosenblat; Ben Meir, David; Sibi, Joseph; Koren, Rumelia

2005-01-01

Primary carcinoma of the male urethra accounts for less than 1% of malignancies in males. Mucinous adenocarcinoma of the urethra is extremely rare, and its biologic behavior is not well known. We report a case of mucinous adenocarcinoma showing the histologic features of colloid adenocarcinoma that appears to have evolved either by neoplastic degeneration of goblet cells found in the urethral epithelium or by malignant degeneration of persistent glandular elements of uretheritis cystica and glandularis.

Well-differentiated fetal adenocarcinoma: A very uncommon malignant lung tumor

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H. El Ouazzani

2012-01-01

Full Text Available Well-differentiated fetal adenocarcinoma (WDFA is a very uncommon malignant tumor originating in the lung. This report describes the case of a 38-year-old woman with a WDFA treated by surgery. The malignancy is low grade and associated with a good prognosis, and so it is important for clinicians to be aware of and to identify this rare variant of adenocarcinoma. Resumo: O adenocarcinoma fetal bem diferenciado (WDFA, de acordo com a sigla em inglês é um tumor maligno no pulmão muito invulgar que tem origem no pulmão. Este relatório descreve o caso de uma mulher de 38 anos com WDFA tratada através de cirurgia. A malignidade é de baixo grau e está associada a um bom prognóstico e, por isso, é importante que os clínicos estejam atentos e identifiquem esta variante rara de adenocarcinoma. Keywords: Well-differentiated fetal adenocarcinoma, Lung, Good prognosis, Palavras-chave: Adenocarcinoma fetal bem diferenciado, pulmão, bom prognóstico

Intramucosal adenocarcinoma of the ileum originated 40 years after ileosigmoidostomy

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Sameshima Shinichi

2009-04-01

Full Text Available Abstract Background Small bowel adenocarcinomas (SBAs are rare carcinomas. They are asymptomatic and usually neither endoscopy nor contrast studies are performed for screening Case presentation A 72-year-old Japanese male had a positive fecal occult blood test at a regular check-up in 2006. He suffered appendicitis and received an ileosigmoidostomy in 1966. A colonoscopy revealed an irregular mucosal lesion with an unclear margin at the ileum side of the anastomosis. A mucosal biopsy specimen showed adenocarcinoma histopathologically. Excision of the anastomosis was performed for this patient. The resected specimen showed a flat mucosal lesion with a slight depression at the ileum adjacent to the anastomosis. Histological examination revealed a well differentiated intramucosal adenocarcinoma (adenocarcinoma in situ. Immunohistological staining demonstrated the overexpression of p53 protein in the adenocarcinoma. Conclusion Adenocarcinoma of the ileum at such an early stage is a very rare event. In this case, there is a possibility that the ileosigmoidostomy resulted in a back flow of colonic stool to the ileum that caused the carcinogenesis of the small intestine.

Mitochondrial markers predict recurrence, metastasis and tamoxifen-resistance in breast cancer patients: Early detection of treatment failure with companion diagnostics.

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Sotgia, Federica; Fiorillo, Marco; Lisanti, Michael P

2017-09-15

Here, we used a data-mining and informatics approach to discover new biomarkers of resistance to hormonal therapy in breast cancer. More specifically, we investigated whether nuclear-encoded genes associated with mitochondrial biogenesis can be used to predict tumor recurrence, distant metastasis and treatment failure in high-risk breast cancer patients. Overall, this strategy allowed us to directly provide in silico validation of the prognostic value of these mitochondrial components in large and clinically relevant patient populations, with >15 years of follow-up data. For this purpose, we employed a group of 145 ER(+) luminal A breast cancer patients, with lymph-node (LN) metastasis at diagnosis, that were treated with tamoxifen, but not any chemotherapy agents. Using this approach, we identified >60 new individual mitochondrial biomarkers that predicted treatment failure and tumor recurrence, with hazard-ratios (HR) of up to 4.17 ( p =2.2e-07). These include mitochondrial chaperones (HSPD1, HSPA9), membrane proteins (VDAC2, TOMM70A) and anti-oxidants (SOD2), as well as 18 different mitochondrial ribosomal proteins (MRPs) and >20 distinct components of the OXPHOS complexes. In addition, we combined 4 mitochondrial proteins (HSPD1, UQCRB, MRPL15, COX17), to generate a compact mitochondrial gene signature, associated with a HR of 5.34 ( p =1e-09). This signature also successfully predicted distant metastasis and was effective in larger groups of ER(+) ( N =2,447), basal ( N =540) and HER2(+) ( N =193) breast cancers. It was also effective in all breast cancers ( N =3,180), if considered together as a single group. Based on this analysis, we conclude that mitochondrial biogenesis should be considered as a new therapeutic target for overcoming tumor recurrence, distant metastasis and treatment failure in patients with breast cancer. In summary, we identified individual mitochondrial biomarkers and 2 compact mitochondrial gene signatures that can be used to predict

Experiment list: SRX099864 [Chip-atlas[Archive

Lifescience Database Archive (English)

Full Text Available ction=Pleura|Tissue Diagnosis=Adenocarcinoma 25775296,94.5,18.3,57005 GSM808753: MCF7 CTCF REP2 source_name=breast adenocarcinoma... cells || cell type=breast adenocarcinoma cells || cell line=MCF7 || antibody=CTCF http

Experiment list: SRX099863 [Chip-atlas[Archive

Lifescience Database Archive (English)

Full Text Available ction=Pleura|Tissue Diagnosis=Adenocarcinoma 22593576,94.8,16.6,51049 GSM808752: MCF7 CTCF REP1 source_name=breast adenocarcinoma... cells || cell type=breast adenocarcinoma cells || cell line=MCF7 || antibody=CTCF http

Quantitative CT analysis of pulmonary ground-glass opacity nodules for distinguishing invasive adenocarcinoma from non-invasive or minimally invasive adenocarcinoma: the added value of using iodine mapping.

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Son, Ji Ye; Lee, Ho Yun; Kim, Jae-Hun; Han, Joungho; Jeong, Ji Yun; Lee, Kyung Soo; Kwon, O Jung; Shim, Young Mog

2016-01-01

To determine whether quantitative analysis of iodine-enhanced images generated from dual-energy CT (DECT) have added value in distinguishing invasive adenocarcinoma from non-invasive or minimally invasive adenocarcinoma (MIA) showing ground-glass nodule (GGN). Thirty-four patients with 39 GGNs were enrolled in this prospective study and underwent DECT followed by complete tumour resection. Various quantitative imaging parameters were assessed, including virtual non-contrast (VNC) imaging and iodine-enhanced imaging. Of all 39 GGNs, four were adenocarcinoma in situ (AIS) (10 %), nine were MIA (23 %), and 26 were invasive adenocarcinoma (67 %). When assessing only VNC imaging, multivariate analysis revealed that mass, uniformity, and size-zone variability were independent predictors of invasive adenocarcinoma (odds ratio [OR] = 19.92, P = 0.02; OR = 0.70, P = 0.01; OR = 16.16, P = 0.04, respectively). After assessing iodine-enhanced imaging with VNC imaging, both mass on the VNC imaging and uniformity on the iodine-enhanced imaging were independent predictors of invasive adenocarcinoma (OR = 5.51, P = 0.04 and OR = 0.67, P VNC imaging alone, from 0.888 to 0.959, respectively (P = 0.029). Quantitative analysis using iodine-enhanced imaging metrics versus VNC imaging metrics alone generated from DECT have added value in distinguishing invasive adenocarcinoma from AIS or MIA. Quantitative analysis using DECT was used to distinguish invasive adenocarcinoma. Tumour mass and uniformity were independent predictors of invasive adenocarcinoma. Diagnostic performance was improved after adding iodine parameters to VNC parameters.

Parallel evolution under chemotherapy pressure in 29 breast cancer cell lines results in dissimilar mechanisms of resistance.

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Bálint Tegze

Full Text Available BACKGROUND: Developing chemotherapy resistant cell lines can help to identify markers of resistance. Instead of using a panel of highly heterogeneous cell lines, we assumed that truly robust and convergent pattern of resistance can be identified in multiple parallel engineered derivatives of only a few parental cell lines. METHODS: Parallel cell populations were initiated for two breast cancer cell lines (MDA-MB-231 and MCF-7 and these were treated independently for 18 months with doxorubicin or paclitaxel. IC50 values against 4 chemotherapy agents were determined to measure cross-resistance. Chromosomal instability and karyotypic changes were determined by cytogenetics. TaqMan RT-PCR measurements were performed for resistance-candidate genes. Pgp activity was measured by FACS. RESULTS: All together 16 doxorubicin- and 13 paclitaxel-treated cell lines were developed showing 2-46 fold and 3-28 fold increase in resistance, respectively. The RT-PCR and FACS analyses confirmed changes in tubulin isofom composition, TOP2A and MVP expression and activity of transport pumps (ABCB1, ABCG2. Cytogenetics showed less chromosomes but more structural aberrations in the resistant cells. CONCLUSION: We surpassed previous studies by parallel developing a massive number of cell lines to investigate chemoresistance. While the heterogeneity caused evolution of multiple resistant clones with different resistance characteristics, the activation of only a few mechanisms were sufficient in one cell line to achieve resistance.

Downregulation of COX-2 and CYP 4A signaling by isoliquiritigenin inhibits human breast cancer metastasis through preventing anoikis resistance, migration and invasion

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Zheng, Hao; Li, Ying [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Wang, Yuzhong [Key Laboratory for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079 (China); Zhao, Haixia [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Zhang, Jing [Animal Experimental Center of Wuhan University, Wuhan 430071 (China); Chai, Hongyan [Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Tang, Tian [Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060 (China); Yue, Jiang [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Guo, Austin M., E-mail: Austin_Guo@nymc.edu [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Department of Pharmacology, New York Medical College, Valhalla, NY 10595 (United States); Yang, Jing, E-mail: yangjingliu2013@163.com [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China)

2014-10-01

Flavonoids exert extensive in vitro anti-invasive and in vivo anti-metastatic activities. Anoikis resistance occurs at multiple key stages of the metastatic cascade. Here, we demonstrate that isoliquiritigenin (ISL), a flavonoid from Glycyrrhiza glabra, inhibits human breast cancer metastasis by preventing anoikis resistance, migration and invasion through downregulating cyclooxygenase (COX)-2 and cytochrome P450 (CYP) 4A signaling. ISL induced anoikis in MDA-MB-231 and BT-549 human breast cancer cells as evidenced by flow cytometry and the detection of caspase cleavage. Moreover, ISL inhibited the mRNA expression of phospholipase A2, COX-2 and CYP 4A and decreased the secretion of prostaglandin E{sub 2} (PGE{sub 2}) and 20-hydroxyeicosatetraenoic acid (20-HETE) in detached MDA-MB-231 cells. In addition, it decreased the levels of phospho-PI3K (Tyr{sup 458}), phospho-PDK (Ser{sup 241}) and phospho-Akt (Thr{sup 308}). Conversely, the exogenous addition of PGE{sub 2}, WIT003 (a 20-HETE analog) and an EP4 agonist (CAY10580) or overexpression of constitutively active Akt reversed ISL-induced anoikis. ISL exerted the in vitro anti-migratory and anti-invasive activities, whereas the addition of PGE{sub 2}, WIT003 and CAY10580 or overexpression of constitutively active Akt reversed the in vitro anti-migratory and anti-invasive activities of ISL in MDA-MB-231 cells. Notably, ISL inhibited the in vivo lung metastasis of MDA-MB-231 cells, together with decreased intratumoral levels of PGE{sub 2}, 20-HETE and phospho-Akt (Thr{sup 308}). In conclusion, ISL inhibits breast cancer metastasis by preventing anoikis resistance, migration and invasion via downregulating COX-2 and CYP 4A signaling. It suggests that ISL could be a promising multi-target agent for preventing breast cancer metastasis, and anoikis could represent a novel mechanism through which flavonoids may exert the anti-metastatic activities. - Highlights: • Isoliquiritigenin induces anoikis and suppresses

Novel oral administrated paclitaxel micelles with enhanced bioavailability and antitumor efficacy for resistant breast cancer.

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Zhang, Ting; Luo, Jingwen; Fu, Yao; Li, Hanmei; Ding, Rui; Gong, Tao; Zhang, Zhirong

2017-02-01

Paclitaxel (PTX) is a widely used antineoplastic drug in clinic. Due to poor aqueous solubility, it is administrated by intravenous infusion of cremophor EL containing formulation with serious adverse effects. The low oral bioavailability is a great challenge for oral formulation development. In addition, P-gp mediated multidrug resistance limit its clinical use in various resistant cancers. In this study, a novel super-antiresistant PTX micelle formulation for oral administration was developed. A P-gp inhibitor, bromotetrandrine (W198) was co-encapsulated in the micelle. The micelles were composed of Solutol HS 15 and d-a-tocopheryl polyethylene glycol succinate to avoid Cremophor EL induced toxicity. The micelles were round with a mean particle size of ∼13nm and an encapsulation efficiency of ∼90%. A series of in vitro evaluations were performed in non-resistant MCF-7 cells and resistant MCF-7/Adr cells. The super-antiresistant PTX micelles showed higher cell uptake efficiency, significantly increased cytotoxicity and antimitotic effect in drug resistant MCF-7/Adr cells when compared with Taxol and other PTX micelle formulations. Compared with Taxol, the super-antiresistant PTX micelles significantly improved bioavailability after oral administration in rats, and inhibited tumor growth in multidrug resistance xenografted MCF-7/Adr nude mice. In summary, the noval super-antiresistant PTX micelles showed a great potential for oral delivery of PTX against resistant breast cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

Lung adenocarcinoma mimicking pulmonary fibrosis-a case report

International Nuclear Information System (INIS)

Mehić, Bakir; Duranović Rayan, Lina; Bilalović, Nurija; Dohranović Tafro, Danina; Pilav, Ilijaz

2016-01-01

Lung cancer is usually presented with cough, dyspnea, pain and weight loss, which is overlapping with symptoms of other lung diseases such as pulmonary fibrosis. Pulmonary fibrosis shows characteristic reticular and nodular pattern, while lung cancers are mostly presented with infiltrative mass, thick-walled cavitations or a solitary nodule with spiculated borders. If the diagnosis is established based on clinical symptoms and CT findings, it would be a misapprehension. We report a case of lung adenocarcinoma whose symptoms as well as clinical images overlapped strongly with pulmonary fibrosis. The patient’s non-productive cough, progressive dyspnea, restrictive pattern of pulmonary function test and CT scans (showing reticular interstitial opacities) were all indicative of pulmonary fibrosis. The patient underwent a treatment consisting of corticosteroids and antibiotics, to no avail. Histopathology of the lung showed that the patient suffered from mucinous adenocarcinoma. Albeit the immunohistochemical staining was not consistent with lung adenocarcinoma, tumor’s morphological characteristics were consistent, and were used to make the definitive diagnosis. Given the fact that radiography cannot always make a clear-cut difference between pulmonary fibrosis and lung adenocarcinomas, and that clinical symptoms often overlap, histological examination should be considered as gold standard for diagnosis of lung adenocarcinoma

Adenocarcinoma of the urinary bladder, mesonephroid type: a rare case

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Mahmoud Abbas

2013-02-01

Full Text Available Primary adenocarcinoma of the urinary bladder is a rare disease. It occurs in 0.5-2% of all bladder cancers and is discussed as the malignant counterpart of nephrogenic adenomas. We report a 46-year-old white female presented with gross hematuria for clinical examination. Histopathology revealed pT2, Pn1, L1, G2 adenocarcinoma of the bladder and carcinoma in situ according to the TNM classification. Computed tomography scan diagnostic was unremarkable. Patients with adenocarcinoma of the urinary bladder should be treated vigorously and without time delay. Only 7 cases of adenocarcinoma in the urinary bladder (mesonephroid have been described until now. We present a case of clear cell adenocarcinoma of the urinary bladder, mesonephroid type that early diagnosed and till now 3 months after the cystectomy without symptoms and without complications.

Effects of Aerobic and Resistance Exercise on Metabolic Syndrome, Sarcopenic Obesity, and Circulating Biomarkers in Overweight or Obese Survivors of Breast Cancer: A Randomized Controlled Trial.

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Dieli-Conwright, Christina M; Courneya, Kerry S; Demark-Wahnefried, Wendy; Sami, Nathalie; Lee, Kyuwan; Buchanan, Thomas A; Spicer, Darcy V; Tripathy, Debu; Bernstein, Leslie; Mortimer, Joanne E

2018-03-20

Purpose Metabolic syndrome is associated with an increased risk of cardiovascular disease, type 2 diabetes, and breast cancer recurrence in survivors of breast cancer. This randomized controlled trial assessed the effects of a 16-week combined aerobic and resistance exercise intervention on metabolic syndrome, sarcopenic obesity, and serum biomarkers among ethnically diverse, sedentary, overweight, or obese survivors of breast cancer. Methods Eligible survivors of breast cancer (N = 100) were randomly assigned to exercise (n = 50) or usual care (n = 50). The exercise group participated in supervised moderate-to-vigorous-65% to 85% of heart rate maximum-aerobic and resistance exercise three times per week for 16 weeks. Metabolic syndrome z-score (primary outcome), sarcopenic obesity, and serum biomarkers were measured at baseline, postintervention (4 months), and 3-month follow-up (exercise only). Results Participants were age 53 ± 10.4 years, 46% were obese, and 74% were ethnic minorities. Adherence to the intervention was 95%, and postintervention assessments were available in 91% of participants. Postintervention metabolic syndrome z-score was significantly improved in exercise versus usual care (between-group difference, -4.4; 95% CI, -5.9 to -2.7; P metabolic syndrome variables remained significantly improved compared with baseline in the exercise group ( P exercise effectively attenuated metabolic syndrome, sarcopenic obesity, and relevant biomarkers in an ethnically diverse sample of sedentary, overweight, or obese survivors of breast cancer. Our findings suggest a targeted exercise prescription for improving metabolic syndrome in survivors of breast cancer and support the incorporation of supervised clinical exercise programs into breast cancer treatment and survivorship care plans.

Exosomal MicroRNA MiR-1246 Promotes Cell Proliferation, Invasion and Drug Resistance by Targeting CCNG2 in Breast Cancer.

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Li, Xiu Juan; Ren, Zhao Jun; Tang, Jin Hai; Yu, Qiao

2017-01-01

Treatment of breast cancer remains a clinical challenge. This study aims to validate exosomal microRNA-1246 (miR-1246) as a serum biomarker for breast cancer and understand the underlying mechanism in breast cancer progression. The expression levels of endogenous and exosomal miRNAs were examined by real time PCR, and the expression level of the target protein was detected by western blot. Scanning electron and confocal microscopy were used to characterize exosomes and to study their uptake and transfer. Luciferase reporter plasmids and its mutant were used to confirm direct targeting. Furthermore, the functional significance of exosomal miR-1246 was estimated by invasion assay and cell viability assay. In this study, we demonstrate that exosomes carrying microRNA can be transferred among different cell lines through direct uptake. miR-1246 is highly expressed in metastatic breast cancer MDA-MB-231 cells compared to non-metastatic breast cancer cells or non-malignant breast cells. Moreover, miR-1246 can suppress the expression level of its target gene, Cyclin-G2 (CCNG2), indicating its functional significance. Finally, treatment with exosomes derived from MDA-MB-231 cells could enhance the viability, migration and chemotherapy resistance of non-malignant HMLE cells. Together, our results support an important role of exosomes and exosomal miRNAs in regulating breast tumor progression, which highlights their potential for applications in miRNA-based therapeutics. © 2017 The Author(s). Published by S. Karger AG, Basel.

Exosomal MicroRNA MiR-1246 Promotes Cell Proliferation, Invasion and Drug Resistance by Targeting CCNG2 in Breast Cancer

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Xiu Juan Li

2017-12-01

Full Text Available Background/Aims: Treatment of breast cancer remains a clinical challenge. This study aims to validate exosomal microRNA-1246 (miR-1246 as a serum biomarker for breast cancer and understand the underlying mechanism in breast cancer progression. Methods: The expression levels of endogenous and exosomal miRNAs were examined by real time PCR, and the expression level of the target protein was detected by western blot. Scanning electron and confocal microscopy were used to characterize exosomes and to study their uptake and transfer. Luciferase reporter plasmids and its mutant were used to confirm direct targeting. Furthermore, the functional significance of exosomal miR-1246 was estimated by invasion assay and cell viability assay. Results: In this study, we demonstrate that exosomes carrying microRNA can be transferred among different cell lines through direct uptake. miR-1246 is highly expressed in metastatic breast cancer MDA-MB-231 cells compared to non-metastatic breast cancer cells or non-malignant breast cells. Moreover, miR-1246 can suppress the expression level of its target gene, Cyclin-G2 (CCNG2, indicating its functional significance. Finally, treatment with exosomes derived from MDA-MB-231 cells could enhance the viability, migration and chemotherapy resistance of non-malignant HMLE cells. Conclusions: Together, our results support an important role of exosomes and exosomal miRNAs in regulating breast tumor progression, which highlights their potential for applications in miRNA-based therapeutics.

Molecular profiling identifies prognostic markers of stage IA lung adenocarcinoma.

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Zhang, Jie; Shao, Jinchen; Zhu, Lei; Zhao, Ruiying; Xing, Jie; Wang, Jun; Guo, Xiaohui; Tu, Shichun; Han, Baohui; Yu, Keke

2017-09-26

We previously showed that different pathologic subtypes were associated with different prognostic values in patients with stage IA lung adenocarcinoma (AC). We hypothesize that differential gene expression profiles of different subtypes may be valuable factors for prognosis in stage IA lung adenocarcinoma. We performed microarray gene expression profiling on tumor tissues micro-dissected from patients with acinar and solid predominant subtypes of stage IA lung adenocarcinoma. These patients had undergone a lobectomy and mediastinal lymph node dissection at the Shanghai Chest Hospital, Shanghai, China in 2012. No patient had preoperative treatment. We performed the Gene Set Enrichment Analysis (GSEA) analysis to look for gene expression signatures associated with tumor subtypes. The histologic subtypes of all patients were classified according to the 2015 WHO lung Adenocarcinoma classification. We found that patients with the solid predominant subtype are enriched for genes involved in RNA polymerase activity as well as inactivation of the p53 pathway. Further, we identified a list of genes that may serve as prognostic markers for stage IA lung adenocarcinoma. Validation in the TCGA database shows that these genes are correlated with survival, suggesting that they are novel prognostic factors for stage IA lung adenocarcinoma. In conclusion, we have uncovered novel prognostic factors for stage IA lung adenocarcinoma using gene expression profiling in combination with histopathology subtyping.

Experiment list: SRX099866 [Chip-atlas[Archive

Lifescience Database Archive (English)

Full Text Available tion=Pleura|Tissue Diagnosis=Adenocarcinoma 52920745,93.0,40.4,27135 GSM808755: MCF7 cMYC REP2 source_name=breast adenocarcinoma... cells || cell type=breast adenocarcinoma cells || cell line=MCF7 || antibody=cMYC http:

Experiment list: SRX099865 [Chip-atlas[Archive

Lifescience Database Archive (English)

Full Text Available tion=Pleura|Tissue Diagnosis=Adenocarcinoma 48518944,65.7,26.5,32221 GSM808754: MCF7 cMYC REP1 source_name=breast adenocarcinoma... cells || cell type=breast adenocarcinoma cells || cell line=MCF7 || antibody=cMYC http:

Targeting FASN for Breast Cancer Treatment by Repositioning PPIs

Science.gov (United States)

2017-01-01

we found that fatty acid synthase (FASN) up-regulation causes resistance to multiple anticancer drugs including doxorubicine and cisplatin ...be accomplished to (1) investigate the mechanism of FASN action in drug resistance in breast cancers; (2) determine efficacy of PPIs as single agents...Tasks proposed in SOW for year 1. Major Task 1: Determine the mechanism of FASN function in breast cancer drug resistance (months 1- 16). For this

An Acquired HER2T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer.

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Hanker, Ariella B; Brewer, Monica Red; Sheehan, Jonathan H; Koch, James P; Sliwoski, Gregory R; Nagy, Rebecca; Lanman, Richard; Berger, Michael F; Hyman, David M; Solit, David B; He, Jie; Miller, Vincent; Cutler, Richard E; Lalani, Alshad S; Cross, Darren; Lovly, Christine M; Meiler, Jens; Arteaga, Carlos L

2017-06-01

We report a HER2 T798I gatekeeper mutation in a patient with HER2 L869R -mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2 L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3 E928G , also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2 T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2 T798I reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2 L869R but not HER2 L869R/T798I In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2 L869R/T798I -induced signaling and cell growth. Acquisition of HER2 T798I upon development of resistance to neratinib in a breast cancer with an initial activating HER2 mutation suggests HER2 L869R is a driver mutation. HER2 T798I -mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib. Significance: We found an acquired HER2 gatekeeper mutation in a patient with HER2 -mutant breast cancer upon clinical progression on neratinib. We speculate that HER2 T798I may arise as a secondary mutation following response to effective HER2 tyrosine kinase inhibitors (TKI) in other cancers with HER2 -activating mutations. This resistance may be overcome by other irreversible HER2 TKIs, such as afatinib. Cancer Discov; 7(6); 575-85. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 539 . ©2017 American Association for Cancer Research.

Esophageal Adenocarcinoma Arising from Barrett's Epithelium in Taiwan

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Chia-Hung Tu

2007-08-01

Full Text Available The prevalence of Barrett's esophagus (BE in Eastern countries is rising to match the prevalence in the West. However, a corresponding trend of BE-associated adenocarcinoma has yet to be observed in Asia. Historically, adenocarcinoma complicating BE has been considered a rare event in Taiwan. In the present report, we collected three Taiwanese cases of esophageal adenocarcinoma arising from BE. The first case was a 37-year-old man with an advanced cancer that developed on pre-existing BE after a 3-year interval without endoscopic surveillance. The second case was a 63-year-old man who presented with odynophagia and was found to have an ulcerative tumor centered on the characteristic Barrett's mucosa. The final case was a 44-year-old man who presented with gradual-onset dysphagia and weight loss, without typical reflux symptom. Our report emphasizes the need for an updated epidemiologic study to determine the incidence of BE-associated adenocarcinoma in Taiwan.

Sulphamoylated 2-methoxyestradiol analogues induce apoptosis in adenocarcinoma cell lines.

Directory of Open Access Journals (Sweden)

Michelle Visagie

Full Text Available 2-Methoxyestradiol (2ME2 is a naturally occurring estradiol metabolite which possesses antiproliferative, antiangiogenic and antitumor properties. However, due to its limited biological accessibility, synthetic analogues have been synthesized and tested in attempt to develop drugs with improved oral bioavailability and efficacy. The aim of this study was to evaluate the antiproliferative effects of three novel in silico-designed sulphamoylated 2ME2 analogues on the HeLa cervical adenocarcinoma cell line and estrogen receptor-negative breast adenocarcinoma MDA-MB-231 cells. A dose-dependent study (0.1-25 μM was conducted with an exposure time of 24 hours. Results obtained from crystal violet staining indicated that 0.5 μM of all 3 compounds reduced the number of cells to 50%. Lactate dehydrogenase assay was used to assess cytotoxicity, while the mitotracker mitochondrial assay and caspase-6 and -8 activity assays were used to investigate the possible occurrence of apoptosis. Tubulin polymerization assays were conducted to evaluate the influence of these sulphamoylated 2ME2 analogues on tubulin dynamics. Double immunofluorescence microscopy using labeled antibodies specific to tyrosinate and detyrosinated tubulin was conducted to assess the effect of the 2ME2 analogues on tubulin dynamics. An insignificant increase in the level of lactate dehydrogenase release was observed in the compounds-treated cells. These sulphamoylated compounds caused a reduction in mitochondrial membrane potential, cytochrome c release and caspase 3 activation indicating apoptosis induction by means of the intrinsic pathway in HeLa and MDA-MB-231 cells. Microtubule depolymerization was observed after exposure to these three sulphamoylated analogues.

Efficacy and mechanism of action of Proellex, an antiprogestin in aromatase overexpressing and Letrozole resistant T47D breast cancer cells.

Science.gov (United States)

Gupta, Akash; Mehta, Rajeshwari; Alimirah, Fatouma; Peng, Xinjian; Murillo, Genoveva; Wiehle, Ronald; Mehta, Rajendra G

2013-01-01

Aromatase inhibitors (AI) are considered as a first line therapy for ER+PR+ breast cancers. However, many patients acquire resistance to AI. In this study, we determined the response of antiprogestin CDB-4124 (Proellex) on the aromatase overexpressing and Letrozole resistant cell lines and also studies its mechanism of action in inhibition of breast cancer cell proliferation. For these studies we generated aromatase overexpressing T47D (T47Darom) and respective control (T47Dcon) breast cancer cell lines by stable transfection with plasmid containing CYP19A1 gene, or empty vector respectively. Letrozole resistant cell line (T47DaromLR) was generated by incubating T47Darom for 75 weeks in the presence of 10 μM Letrozole. Cell proliferation was determined by MTT or crystal violet assays. Gene expressions were quantified by QRT-PCR whereas proteins were identified by western blot analyses, flow cytometry and immunofluorescence staining. Aromatase activity was determined by estradiol ELISA. The effects of Proellex on the anchorage independent growth were measured by soft agar colony formation. Statistical differences between the various groups were determined by Student's 't' test or ANOVA followed by Bonferroni's post hoc test. Results showed that T47Darom and T47DaromLR cell lines had significantly higher aromatase expression (mRNA; 80-90 fold and protein) and as a result exhibited increased aromatization of testosterone to estradiol as compared to T47Dcon. Both these cell lines showed enhanced growth in the presence of Testosterone (50-60%). In T47DaromLR cells increased PR-B and EGFR expression as compared to T47Dcon cells was observed. Proellex and other known aromatase inhibitors (Letrozole, Anastrozole, and Exemestane) inhibited testosterone induced cell proliferation and anchorage independent growth of T47Darom cells. Cell growth inhibition was significantly greater when cells were treated with Proellex alone or in combination with other AIs as compared to AIs

Metástasis mandibular de adenocarcinoma gástrico: Presentación de un caso Mandibular metastases of gastric adenocarcinoma: A case report

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J. Ferreras Granado

2007-10-01

Full Text Available Los tumores malignos de la cavidad oral y mandíbula representan aproximadamente un 5% de todas las neoplasias malignas del cuerpo, y sólo entre el 1 y el 4% son consideradas como metástasis. Tienen su localización más frecuente a nivel de la mandíbula (80%, fundamentalmente en la región molar. Las metástasis mandibulares, cuando aparecen, suelen tener su origen en tumores primarios que asientan en la mama, pulmón, riñón, tiroides, intestinos y próstata; y con menor frecuencia en el estómago, testículos y vesícula biliar. Suelen afectar a pacientes de edad avanzada (4ª-7ª décadas de la vida sin predilección por el sexo. El tratamiento en general es paliativo y pasa por el uso de la radioterapia, quimioterapia y hormonoterapia, reservando la cirugía para casos aislados. Describimos un caso de metástasis mandibular en un paciente adulto como primera manifestación clínica de un adenocarcinoma gástrico.Malignant tumors of the mouth and jaws represents approximately 5% of all malignant neoplasms in the body, and only 1-4% are considered to be metastatic. They are most frequently located in the mandible (80%, fundamentally in the molar region. Metastases to the jaws are usually from breast, lung, kidney, thyroid gland, intestines, and prostate gland; and less frequently from stomach, testes, and bladder. They are more frequent in elderly patients (between 4th and 7th decades with no gender differences. Treatment is usually palliative and based on the use of radiotherapy, chemotherapy andhormonal therapy. Surgery is only used in selected cases. A case of mandibular metastases as first sign of malignant disease of gastric adenocarcinoma is reported.

Soft-tissue metastasis revealing a pancreatic adenocarcinoma: One ...

African Journals Online (AJOL)

Soft tissue metastases from pancreatic adenocarcinoma are rare lesions and can be the source of diagnostic confusion both clinically and pathologically. To our knowledge, one patient has been reported on with soft tissue lesions that ultimately disclose a pancreatic adenocarcinoma. We report here on a patient who ...

Quantitative CT analysis of pulmonary ground-glass opacity nodules for distinguishing invasive adenocarcinoma from non-invasive or minimally invasive adenocarcinoma: the added value of using iodine mapping

Energy Technology Data Exchange (ETDEWEB)

Son, Ji Ye; Lee, Ho Yun; Kim, Jae-Hun; Lee, Kyung Soo [Sungkyunkwan University School of Medicine, Department of Radiology and Center for Imaging Science, Samsung Medical Center, 81 Irwon-Ro, Gangnam-gu, Seoul (Korea, Republic of); Han, Joungho [Sungkyunkwan University School of Medicine, Department of Pathology, Samsung Medical Center, Seoul (Korea, Republic of); Jeong, Ji Yun [Sungkyunkwan University School of Medicine, Department of Pathology, Samsung Medical Center, Seoul (Korea, Republic of); Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Department of Pathology, Daegu (Korea, Republic of); Kwon, O.J. [Sungkyunkwan University School of Medicine, Division of Respiratory and Critical Medicine of the Department of Internal Medicine, Samsung Medical Center, Seoul (Korea, Republic of); Shim, Young Mog [Sungkyunkwan University School of Medicine, Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, 81 Irwon-Ro, Gangnam-gu, Seoul (Korea, Republic of)

2016-01-15

To determine whether quantitative analysis of iodine-enhanced images generated from dual-energy CT (DECT) have added value in distinguishing invasive adenocarcinoma from non-invasive or minimally invasive adenocarcinoma (MIA) showing ground-glass nodule (GGN). Thirty-four patients with 39 GGNs were enrolled in this prospective study and underwent DECT followed by complete tumour resection. Various quantitative imaging parameters were assessed, including virtual non-contrast (VNC) imaging and iodine-enhanced imaging. Of all 39 GGNs, four were adenocarcinoma in situ (AIS) (10 %), nine were MIA (23 %), and 26 were invasive adenocarcinoma (67 %). When assessing only VNC imaging, multivariate analysis revealed that mass, uniformity, and size-zone variability were independent predictors of invasive adenocarcinoma (odds ratio [OR] = 19.92, P = 0.02; OR = 0.70, P = 0.01; OR = 16.16, P = 0.04, respectively). After assessing iodine-enhanced imaging with VNC imaging, both mass on the VNC imaging and uniformity on the iodine-enhanced imaging were independent predictors of invasive adenocarcinoma (OR = 5.51, P = 0.04 and OR = 0.67, P < 0.01). The power of diagnosing invasive adenocarcinoma was improved after adding the iodine-enhanced imaging parameters versus VNC imaging alone, from 0.888 to 0.959, respectively (P = 0.029). Quantitative analysis using iodine-enhanced imaging metrics versus VNC imaging metrics alone generated from DECT have added value in distinguishing invasive adenocarcinoma from AIS or MIA. (orig.)

Quantitative CT analysis of pulmonary ground-glass opacity nodules for distinguishing invasive adenocarcinoma from non-invasive or minimally invasive adenocarcinoma: the added value of using iodine mapping

International Nuclear Information System (INIS)

Son, Ji Ye; Lee, Ho Yun; Kim, Jae-Hun; Lee, Kyung Soo; Han, Joungho; Jeong, Ji Yun; Kwon, O.J.; Shim, Young Mog

2016-01-01

To determine whether quantitative analysis of iodine-enhanced images generated from dual-energy CT (DECT) have added value in distinguishing invasive adenocarcinoma from non-invasive or minimally invasive adenocarcinoma (MIA) showing ground-glass nodule (GGN). Thirty-four patients with 39 GGNs were enrolled in this prospective study and underwent DECT followed by complete tumour resection. Various quantitative imaging parameters were assessed, including virtual non-contrast (VNC) imaging and iodine-enhanced imaging. Of all 39 GGNs, four were adenocarcinoma in situ (AIS) (10 %), nine were MIA (23 %), and 26 were invasive adenocarcinoma (67 %). When assessing only VNC imaging, multivariate analysis revealed that mass, uniformity, and size-zone variability were independent predictors of invasive adenocarcinoma (odds ratio [OR] = 19.92, P = 0.02; OR = 0.70, P = 0.01; OR = 16.16, P = 0.04, respectively). After assessing iodine-enhanced imaging with VNC imaging, both mass on the VNC imaging and uniformity on the iodine-enhanced imaging were independent predictors of invasive adenocarcinoma (OR = 5.51, P = 0.04 and OR = 0.67, P < 0.01). The power of diagnosing invasive adenocarcinoma was improved after adding the iodine-enhanced imaging parameters versus VNC imaging alone, from 0.888 to 0.959, respectively (P = 0.029). Quantitative analysis using iodine-enhanced imaging metrics versus VNC imaging metrics alone generated from DECT have added value in distinguishing invasive adenocarcinoma from AIS or MIA. (orig.)

Multigene deletions in lung adenocarcinomas from irradiated and control mice

International Nuclear Information System (INIS)

Zhang, Y.; Woloschak, G.E.

1996-01-01

K-ras codon 12 point mutations mRb and p53 gene deletions were examined in tissues from 120 normal lungs and lung adenocarcinomas that were Formalin-treated and paraffin-embedded 25 years ago. The results showed that 12 of 60 (20%) lung adenocarcinomas had mRb deletions. All lung adenocarcinomas that were initially found bearing deleted mRb had p53 deletions (15 of 15; 100%). A significantly higher mutation frequency for K-ras codon 12 point mutations was also found in the lung adenocarcinomas from mice exposed to 24 once-weekly neutron irradiation (10 of 10; 100%) compared with those exposed to 24 or 60 once-weekly γ-ray doses (5 of 10; 50%). The data suggested that p53 and K-ras gene alterations were two contributory factors responsible for the increased incidence of lung adenocarcinoma in B6CF 1 male mice exposed to protracted neutron radiation

HIF-1 activation induces doxorubicin resistance in MCF7 3-D spheroids via P-glycoprotein expression: a potential model of the chemo-resistance of invasive micropapillary carcinoma of the breast

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Doublier Sophie

2012-01-01

Full Text Available Abstract Background Invasive micropapillary carcinoma (IMPC of the breast is a distinct and aggressive variant of luminal type B breast cancer that does not respond to neoadjuvant chemotherapy. It is characterized by small pseudopapillary clusters of cancer cells with inverted cell polarity. To investigate whether hypoxia-inducible factor-1 (HIF-1 activation may be related to the drug resistance described in this tumor, we used MCF7 cancer cells cultured as 3-D spheroids, which morphologically simulate IMPC cell clusters. Methods HIF-1 activation was measured by EMSA and ELISA in MCF7 3-D spheroids and MCF7 monolayers. Binding of HIF-1α to MDR-1 gene promoter and modulation of P-glycoprotein (Pgp expression was evaluated by ChIP assay and FACS analysis, respectively. Intracellular doxorubicin retention was measured by spectrofluorimetric assay and drug cytotoxicity by annexin V-FITC measurement and caspase activity assay. Results In MCF7 3-D spheroids HIF-1 was activated and recruited to participate to the transcriptional activity of MDR-1 gene, coding for Pgp. In addition, Pgp expression on the surface of cells obtained from 3-D spheroids was increased. MCF7 3-D spheroids accumulate less doxorubicin and are less sensitive to its cytotoxic effects than MCF7 cells cultured as monolayer. Finally, HIF-1α inhibition either by incubating cells with 3-(5'-hydroxymethyl-2'-furyl-1-benzylindazole (a widely used HIF-1α inhibitor or by transfecting cells with specific siRNA for HIF-1α significantly decreased the expression of Pgp on the surface of cells and increased the intracellular doxorubicin accumulation in MCF7 3-D spheroids. Conclusions MCF7 breast cancer cells cultured as 3-D spheroids are resistant to doxorubicin and this resistance is associated with an increased Pgp expression in the plasma membrane via activation of HIF-1. The same mechanism may be suggested for IMPC drug resistance.

Molecular biology of breast cancer stem cells: potential clinical applications.

Science.gov (United States)

Nguyen, Nam P; Almeida, Fabio S; Chi, Alex; Nguyen, Ly M; Cohen, Deirdre; Karlsson, Ulf; Vinh-Hung, Vincent

2010-10-01

Breast cancer stem cells (CSC) have been postulated recently as responsible for failure of breast cancer treatment. The purpose of this study is to review breast CSCs molecular biology with respect to their mechanism of resistance to conventional therapy, and to develop treatment strategies that may improve survival of breast cancer patients. A literature search has identified in vitro and in vivo studies of breast CSCs. Breast CSCs overexpress breast cancer resistance protein (BCRP) which allows cancer cells to transport actively chemotherapy agents out of the cells. Radioresistance is modulated through activation of Wnt signaling pathway and overexpression of genes coding for glutathione. Lapatinib can selectively target HER-2 positive breast CSCs and improves disease-free survival in these patients. Metformin may target basal type breast CSCs. Parthenolide and oncolytic viruses are promising targeting agents for breast CSCs. Future clinical trials for breast cancer should include anti-cancer stem cells targeting agents in addition to conventional chemotherapy. Hypofractionation radiotherapy may be indicated for residual disease post chemotherapy. 2010 Elsevier Ltd. All rights reserved.

Effect of acadesine on breast cancer cells under hypoxia

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A. M. Shcherbakov

2017-01-01

Full Text Available The riboside derivative acadesine (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside is currently being tested in clinical trials as a promising anti-tumor drug. Intracellular target of acadesine is adenosine monophosphate-activated protein kinase (АМРК, an important regulatory molecule of energy metabolism. It is expected that acadesine would be active in tumors under hypoxia conditions. In normoxia (cells incubated in 21 % oxygen, acadesine inhibited proliferation and induced cell death of breast adenocarcinoma, including the triple negative breast cancer line. When oxygen partial pressure was decreased to 1 % (experimental hypoxia, acadesine inhibited activation of reporter construct responsive to HIF-1α (hypoxia inducible factor 1 alpha transcription factor. This effect was observed for acadesine in concentrations close to cytotoxic. Acadesine retained cytotoxicity under hypoxia and decreased the survival of the MDA-MB-231 cell line when used in combination with cisplatin. These results considerably widen acadesine’s field of application and allow to assume its efficacy in chemotherapy combination regimens for breast cancer, including the tumors with low oxygenation.

[A paclitaxel-resistant case of recurrent breast cancer responded to combination therapy of capecitabine and trastuzumab].

Science.gov (United States)

Marutaka, Masahito; Suguri, Takayasu; Miyake, Mikio; Yoshimura, Kouichi

2005-12-01

The patient was a 72-year-old female. Under the supervision of her former doctor, this patient had an operation and adjuvant chemotherapy for progressive breast cancer. During the following period, local recurrence of breast cancer and pulmonary lymphopathia developed. Although medication with paclitaxel was attempted, the focus was resistant to this treatment, and metastasis to the brain was also observed. Due to the dyscrasia above, the patient had difficulty breathing and became bedridden. Subsequently, combination treatment of capecitabine and trastuzumab was attempted. As a result,metastasis in the brain and pulmonary lymphopathia were improved. The patient recovered enough to be discharged at one time. However, his condition took a turn for the worse after the interruption of the combination treatment by a side effect. In conclusion, the combination treatment of capecitabine and trastuzumab is thought to be effective for non-responders to paclitaxel.

In vivo detection of multidrug-resistant (MDR1) phenotype by technetium-99m sestamibi scan in untreated breast cancer patients

International Nuclear Information System (INIS)

Del Vecchio, S.; Ciarmiello, A.; Potena, M.I.; Carriero, M.V.; Mainolfi, C.; Botti, G.; Thomas, R.; Cerra, M.; D'Aiuto, G.; Tsuruo, T.; Salvatore, M.

1997-01-01

Technetium-99m sestamibi is a transport substrate recognised by the multidrug-resistant P-glycoprotein (Pgp). To test whether 99m Tc-sestamibi efflux is enhanced in breast carcinomas overexpressing Pgp, we determined the efflux rates of 99m Tc-sestamibi and Pgp levels in tumours from 30 patients with untreated breast carcinoma. Patients were intravenously injected with 740 MBq of 99m Tc-sestamibi and underwent a 15-min dynamic study followed by the acquisition of static planar images at 0.5, 1, 2 and 4 h. Tumour specimens were obtained from each patient 24 h after 99m Tc-sestamibi scan and Pgp levels were determined using 125 I-MRK16 monoclonal antibody and in vitro quantitative autoradiography. All breast carcinomas showed high uptake of 99m Tc-sestamibi and data from region of interest analysis on sequential images were fitted with a monoexponential function. The efflux rates of 99m Tc-sestamibi, calculated from decay-corrected time-activity curves, ranged between 0.00121 and 0.01690 min -1 and were directly correlated with Pgp levels measured in the same tumours (r=0.62; P 99m Tc-sestamibi efflux from tumours of group A was 2.7 times higher than that observed in tumours of group B (0.00686 ±0.00390 min -1 vs 0.00250 ±0.00090 min -1 , P 99m Tc-sestamibi showed a sensitivity and a specificity of 80% and 95%, respectively. In conclusion, the efflux rate of 99m Tc-sestamibi may be used for the in vivo identification of the multidrug resistant (MDR1) phenotype in untreated breast cancer patients. (orig.). With 7 figs., 3 tabs

File list: DNS.Lng.20.AllAg.Lung_adenocarcinoma [Chip-atlas[Archive

Lifescience Database Archive (English)

Full Text Available DNS.Lng.20.AllAg.Lung_adenocarcinoma mm9 DNase-seq Lung Lung adenocarcinoma http://...dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/DNS.Lng.20.AllAg.Lung_adenocarcinoma.bed ...

A case of alpha-fetoprotein-producing esophageal adenocarcinoma.

Science.gov (United States)

Chen, Yi-Yu; Hsu, Wen-Hung; Hu, Huang-Ming; Wu, Deng-Chyang; Lin, Wen-Yi

2013-02-01

Alpha-fetoprotein is a well-known tumor marker in the screening and follow-up of hepatocellular carcinoma. In Taiwanese society, a high prevalence of hepatitis and hepatoma and elevation of alpha-fetoprotein associated with liver function impairment usually suggested clinics undertake further examination for liver or genital tumor. We report the case of 45-year-old man who was found to have an alpha-fetoprotein-producing esophageal adenocarcinoma with an initial presentation of liver function impairment and rapid elevation of alpha-fetoprotein. Esophageal cancer was diagnosed via endoscope and a biopsy proved the presence of adenocarcinoma. A small endoscopic biopsy specimen failed to identify the alpha-fetoprotein positive tumor cell. Esophagectomy was performed and histopathological study of surgical specimen revealed grade II adenocarcinoma with regional metastatic lymphadenopathy. Immunohistochemical study was focal positive for alpha-fetoprotein. Serum alpha-fetoprotein declined transiently after esophagectomy and fluctuation of alpha-fetoprotein level was noted during the treatment with adjuvant chemotherapy. Finally, 19 months after the operation, the patient died due to multiple organ metastases with multiple organ failure. Thus, a small specimen for upper endoscopy may not be sufficient in the presence of alpha-fetoprotein-producing adenocarcinoma. Monitoring of serum alpha-fetoprotein may be useful in the evaluation and follow-up of esophageal alpha-fetoprotein-producing adenocarcinoma. Copyright © 2012. Published by Elsevier B.V.

Dendritic cells in Barrett's esophagus and esophageal adenocarcinoma.

Science.gov (United States)

Bobryshev, Yuri V; Tran, Dinh; Killingsworth, Murray C; Buckland, Michael; Lord, Reginald V N

2009-01-01

Like other premalignant conditions that develop in the presence of chronic inflammation, the development and progression of Barrett's esophagus is associated with the development of an immune response, but how this immune response is regulated is poorly understood. A comprehensive literature search failed to find any report of the presence of dendritic cells in Barrett's intestinal metaplasia and esophageal adenocarcinoma and this prompted our study. We used immunohistochemical staining and electron microscopy to examine whether dendritic cells are present in Barrett's esophagus and esophageal adenocarcinoma. Immunohistochemical staining with CD83, a specific marker for dendritic cells, was performed on paraffin-embedded sections of Barrett's intestinal metaplasia (IM, n = 12), dysplasia (n = 11) and adenocarcinoma (n = 14). CD83+ cells were identified in the lamina propria surrounding intestinal type glands in Barrett's IM, dysplasia, and cancer tissues. Computerized quantitative analysis showed that the numbers of dendritic cells were significantly higher in cancer tissues. Double immunostaining with CD83, CD20, and CD3, and electron microscopy demonstrated that dendritic cells are present in Barrett's esophagus and form clusters with T cells and B cells directly within the lamina propria. These findings demonstrate that dendritic cells are present in Barrett's tissues, with a significant increase in density in adenocarcinoma compared to benign Barrett's esophagus. Dendritic cells may have a role in the pathogenesis and immunotherapy treatment of Barrett's esophagus and adenocarcinoma.

Immunoscintigraphy of adenocarcinomas by means of 111In-labelled F(ab')2 fragments of anti-CEA monoclonal antibody F023C5

International Nuclear Information System (INIS)

Riva, P.; Paganelli, G.; Callegaro, L.

1988-01-01

F(ab') 2 fragments of F023C5, an anti-CEA monoclonal antibody, were conjugated to diethylenetriamine pentaacetic acid (DTPA) and converted into a ready to use reagent for instant 111 In-labelling. The resulting 111 In radiopharmaceutical was administered intravenously and tested for its ability to image (at 48-72 h after administration) 31 primary and 85 metastatic carcinoma lesions in 70 adenocarcinoma patients (26 gastrointestinal, 18 breast and 26 lung tumour patients) whose serum CEA was elevated in 43 cases and normal in the other 27. (author)

Identification of distinct phenotypes of locally advanced pancreatic adenocarcinoma.

LENUS (Irish Health Repository)

Teo, Minyuen

2013-03-01

A significant number of pancreatic ductal adenocarcinoma present as locally advanced disease. Optimal treatment remains controversial. We sought to analyze the clinical course of locally advanced pancreatic adenocarcinoma (LAPC) in order to identify potential distinct clinical phenotypes.

[Right Hemi-Colectomy for a Metastatic Transverse Colon Tumor from Breast Cancer Following Bilateral Breast Cancer Resection - A Case Report].

Science.gov (United States)

Okamura, Shu; Yanagisawa, Tetsu; Ohishi, Kazuhito; Murata, Kohei; Nushijima, Yoichiro; Hamano, Rie; Fukuchi, Nariaki; Ebisui, Chikara; Yokouchi, Hideoki; Kinuta, Masakatsu

2016-11-01

We herein report the case of a 75-year-old female patient who underwent 4 surgeries for bilateral breast cancer and its recurrence. When she presented at a clinic with an irritable colon, a fist-sized tumor was palpated in the right upper abdomen at her first medical examination. Abdominal CT scan at the clinic revealed a tumor with a maximum diameter of 10 cm on the right side of the transverse colon and multiple swollen mesenteric lymph nodes. Therefore, the patient was referred to our hospital for surgery. Colonoscopy revealed stenosis of the same lesion with an edematous mucosa and sclerosis. Using immunohistochemistry, a biopsy specimen from the lesion tested positive for CK AE1+AE3, and negative for CD20(-)and CD3 (-). As a result, the tumor was diagnosed as a poorly differentiated adenocarcinoma. We performed right hemicolectomy to avoid her intestinal obstruction. Tumor cells were mainly present at the subserosa, according to HEstaining. Using immunostaining, the cells were tested for the following markers: CDX2(-), GCDFP15(weakly positive), CK7(strongly positive), CD20(partially positive), E R(+), PgR(-), and HER2(1+), characterizing the tumor as metastasis of breast cancer. Although gastro-intestinal metastasis from breast cancer is rare, and colon metastasis is even rarer, it might be necessary to rule out the possibility of a metastatic colon tumor from breast cancer when treating patients with a colon tumor who have undergone surgery for breast cancer.

File list: Pol.Lng.10.AllAg.Lung_adenocarcinoma [Chip-atlas[Archive

Lifescience Database Archive (English)

Full Text Available Pol.Lng.10.AllAg.Lung_adenocarcinoma mm9 RNA polymerase Lung Lung adenocarcinoma ht...tp://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Pol.Lng.10.AllAg.Lung_adenocarcinoma.bed ...

Primary adenocarcinoma of lung: A pictorial review of recent updates

Energy Technology Data Exchange (ETDEWEB)

Gaikwad, Anand, E-mail: anandgaik@yahoo.co.in [Department of Diagnostic Imaging, The Ottawa Hospital, University of Ottawa, Ottawa, ON (Canada); Gupta, Ashish, E-mail: ashgupta@toh.on.ca [Department of Diagnostic Imaging, The Ottawa Hospital, University of Ottawa, Ottawa, ON (Canada); Hare, Sam, E-mail: samanjeet@btinternet.com [Department of Diagnostic Imaging, The Ottawa Hospital, University of Ottawa, Ottawa, ON (Canada); Gomes, Marcio, E-mail: mgomes@toh.on.ca [Department of Pathology and Laboratory Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON (Canada); Sekhon, Harman, E-mail: hsekhon@toh.on.ca [Department of Pathology and Laboratory Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON (Canada); Souza, Carolina, E-mail: csouza@ottawahospital.on.ca [Department of Diagnostic Imaging, The Ottawa Hospital, University of Ottawa, Ottawa, ON (Canada); Inacio, Joao, E-mail: joao.r.inacio@gmail.com [Department of Diagnostic Imaging, The Ottawa Hospital, University of Ottawa, Ottawa, ON (Canada); Lad, Shilpa, E-mail: slad@toh.on.ca [Department of Diagnostic Imaging, The Ottawa Hospital, University of Ottawa, Ottawa, ON (Canada); Seely, Jean, E-mail: jeseely@ottawahospital.on.ca [Department of Diagnostic Imaging, The Ottawa Hospital, University of Ottawa, Ottawa, ON (Canada)

2012-12-15

Primary adenocarcinoma of lung has replaced squamous cell carcinoma as the commonest histological subtype of lung cancer and the incidence of primary lung adenocarcinoma appears to be rising. Although the main factors behind this ‘epidemic-like’ situation are largely undiscovered, filter cigarettes appear to significantly contribute to this shift in the histopathological spectrum. The new multidisciplinary classification of adenocarcinoma of lung was introduced to address advances in clinical, pathological, radiological and molecular sciences. The purpose of this essay is to discuss various classes of lung adenocarcinoma in the new classification with their classical imaging features on computed tomography and summarise the recent advances in the field of radiology and review radiology recommendations.

Primary bladder adenocarcinoma: Case report with long-term follow-up

Directory of Open Access Journals (Sweden)

Annemarie Uhlig

2018-05-01

Full Text Available Primary Bladder Adenocarcinoma is a rare malignancy that has been observed in a heterogeneous patient population.This case report presents a 51 year old female with muscle-invasive primary bladder adenocarcinoma diagnosed in 2008. After transurethral resection and cystectomy with ileum neobladder adjuvant radiochemotherapy was administered. Two years later, a symptomatic fistula between neobladder and ileoileal anastomosis was excised, resulting in urinary incontinency. In 2016, the patient shows no signs of disease relapse but suffers from reduction of bladder capacity.This case report presents classical symptoms of adenocarcinoma of the bladder and a possible treatment regimen with associated side effects. Keywords: Adenocarcinoma, Urinary bladder, Urinary diversion, Urinary fistula, Oncology

Magnetic resonance imaging findings and prognosis of gastric-type mucinous adenocarcinoma (minimal deviation adenocarcinoma or adenoma malignum) of the uterine corpus: Two case reports

OpenAIRE

HINO, MAYO; YAMAGUCHI, KEN; ABIKO, KAORU; YOSHIOKA, YUMIKO; HAMANISHI, JUNZO; KONDOH, EIJI; KOSHIYAMA, MASAFUMI; BABA, TSUKASA; MATSUMURA, NORIOMI; MINAMIGUCHI, SACHIKO; KIDO, AKI; KONISHI, IKUO

2016-01-01

Our group previously documented the first, very rare case of primary gastric-type mucinous adenocarcinoma of the uterine corpus. Although this type of endometrial cancer appears to be similar to the gastric-type adenocarcinoma of the uterine cervix, its main symptoms, appearance on magnetic resonance imaging (MRI) and prognosis have not been fully elucidated due to its rarity. We herein describe an additional case of gastric-type mucinous adenocarcinoma of the endometrium and review the relev...

Comparing exercise responses to aerobic plus resistance training between postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy and healthy women.

Science.gov (United States)

Paulo, Thais R S de; Winters-Stone, Kerri M; Viezel, Juliana; Rossi, Fabricio E; Aro, Bruna L; Trindade, Ana Carolina A C; Codogno, Jamile S; Freitas Junior, Ismael F

2018-04-12

The aim of this study was to explore whether postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy differ from healthy postmenopausal women in their response to the same aerobic + resistance training. The participants were separated into two groups: postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy for an average of 20 months (18 women) and healthy postmenopausal women (24 women). We assessed aerobic capacity (predicted maximum oxygen uptake (VO 2 max) and maximum running velocity test (Vmax)) through a walking test, upper and lower body muscle strength using an estimated one-repetition maximum test, and body composition by dual-energy X-ray absorptiometry at baseline and at three, six, and nine months, respectively. The exercise program was performed three times/week over nine months and consisted of 40 min of machine-based strength training (seated cable row, bench press, leg extension, leg press, and leg curl, as well as bridge, abdominal, and standard plank exercises) followed by 30 min of treadmill walking. Analysis of variance (ANOVA) with repeated measures was used to compare the groups over time. Postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy and healthy postmenopausal women presented similar improvements in estimated lower body strength, predicted VO 2max and V max , and body fat mass. For maximal upper body strength, there was a significant group x time interaction after six months of training (p = 0.01). The healthy postmenopausal women presented a significant increase in upper body strength after six months, while postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy demonstrated an improvement only at nine months of training. The breast cancer survivors undergoing aromatase inhibitor therapy presented increased lean mass while healthy postmenopausal women maintained values over time (Breast cancer: 33.7 ± 3.9(Pre) vs. 34.1�

File list: ALL.Lng.05.AllAg.Lung_adenocarcinoma [Chip-atlas[Archive

Lifescience Database Archive (English)

Full Text Available ALL.Lng.05.AllAg.Lung_adenocarcinoma mm9 All antigens Lung Lung adenocarcinoma SRX2...RX213848 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/ALL.Lng.05.AllAg.Lung_adenocarcinoma.bed ...

An unusual case of isolated, serial metastases of gallbladder carcinoma involving the chest wall, axilla, breast and lung parenchyma

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Matthew J. Iott

2013-02-01

Full Text Available In the English literature, only 9 cases of adenocarcinoma of the gallbladder with cutaneous metastasis have been reported so far. One case of multiple cutaneous metastases along with deposits in the breast tissue has been reported. We present a case of incidental metastatic gallbladder carcinoma with no intra-abdominal disease presenting as a series of four isolated cutaneous right chest wall, axillary nodal, breast and pulmonary metastases following resection and adjuvant chemoradiation for her primary tumor. In spite of the metastatic disease coupled with the aggressive nature of the cancer, this patient reported that her energy level had returned to baseline with a good appetite and a stable weight indicating a good performance status and now is alive at 25 months since diagnosis. Her serially-presented, oligometastatic diseases were well-controlled by concurrent chemoradiation and stereotactic radiation therapy. We report this case study because of its rarity and for the purpose of complementing current literature with an additional example of cutaneous metastasis from adenocarcinoma of the gallbladder.

Furanodiene Induces Extrinsic and Intrinsic Apoptosis in Doxorubicin-Resistant MCF-7 Breast Cancer Cells via NF-κB-Independent Mechanism.

Science.gov (United States)

Zhong, Zhang-Feng; Yu, Hai-Bing; Wang, Chun-Ming; Qiang, Wen-An; Wang, Sheng-Peng; Zhang, Jin-Ming; Yu, Hua; Cui, Liao; Wu, Tie; Li, De-Qiang; Wang, Yi-Tao

2017-01-01

Chemotherapy is used as a primary approach in cancer treatment after routine surgery. However, chemo-resistance tends to occur when chemotherapy is used clinically, resulting in poor prognosis and recurrence. Currently, Chinese medicine may provide insight into the design of new therapies to overcome chemo-resistance. Furanodiene, as a heat-sensitive sesquiterpene, is isolated from the essential oil of Rhizoma Curcumae . Even though mounting evidence claiming that furanodiene possesses anti-cancer activities in various types of cancers, the underlying mechanisms against chemo-resistant cancer are not fully clear. Our study found that furanodiene could display anti-cancer effects by inhibiting cell viability, inducing cell cytotoxicity, and suppressing cell proliferation in doxorubicin-resistant MCF-7 breast cancer cells. Furthermore, furanodiene preferentially causes apoptosis by interfering with intrinsic/extrinsic-dependent and NF-κB-independent pathways in doxorubicin-resistant MCF-7 cells. These observations also prompt that furanodiene may be developed as a promising natural product for multidrug-resistant cancer therapy in the future.

Bilateral orbital tumour as the presentation of mammographically occult breast cancer

Energy Technology Data Exchange (ETDEWEB)

Lell, M.; Schulz-Wendtland, R.; Bautz, W.A. [Institute of Radiology, University of Erlangen-Nuernberg, Maximiliansplatz 1, 91504, Erlangen (Germany); Hafner, A. [Department of Ophthalmology, University of Erlangen-Nuernberg, Maximiliansplatz 1, 91504, Erlangen (Germany); Magener, A. [Institute of Pathology, University of Erlangen-Nuernberg, Maximiliansplatz 1, 91504, Erlangen (Germany); Tomandl, B.F. [Department of Neuroradiology, University of Erlangen-Nuernberg, Maximiliansplatz 1, 91504, Erlangen (Germany)

2004-08-01

We report a rare case of bilateral orbital metastases as the presentation in a 63-year-old woman. Biopsy of a diffusely infiltrated medial rectus muscle suggested metastatic adenocarcinoma. Investigation revealed a palpable mass of the right breast not shown on mammography or sonography. Invasive lobular carcinoma was found at core-needle biopsy with histological features identical to those of the orbital lesion. Metastases to the extraocular muscles are uncommon, particularly as the initial abnormality in the absence of disseminated disease. (orig.)

ALDH1-high ovarian cancer stem-like cells can be isolated from serous and clear cell adenocarcinoma cells, and ALDH1 high expression is associated with poor prognosis.

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Takafumi Kuroda

Full Text Available Cancer stem-like cells (CSCs/cancer-initiating cells (CICs are defined as a small population of cancer cells that have high tumorigenicity. Furthermore, CSCs/CICs are resistant to several cancer therapies, and CSCs/CICs are therefore thought to be responsible for cancer recurrence after treatment and distant metastasis. In epithelial ovarian cancer (EOC cases, disease recurrence after chemotherapy is frequently observed, suggesting ovarian CSCs/CICs are involved. There are four major histological subtypes in EOC, and serous adenocarcinoma and clear cell adenocarcinoma are high-grade malignancies. We therefore analyzed ovarian CSCs/CICs from ovarian carcinoma cell lines (serous adenocarcinoma and clear cell adenocarcinoma and primary ovarian cancer cells in this study. We isolated ovarian CSCs/CICs as an aldehyde dehydrogenase 1 high (ALDH1(high population from 6 EOC cell lines (3 serous adenocarcinomas and 3 clear cell adenocarcinomas by the ALDEFLUOR assay. ALDH1(high cells showed greater sphere-forming ability, higher tumorigenicity and greater invasive capability, indicating that ovarian CSCs/CICs are enriched in ALDH1(high cells. ALDH1(high cells could also be isolated from 8 of 11 primary ovarian carcinoma samples. Immunohistochemical staining revealed that higher ALDH1 expression levels in ovary cancer cases are related to poorer prognosis in both serous adenocarcinoma cases and clear cell adenocarcinoma cases. Taken together, the results indicate that ALDH1 is a marker for ovarian CSCs/CICs and that the expression level of ALDH1 might be a novel biomarker for prediction of poor prognosis.

Adenocarcinoma de apêndice: relato de dois casos

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Alexandre Cruz Henriques

Full Text Available The authors report two cases of patients with appendix adenocarcinoma, manifested as a syndrome of abdominal tumor of unknown origin. It was not possible to perform etiological diagnosis in the preoperative period for any of them. Literature data show that large locoregional tumor is a manifestation of appendix adenocarcinoma, although acute appendicites is the most frequent clinical manifestation. Preoperative diagnosis is rare and usually performed during laparotomy or through histopathological examination of the specimen. In large tumors, total mass resection including hemicolectomy should be carried out whenever possible. Whenever diagnosis of appendix adenocarcinoma is performed by the histopathological examination of the acute appendicites specimen, re-intervention is indicated for a right hemicolectomy.

Hepatoid Adenocarcinoma of the Urachus

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Daniel Fernando Gallego

2016-01-01

Full Text Available Hepatoid adenocarcinoma of the urachus is a rare condition. We present the case of a 51-year-old female who developed abdominal pain and hematuria. Pelvic magnetic resonance imaging (MRI reported an urachal mass with invasion to the bladder that was resected by partial cystectomy. On light microscopy the tumor resembled liver architecture, with polygonal atypical cells in nest formation and trabecular structures. Immunochemistry was positive for alfa-fetoprotein (AFP and serum AFP was elevated. Hepatoid adenocarcinomas have been reported in multiple organs, being most commonly found in the stomach and the ovaries. Bladder compromise has been rarely described in the literature, and it has been associated with poor prognosis, low remission rates, and early metastasis.

Adenocarcinoma of the prostrate

Energy Technology Data Exchange (ETDEWEB)

Bruce, A.W.; Trachtenberg, J.

1987-01-01

This books contains 13 chapters. Some of the chapter titles are: Imaging Techniques in the Diagnosis and Pelvic Staging of Prostatic Cancer; Interstitial Radiotherapy; The Case for External Beam Radiotherapy of Certain Adenocarcinomas of the Prostate; and Chemotherapy of Prostatic Cancer.

Paratesticular adenocarcinoma. Unusual presentation of metastasis of pancreatic cancer

International Nuclear Information System (INIS)

Ocvirk, J.; Seruga, B.

2007-01-01

Metastatic paratesticular adenocarcinoma from the pancreatic cancer is very rare. To our knowledge, there are less than 20 cases published in the literature. We experienced a case of paratesticular adenocarcinoma from the primary pancreatic cancer. A 42-year-old man was presented with locoregionally advanced carcinoma of the tail of the pancreas with intraoperatively found liver metastases and with a tumour in the right hemi-scrotum. Ultrasound of the scrotum revealed a paratesticular tumour. A fine needle aspiration biopsy (FNAB) confirmed a poorly differentiated adenocarcinoma and it was in concordance with the diagnosis of the primary tumour. The patient started treatment with chemotherapy with gemcitabine. Unfortunately, he progressed one month later and the treatment was discontinued. Outcome in the adenocarcinoma of the pancreas is dismal. The only possible treatment option for metastatic disease is systemic therapy but the results are disappointing, as in the present case. (author)

Different time trend and management of esophagogastric junction adenocarcinoma in three Asian countries.

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Hatta, Waku; Tong, Daniel; Lee, Yeong Yeh; Ichihara, Shin; Uedo, Noriya; Gotoda, Takuji

2017-04-01

Esophagogastric junction (EGJ) adenocarcinoma has been on the increase in Western countries. However, in Asian countries, data on the incidence of EGJ adenocarcinoma are evidently lacking. In the present review, we focus on the current clinical situation of EGJ adenocarcinoma in three Asian countries: Japan, Hong Kong, and Malaysia. The incidence of EGJ adenocarcinoma has been reported to be gradually increasing in Malaysia and Japan, whereas it has stabilized in Hong Kong. However, the number of cases in these countries is comparatively low compared with Western countries. A reason for the reported difference in the incidence and time trend of EGJ adenocarcinoma among the three countries may be explained by two distinct etiologies: one arising from chronic gastritis similar to distal gastric cancer, and the other related to gastroesophageal reflux disease similar to esophageal adenocarcinoma including Barrett's adenocarcinoma. This review also shows that there are several concerns in clinical practice for EGJ adenocarcinoma. In Hong Kong and Malaysia, many EGJ adenocarcinomas have been detected at a stage not amenable to endoscopic resection. In Japan, histological curability criteria for endoscopic resection cases have not been established. We suggest that an international collaborative study using the same definition of EGJ adenocarcinoma may be helpful not only for clarifying the characteristics of these cancers but also for improving the clinical outcome of these patients. © 2017 The Authors. Digestive Endoscopy © 2017 Japan Gastroenterological Endoscopy Society.

Adenocarcinoma uretral em uma cadela Urethral adenocarcinoma in a bitch

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Marcia Cristina da Silva

2005-08-01

Full Text Available Tumores primários de uretra são raros em animais e há poucos relatos em cães. A ocorrência é maior em cadelas idosas, não havendo predileção por raça. Disúria, estrangúria e hematúria são sinais clínicos associados a esses tumores. É relatado um caso de adenocarcinoma primário de uretra em um cadela Poodle de 12 anos de idade que apresentava aumento de volume no membro pélvico esquerdo. Na necropsia, foram encontradas metástases na articulação femorotibial esquerda, na glândula adrenal e no rim.Urethral primary tumors are rare in animals and there are only few reports in dogs. They are more frequent in old bitches and have no breed predilection. Clinical signs associated with urethral primary tumors include dysuria, strangury and hematuria. We report a case of primary urethral adenocarcinoma in a 12-year-old female Poodle that was presented with localized volume enlargement in the left pelvic limb. At necropsy metastasis were found at the left femorotibial joint, adrenal gland and kidney.

Prostatic adenocarcinoma with glomeruloid features.

Science.gov (United States)

Pacelli, A; Lopez-Beltran, A; Egan, A J; Bostwick, D G

1998-05-01

A wide variety of architectural patterns of adenocarcinoma may be seen in the prostate. We have recently encountered a hitherto-undescribed pattern of growth characterized by intraluminal ball-like clusters of cancer cells reminiscent of renal glomeruli, which we refer to as prostatic adenocarcinoma with glomeruloid features. To define the architectural features, frequency, and distribution of prostatic adenocarcinoma with glomeruloid features, we reviewed 202 totally embedded radical prostatectomy specimens obtained between October 1992 and April 1994 from the files of the Mayo Clinic. This series was supplemented by 100 consecutive needle biopsies with prostatic cancer from January to February 1996. Prostatic adenocarcinoma with glomeruloid features was characterized by round to oval epithelial tufts growing within malignant acini, often supported by a fibrovascular core. The epithelial cells were sometimes arranged in semicircular concentric rows separated by clefted spaces. In the radical prostatectomy specimens, nine cases (4.5%) had glomeruloid features. The glomeruloid pattern constituted 5% to 20% of each cancer (mean, 8.33%) and was usually located at the apex or in the peripheral zone of the prostate. Seven cases were associated with a high Gleason score (7 or 8), one with a score of 6, and one with a score of 5. All cases were associated with high-grade prostatic intraepithelial neoplasia and extensive perineural invasion. Pathological stages included T2c (three cases), T3b (four cases), and T3c (two cases); one of the T3b cases had lymph node metastases (N1). Three (3%) of 100 consecutive routine needle biopsy specimens with cancer showed glomeruloid features, and this pattern constituted 5% to 10% of each cancer (mean, 6.7%). The Gleason score was 6 for two cases and 8 for one case. Two cases were associated with high-grade prostatic intraepithelial neoplasia, and one case had perineural invasion. Glomeruloid features were not observed in any benign or

Secondhand Tobacco Smoke Exposure and Lung Adenocarcinoma In Situ/Minimally Invasive Adenocarcinoma (AIS/MIA).

Science.gov (United States)

Kim, Claire H; Lee, Yuan-Chin Amy; Hung, Rayjean J; Boffetta, Paolo; Xie, Dong; Wampfler, Jason A; Cote, Michele L; Chang, Shen-Chih; Ugolini, Donatella; Neri, Monica; Le Marchand, Loic; Schwartz, Ann G; Morgenstern, Hal; Christiani, David C; Yang, Ping; Zhang, Zuo-Feng

2015-12-01

The aim of this study was to estimate the effect of exposure to secondhand tobacco smoke on the incidence of lung adenocarcinoma in situ/minimally invasive adenocarcinoma (AIS/MIA). Data from seven case-control studies participating in the International Lung Cancer Consortium (ILCCO) were pooled, resulting in 625 cases of AIS/MIA and 7,403 controls, of whom 170 cases and 3,035 controls were never smokers. Unconditional logistic regression was used to estimate adjusted ORs (ORadj) and 95% confidence intervals (CI), controlling for age, sex, race, smoking status (ever/never), and pack-years of smoking. Study center was included in the models as a random-effects intercept term. Ever versus never exposure to secondhand tobacco smoke was positively associated with AIS/MIA incidence in all subjects (ORadj = 1.48; 95% CI, 1.14-1.93) and in never smokers (ORadj = 1.45; 95% CI, 1.00-2.12). There was, however, appreciable heterogeneity of ORadj across studies (P = 0.01), and the pooled estimates were largely influenced by one large study (40% of all cases and 30% of all controls). These findings provide weak evidence for an effect of secondhand tobacco smoke exposure on AIS/MIA incidence. Further studies are needed to assess the impact of secondhand tobacco smoke exposure using the newly recommended classification of subtypes of lung adenocarcinoma. ©2015 American Association for Cancer Research.

Camptothecin resistance

DEFF Research Database (Denmark)

Brangi, M; Litman, Thomas; Ciotti, M

1999-01-01

. Glucuronides were found at equal levels in both parental and resistant colon cancer cell lines for epirubicin and to a lesser extent for SN-38 and mitoxantrone. Low levels of glucuronidation could also be detected in the resistant breast cancer cells. These results were confirmed by analysis of the UGT1A...

Gastric metastasis from invasive lobular breast cancer, mimicking primary gastric cancer: A case report.

Science.gov (United States)

Kim, Dae Hoon; Son, Seung-Myoung; Choi, Young Jin

2018-03-01

Gastric metastasis from invasive lobular breast cancer is relatively rare, commonly presented among multiple metastases, several years after primary diagnosis of breast cancer. Importantly, gastric cancer that is synchronously presented with lobular breast cancer can be misdiagnosed as primary gastric cancer; therefore, accurate differential diagnosis is required. A 39-year-old woman was visited to our hospital because of right breast mass and progressive dyspepsia. Invasive lobular carcinoma of breast was diagnosed on core needle biopsy. Gastroscopy revealed a diffuse scirrhous mass at the prepyloric antrum and diagnosed as poorly differentiated adenocarcinoma on biopsy. Synchronous double primary breast and gastric cancers were considered. Detailed pathological analysis focused on immunohistochemical studies of selected antibodies, including those of estrogen receptors, gross cystic disease fluid protein-15, and caudal-type homeobox transcription factor 2, were studied. As a result, gastric lesion was diagnosed as metastatic gastric cancer originating from breast. Right breast conserving surgery was performed, and duodenal stent was inserted under endoscopic guidance to relieve the patient's symptoms. Systemic chemotherapy with combined administration of paclitaxel and trastuzumab was initiated. Forty-one months after the diagnosis, the patient is still undergoing the same therapy. No recurrent lesion has been identified in the breast and evidence of a partial remission of gastric wall thickening has been observed on follow-up studies without new metastatic lesions. Clinical suspicion, repeat endoscopic biopsy, and detailed histological analysis, including immunohistochemistry, are necessary for diagnosis of metastatic gastric cancer from the breast.

E-cadherin and Vimentin as Predictors of Resistance to Preoperative Systemic Therapy in Patients with Advanced Breast Cancer

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Sonar. S. Panigoro

2017-01-01

Full Text Available Loss of E-cadherin and increased vimentin expression are associated with epithelial-mesenchymal transition andcancer stemness which are responsible for treatment resistance. The study aims to evaluate the role of E-cadherin andvimentin as predictors of resistance to preoperative systemic therapy in patients with advanced breast cancer. This wasa cross-sectional analytical study in patients with stage III-IV breast cancer in Dharmais Cancer Hospital and dr. CiptoMangunkusumo National Hospital from July 2015 to April 2016. Patients had biopsy specimens embedded in paraffinblocks. Expressions of E-cadherin and vimentin proteins were done immunohistochemically. Treatment response wasevaluated histopathologically using Miller-Payne criteria on mastectomy specimens. A total of 65 patients were enrolled.Five patients with invasive lobular carcinoma were excluded. Thirty one had chemotherapy and 29 had hormonaltherapy. After treatment, 46 patients were eligible for mastectomy. E-cadherin and vimentin were positive in 28 (60.9%and 11 (20.3% of specimens. Twenty-three (50% patients showed no response. Treatment resistance were associatedwith type of therapy (OR=4.4; 95% CI=1.27-15.41; p=0.017 and vimentin expression (OR=6.75; 95% CI=1.27-30.02;p=0.016. Hormonal therapy (ORadj=6.26; 95%CI=1.59-24.6; p=0.009 and positive vimentin (ORadj=8.75; 95%CI=1.43-57.4; p=0.019 were independent predictors of treatment resistance. In conclusion, E-cadherin and vimentin can beused as predictors of resistance to preoperative systemic therapy in patients with advanced breast cancer. Keywords: breast cancer, cancer stemness, E-cadherin, preoperative therapy, vimentin.   Peran E-cadherin dan Vimentin sebagai Prediktor Resistensi Terapi Sistemik Preoperatif pada Pasien Kanker Payudara Stadium Lanjut Abstrak Hilangnya ekspresi E-cadherin dan meningkatnya ekspresi vimentin dihubungkan dengan epithelial-mesenchymaltransition dan cancer stemness yang bertanggungjawab terhadap

Vanadium(III)-l-cysteine enhances the sensitivity of murine breast adenocarcinoma cells to cyclophosphamide by promoting apoptosis and blocking angiogenesis.

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Basu, Abhishek; Bhattacharjee, Arin; Baral, Rathindranath; Biswas, Jaydip; Samanta, Amalesh; Bhattacharya, Sudin

2017-05-01

Various epidemiological and preclinical studies have already established the cancer chemopreventive potential of vanadium-based compounds. In addition to its preventive efficacy, studies have also indicated the abilities of vanadium-based compounds to induce cell death selectively toward malignant cells. Therefore, the objective of the present investigation is to improve the therapeutic efficacy and toxicity profile of an alkylating agent, cyclophosphamide, by the concurrent use of an organovanadium complex, vanadium(III)-l-cysteine. In this study, vanadium(III)-l-cysteine (1 mg/kg body weight, per os) was administered alone as well as in combination with cyclophosphamide (25 mg/kg body weight, intraperitoneal) in concomitant and pretreatment schedule in mice bearing breast adenocarcinoma cells. The results showed that the combination treatment significantly decreased the tumor burden and enhanced survivability of tumor-bearing mice through generation of reactive oxygen species in tumor cells. These ultimately led to DNA damage, depolarization of mitochondrial membrane potential, and apoptosis in tumor cells. Further insight into the molecular pathway disclosed that the combination treatment caused upregulation of p53 and Bax and suppression of Bcl-2 followed by the activation of caspase cascade and poly (ADP-ribose) polymerase cleavage. Administration of vanadium(III)-l-cysteine also resulted in significant attenuation of peritoneal vasculature and sprouting of the blood vessels by decreasing the levels of vascular endothelial growth factor A and matrix metalloproteinase 9 in the ascites fluid of tumor-bearing mice. Furthermore, vanadium(III)-l-cysteine significantly attenuated cyclophosphamide-induced hematopoietic, hepatic, and genetic damages and provided additional survival advantages. Hence, this study suggested that vanadium(III)-l-cysteine may offer potential therapeutic benefit in combination with cyclophosphamide by augmenting anticancer efficacy and

HSA-based multi-target combination therapy: regulating drugs' release from HSA and overcoming single drug resistance in a breast cancer model.

Science.gov (United States)

Gou, Yi; Zhang, Zhenlei; Li, Dongyang; Zhao, Lei; Cai, Meiling; Sun, Zhewen; Li, Yongping; Zhang, Yao; Khan, Hamid; Sun, Hongbing; Wang, Tao; Liang, Hong; Yang, Feng

2018-11-01

Multi-drug delivery systems, which may be promising solution to overcome obstacles, have limited the clinical success of multi-drug combination therapies to treat cancer. To this end, we used three different anticancer agents, Cu(BpT)Br, NAMI-A, and doxorubicin (DOX), to build human serum albumin (HSA)-based multi-drug delivery systems in a breast cancer model to investigate the therapeutic efficacy of overcoming single drug (DOX) resistance to cancer cells in vivo, and to regulate the drugs' release from HSA. The HSA complex structure revealed that NAMI-A and Cu(BpT)Br bind to the IB and IIA sub-domain of HSA by N-donor residue replacing a leaving group and coordinating to their metal centers, respectively. The MALDI-TOF mass spectra demonstrated that one DOX molecule is conjugated with lysine of HSA by a pH-sensitive linker. Furthermore, the release behavior of three agents form HSA can be regulated at different pH levels. Importantly, in vivo results revealed that the HSA-NAMI-A-Cu(BpT)Br-DOX complex not only increases the targeting ability compared with a combination of the three agents (the NAMI-A/Cu(BpT)Br/DOX mixture), but it also overcomes DOX resistance to drug-resistant breast cancer cell lines.

The feasibility of an exercise intervention in males at risk of oesophageal adenocarcinoma: a randomized controlled trial.

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Brooke M Winzer

Full Text Available To investigate the feasibility and safety of a 24-week exercise intervention, compared to control, in males with Barrett's oesophagus, and to estimate the effect of the intervention, compared to control, on risk factors associated with oesophageal adenocarcinoma development.A randomized controlled trial of an exercise intervention (60 minutes moderate-intensity aerobic and resistance exercise five days/week over 24 weeks; one supervised and four unsupervised sessions versus attention control (45 minutes stretching five days/week over 24 weeks; one supervised and four unsupervised sessions in inactive, overweight/obese (25.0-34.9 kg/m2 males with Barrett's oesophagus, aged 18-70 years. Primary outcomes were obesity-associated hormones relevant to oesophageal adenocarcinoma risk (circulating concentrations of leptin, adiponectin, interleukin-6, tumour necrosis factor-alpha, C-reactive protein, and insulin resistance [HOMA]. Secondary outcomes included waist circumference, body composition, fitness, strength and gastro-oesophageal reflux symptoms. Outcomes were measured at baseline and 24-weeks. Intervention effects were analysed using generalised linear models, adjusting for baseline value.Recruitment was difficult in this population with a total of 33 participants recruited (target sample size: n = 80; 97% retention at 24-weeks. Adherence to the exercise protocol was moderate. No serious adverse events were reported. A statistically significant intervention effect (exercise minus control was observed for waist circumference (-4.5 [95% CI -7.5, -1.4] cm; p < 0.01. Effects on primary outcomes were not statistically significant.This small, exploratory trial provides important information to inform future trial development including recruitment rates and estimates of effect sizes on outcomes related to oesophageal adenocarcinoma risk. Future trials should investigate a combined dietary and exercise intervention to achieve greater weight loss in this

Breast cancer resistance protein (Bcrp1/Abcg2) limits net intestinal uptake of quercetin in rats by facilitating apical efflux of glucuronides

NARCIS (Netherlands)

Sesink, A.L.A.; Arts, I.C.W.; Boer, de V.C.J.; Breedveld, P.; Schellens, J.H.M.; Hollman, P.C.H.; Russel, F.G.M.

2005-01-01

The intestinal absorption of the flavonoid quercetin in rats is limited by the secretion of glucuronidated metabolites back into the gut lumen. The objective of this study was to determine the role of the intestinal efflux transporters breast cancer resistance protein (Bcrp1)/Abcg2 and multidrug

Breast cancer resistance protein (Bcrp1/Abcg2) limits net intestinal uptake of quercetin in rats by facilitating apical efflux of glucuronides.

NARCIS (Netherlands)

Sesink, A.L.; Arts, I.C.; Boer, V.C. de; Breedveld, P.; Schellens, J.H.; Hollman, P.C.H.; Russel, F.G.M.

2005-01-01

The intestinal absorption of the flavonoid quercetin in rats is limited by the secretion of glucuronidated metabolites back into the gut lumen. The objective of this study was to determine the role of the intestinal efflux transporters breast cancer resistance protein (Bcrp1)/Abcg2 and multidrug

A case report of metastatic adenocarcinoma of the gingiva

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Buddula Aravind

2009-01-01

Full Text Available Localized gingival enlargement is often associated with specific systemic medication, abscess formation, trauma or reactive lesions. Scant literature is available reporting enlargement of gingiva due the metastasis of adenocarcinoma from lung. The case report presents a unique case of an adenocarcinoma in the lung metastasizing to the buccal and lingual interdental papillae of teeth numbering 34 and 35. A 72-year-old female was referred to the Mayo Clinic with a recent diagnosis of metastatic stage IV adenocarcinoma of the left lung presented with an abnormal mass located on the left posterior buccal keratinized tissue adjacent to teeth numbering 34-35. Biopsy of the lesion was performed for CK7, CK20, TTF-1 and p63. The tumor cells were positive for CK7 and TTF-1, and weakly positive for p63 suggesting a diagnosis of adenocarcinoma. The periodontist may be in the unique position to be the first oral health care provider to evaluate any biopsy suspicious intra-oral lesions.

FMSP-Nanoparticles Induced Cell Death on Human Breast Adenocarcinoma Cell Line (MCF-7 Cells: Morphometric Analysis

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Firdos Alam Khan

2018-05-01

Full Text Available Currently, breast cancer treatment mostly revolves around radiation therapy and surgical interventions, but often these treatments do not provide satisfactory relief to the patients and cause unmanageable side-effects. Nanomaterials show promising results in treating cancer cells and have many advantages such as high biocompatibility, bioavailability and effective therapeutic capabilities. Interestingly, fluorescent magnetic nanoparticles have been used in many biological and diagnostic applications, but there is no report of use of fluorescent magnetic submicronic polymer nanoparticles (FMSP-nanoparticles in the treatment of human breast cancer cells. In the present study, we tested the effect of FMSP-nanoparticles on human breast cancer cells (MCF-7. We tested different concentrations (1.25, 12.5 and 50 µg/mL of FMSP-nanoparticles in MCF-7 cells and evaluated the nanoparticles response morphometrically. Our results revealed that FMSP-nanoparticles produced a concentration dependent effect on the cancer cells, a dose of 1.25 µg/mL produced no significant effect on the cancer cell morphology and cell death, whereas dosages of 12.5 and 50 µg/mL resulted in significant nuclear augmentation, disintegration, chromatic condensation followed by dose dependent cell death. Our results demonstrate that FMSP-nanoparticles induce cell death in MCF-7 cells and may be a potential anti-cancer agent for breast cancer treatment.

Immunohistochemical assessment of Survivin and Bcl3 expression as potential biomarkers for NF-κB activation in the Barrett metaplasia-dysplasia-adenocarcinoma sequence.

Science.gov (United States)

Puccio, Ignazio; Khan, Saif; Butt, Adil; Graham, David; Sehgal, Vinay; Patel, Dominic; Novelli, Marco; Lovat, Laurence B; Rodriguez-Justo, Manuel; Hamoudi, Rifat A

2018-02-01

Non-dysplastic Barrett's oesophagus (NDBE) occurs as a consequence of an inflammatory response triggered through prolonged gastro-oesophageal reflux and it may precede the development of oesophageal adenocarcinoma. NF-κB activation as a result of the inflammatory response has been shown in NDBE, but the possible mechanism involved in the process is unknown. The aim of this study was to assess, using immunohistochemistry, Survivin and Bcl3 expression as potential biomarkers for NF-κB activation along the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. Survivin is an NF-κB-inducible anti-apoptotic protein, and Bcl3 is a negative regulator of NF-κB. There was progressive upregulation of Survivin expression along the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. Bcl3 expression was upregulated in non-dysplastic Barrett's oesophagus, low-grade, high-grade dysplasia and oesophageal adenocarcinoma when compared to squamous group. The study shows the differential expression of Bcl3 between the squamous and Barrett's stage, suggesting that Bcl3 could be a surrogate marker for early event involving constitutive NF-κB activation. In addition, the study suggests that NF-κB activation may infer resistance to apoptosis through the expression of anti-apoptotic genes such as Survivin, which showed progressive increase in expression throughout the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. This ability to avoid apoptosis may underlie the persistence and malignant predisposition of Barrett's metaplasia. © 2018 The Authors. International Journal of Experimental Pathology © 2018 International Journal of Experimental Pathology.

Opium; an emerging risk factor for gastric adenocarcinoma

Science.gov (United States)

Shakeri, Ramin; Malekzadeh, Reza; Etemadi, Arash; Nasrollahzadeh, Dariush; Aghcheli, Karim; Sotoudeh, Masoud; Islami, Farhad; Pourshams, Akram; Pawlita, Michael; Boffetta, Paolo; Dawsey, Sanford M.; Abnet, Christian C.; Kamangar, Farin

2013-01-01

Opium use has been associated with higher risk of cancers of the esophagus, bladder, larynx, and lung; however, no previous study has examined its association with gastric cancer. There is also little information on the associations between hookah (water pipe) smoking or the chewing of tobacco products and the risk of gastric cancer. In a case-control study in Golestan Province of Iran, we enrolled 309 cases of gastric adenocarcinoma (118 noncardia, 161 cardia, and 30 mixed-location adenocarcinomas) and 613 matched controls. Detailed information on long-term use of opium, tobacco products, and other covariates were collected using structured and validated lifestyle and food frequency questionnaires. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were obtained using conditional logistic regression models. Opium use was associated with an increased risk of gastric adenocarcinoma, with an adjusted OR (95% CI) of 3.1 (1.9 – 5.1), and this increased risk was apparent for both anatomic subsites (cardia and noncardia). There was a dose-response effect, and individuals with the highest cumulative opium use had the strongest association (OR: 4.5; 95%CI: 2.3-8.5). We did not find a statistically significant association between the use of any of the tobacco products and risk of gastric adenocarcinoma, overall or by anatomic subsite. We showed, for the first time, an association between opium use and gastric adenocarcinoma. Given that opium use is a traditional practice in many parts of the world, these results are of public health significance. PMID:23319416

Opium: an emerging risk factor for gastric adenocarcinoma.

Science.gov (United States)

Shakeri, Ramin; Malekzadeh, Reza; Etemadi, Arash; Nasrollahzadeh, Dariush; Aghcheli, Karim; Sotoudeh, Masoud; Islami, Farhad; Pourshams, Akram; Pawlita, Michael; Boffetta, Paolo; Dawsey, Sanford M; Abnet, Christian C; Kamangar, Farin

2013-07-15

Opium use has been associated with higher risk of cancers of the esophagus, bladder, larynx, and lung; however, no previous study has examined its association with gastric cancer. There is also little information on the associations between hookah (water pipe) smoking or the chewing of tobacco products and the risk of gastric cancer. In a case-control study in Golestan Province of Iran, we enrolled 309 cases of gastric adenocarcinoma (118 noncardia, 161 cardia and 30 mixed-location adenocarcinomas) and 613 matched controls. Detailed information on long-term use of opium, tobacco products and other covariates were collected using structured and validated lifestyle and food frequency questionnaires. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were obtained using conditional logistic regression models. Opium use was associated with an increased risk of gastric adenocarcinoma, with an adjusted OR (95% CI) of 3.1 (1.9-5.1), and this increased risk was apparent for both anatomic subsites (cardia and noncardia). There was a dose-response effect, and individuals with the highest cumulative opium use had the strongest association (OR: 4.5; 95% CI: 2.3-8.5). We did not find a statistically significant association between the use of any of the tobacco products and risk of gastric adenocarcinoma, overall or by anatomic subsite. We showed, for the first time, an association between opium use and gastric adenocarcinoma. Given that opium use is a traditional practice in many parts of the world, these results are of public health significance. Copyright © 2013 UICC.

Ultrasonographic findings of metapIastic squamous breast carcinoma and the pathologic correlation

International Nuclear Information System (INIS)

Shin, Jung Hee; Hwang, Asiry; Choi, Hye Young; Sung, Sun Hee; Kim, Yoo Kyung; Lee, Sun Hwa

2004-01-01

We investigated the ultrasonographic (US) appearance of metapIastic squamous breast carcinoma with the pathologic correlation. During an 8-year period, the US appearances of 10 patients with metaplastic squamous breast carcinoma were retrospectively analyzed on the basis of the Breast Imaging and Reporting Data System (BI-RADS) - US lexicon. These 10 patients included 9 patients having invasive adenocarcinomas of the breast with more than 30% squamous metaplasia, and one patient had pure primary squamous cell carcinoma. We correlated the US findings with the pathologic findings. On US, the majority of the tumors showed ovaI shapes (70%), indistinct margins (50%), parallel orientation (80%), echogenic halos (60%), complex echogenicity with solid and cystic components (60%), and posterior enhancement (70%). The findings of calcifications (20%) and metastatic axillary lymph nodes (10%) were rare. On pathologic examination, half of the tumors showed infiltrative microscopic margins. All six cases showing complex echogenicity with solid and cystic components on US were pathologically related to the cystic or necrotic portion, and three of these cases had hemorrhage. On US, metapIastic squamous breast carcinoma mainly manifested as oval, complex, echoic masses with indistinct margins and posterior enhancement that was pathologically related to the cystic or necrotic portions

Backscattering analysis of high frequency ultrasonic imaging for ultrasound-guided breast biopsy

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Cummins, Thomas; Akiyama, Takahiro; Lee, Changyang; Martin, Sue E.; Shung, K. Kirk

2017-03-01

A new ultrasound-guided breast biopsy technique is proposed. The technique utilizes conventional ultrasound guidance coupled with a high frequency embedded ultrasound array located within the biopsy needle to improve the accuracy in breast cancer diagnosis.1 The array within the needle is intended to be used to detect micro- calcifications indicative of early breast cancers such as ductal carcinoma in situ (DCIS). Backscattering analysis has the potential to characterize tissues to improve localization of lesions. This paper describes initial results of the application of backscattering analysis of breast biopsy tissue specimens and shows the usefulness of high frequency ultrasound for the new biopsy related technique. Ultrasound echoes of ex-vivo breast biopsy tissue specimens were acquired by using a single-element transducer with a bandwidth from 41 MHz to 88 MHz utilizing a UBM methodology, and the backscattering coefficients were calculated. These values as well as B-mode image data were mapped in 2D and matched with each pathology image for the identification of tissue type for the comparison to the pathology images corresponding to each plane. Microcalcifications were significantly distinguished from normal tissue. Adenocarcinoma was also successfully differentiated from adipose tissue. These results indicate that backscattering analysis is able to quantitatively distinguish tissues into normal and abnormal, which should help radiologists locate abnormal areas during the proposed ultrasound-guided breast biopsy with high frequency ultrasound.

Exosomes play an important role in the process of psoralen reverse multidrug resistance of breast cancer.

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Wang, Xiaohong; Xu, Chengfeng; Hua, Yitong; Sun, Leitao; Cheng, Kai; Jia, Zhongming; Han, Yong; Dong, Jianli; Cui, Yuzhen; Yang, Zhenlin

2016-12-01

Release of exosomes have been shown to play critical roles in drug resistance by delivering cargo. Targeting the transfer of exosomes from resistant cells to sensitive cells may be an approach to overcome some cases of drug resistance. In this study, we investigated the potential role of exosomes in the process of psoralen reverse multidrug resistance of MCF-7/ADR cells. Exosomes were isolated by differential centrifugation of culture media from MCF-7/ADR cells (ADR/exo) and MCF-7 parental cells (S/exo). Exosomes were characterized by morphology, exosomal markers and size distribution. The ability of ADR/exo to transfer multidrug resistance was assessed by MTT and real-time quantitative PCR. The different formation and secretion of exosomes were detected by immunofluorescence and transmission electron microscopy. Then we performed comparative transcriptomic analysis using RNA-Seq technology and real-time quantitative PCR to better understand the gene expression regulation in exosmes formation and release after psoralen treatment. Our data showed that exosomes derived from MCF-7/ADR cells were able to promote active sequestration of drugs and could induce a drug resistance phenotype by transferring drug-resistance-related gene MDR-1 and P-glycoprotein protein. Psoralen could reduce the formation and secretion of exosomes to overcome drug resistance. There were 21 differentially expressed genes. Gene ontology (GO) pathway analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the most significantly expressed genes were linked to PPAR and P53 signaling pathways which were related to exosomes formation, secretion and cargo sorting. Psoralen can affect the exosomes and induce the reduction of resistance transmission via exosomes might through PPAR and P53 signaling pathways, which might provide a novel strategy for breast cancer resistance to chemotherapy in the future.

Increased risk of gastric adenocarcinoma after treatment of primary gastric diffuse large B-cell lymphoma

International Nuclear Information System (INIS)

Inaba, Koji; Morota, Madoka; Mayahara, Hiroshi; Ito, Yoshinori; Sumi, Minako; Uno, Takashi; Itami, Jun; Kushima, Ryoji; Murakami, Naoya; Kuroda, Yuuki; Harada, Ken; Kitaguchi, Mayuka; Yoshio, Kotaro; Sekii, Shuhei; Takahashi, Kana

2013-01-01

There have been sporadic reports about synchronous as well as metachronous gastric adenocarcinoma and primary gastric lymphoma. Many reports have dealt with metachronous gastric adenocarcinoma in mucosa-associated lymphoid tissue lymphoma of stomach. But to our knowledge, there have been no reports that document the increased incidence of metachronous gastric adenocarcinoma in patients with gastric diffuse large B-cell lymphoma. This retrospective study was conducted to estimate the incidence of metachronous gastric adenocarcinoma after primary gastric lymphoma treatment, especially in diffuse large B-cell lymphoma. The retrospective cohort study of 139 primary gastric lymphoma patients treated with radiotherapy at our hospital. Mean observation period was 61.5 months (range: 3.7-124.6 months). Patients profile, characteristics of primary gastric lymphoma and metachronous gastric adenocarcinoma were retrieved from medical records. The risk of metachronous gastric adenocarcinoma was compared with the risk of gastric adenocarcinoma in Japanese population. There were 10 (7.2%) metachronous gastric adenocarcinoma patients after treatment of primary gastric lymphomas. It was quite high risk compared with the risk of gastric carcinoma in Japanese population of 54.7/100,000. Seven patients of 10 were diffuse large B-cell lymphoma and other 3 patients were mixed type of diffuse large B-cell lymphoma and mucosa associated lymphoid tissue lymphoma. Four patients of 10 metachronous gastric adenocarcinomas were signet-ring cell carcinoma and two patients died of gastric adenocarcinoma. Metachronous gastric adenocarcinoma may have a more malignant potential than sporadic gastric adenocarcinoma. Old age, Helicobacter pylori infection and gastric mucosal change of chronic gastritis and intestinal metaplasia were possible risk factors for metachronous gastric adenocarcinoma. There was an increased risk of gastric adenocarcinoma after treatment of primary gastric lymphoma

Lung adenocarcinoma originates from retrovirus infection of proliferating type 2 pneumocytes during pulmonary post-natal development or tissue repair.

Science.gov (United States)

Murgia, Claudio; Caporale, Marco; Ceesay, Ousman; Di Francesco, Gabriella; Ferri, Nicola; Varasano, Vincenzo; de las Heras, Marcelo; Palmarini, Massimo

2011-03-01

Jaagsiekte sheep retrovirus (JSRV) is a unique oncogenic virus with distinctive biological properties. JSRV is the only virus causing a naturally occurring lung cancer (ovine pulmonary adenocarcinoma, OPA) and possessing a major structural protein that functions as a dominant oncoprotein. Lung cancer is the major cause of death among cancer patients. OPA can be an extremely useful animal model in order to identify the cells originating lung adenocarcinoma and to study the early events of pulmonary carcinogenesis. In this study, we demonstrated that lung adenocarcinoma in sheep originates from infection and transformation of proliferating type 2 pneumocytes (termed here lung alveolar proliferating cells, LAPCs). We excluded that OPA originates from a bronchioalveolar stem cell, or from mature post-mitotic type 2 pneumocytes or from either proliferating or non-proliferating Clara cells. We show that young animals possess abundant LAPCs and are highly susceptible to JSRV infection and transformation. On the contrary, healthy adult sheep, which are normally resistant to experimental OPA induction, exhibit a relatively low number of LAPCs and are resistant to JSRV infection of the respiratory epithelium. Importantly, induction of lung injury increased dramatically the number of LAPCs in adult sheep and rendered these animals fully susceptible to JSRV infection and transformation. Furthermore, we show that JSRV preferentially infects actively dividing cell in vitro. Overall, our study provides unique insights into pulmonary biology and carcinogenesis and suggests that JSRV and its host have reached an evolutionary equilibrium in which productive infection (and transformation) can occur only in cells that are scarce for most of the lifespan of the sheep. Our data also indicate that, at least in this model, inflammation can predispose to retroviral infection and cancer.

Alopecia neoplastica: An uncommon presentation of metastatic breast carcinoma

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Felipe Ladeira de Oliveira

2016-12-01

Full Text Available Cutaneous metastasis may correspond to the initial clinical presentation of hidden internal malignancies. In patients presenting said neoplasia, clinical manifestations of breast cancer reaches 23.9%. Considering that neoplastic alopecia appears as an unusual pattern of the said metastasis, this report describes a case of such uncommon neoplastic alopecia which presents itself as a cutaneous metastasis of rapid progression in a patient with prior breast cancer history. We present a 47-year-old female patient reporting lesions at the scalp, and who was asymptomatic with a 1-year evolution. The patient reported prior breast cancer history and presence of lung metastasis, and was undergoing chemotherapy at the time of consultation. A dermatological evaluation showed only a nodular lesion with erythematous surface and a diameter measuring about 4 cm, firm in consistency, and immovable. She was routed to the Department of Dermatological Surgery, and the results from histopathology were consistent with a diagnosis of metastatic breast adenocarcinoma. Neoplastic alopecia appears as an unusual form of cutaneous metastasis which is predominantly described in association with breast cancer. The lesion’s clinical features play a crucial role at the differential diagnosis, as the presence of erythema could distinguish neoplastic alopecia from alopecia areata. The existence of cutaneous metastasis leads to unfavorable outcomes. As a conclusion, cutaneous evaluation of patients is essential for treating visceral metastases, since the forms of cutaneous metastasis are diverse and can also affect the scalp.

The expression and significance of multi-drug resistance genes in breast cancer stem cells%乳腺癌干细胞多药耐药基因的表达及意义

Institute of Scientific and Technical Information of China (English)

Zhi Li; Chunping Liu; Yanli He; Jinghui Zhang; Tao Huang

2008-01-01

Objective:To approach the expressions of MDR1 and BCRP in breast cancer stem cells and differentiated cells.Methods:The breast cancer stem calls were separated from human breast cancer primary tissues and MCF-7 by flow cytometry.Then we measured the expressions of MDR1 and BCRP with different subset cells by Realtime-PCR.Results:Contrasted with breast cancer differentiated cells,the expressions of MDR1 and BCRP in breast cancer stem calls were higher (P＜0.01),and the proportion of stem cells rose after chemotherapy (P＜0.01).Conclusion:Contrasted with breast cancer differentiated cells,breast cancer stem cells have stronger ability of clrug-resistanca with higher level of multi-drug resistance genes,and it is one of key points for chemotherapy failure of breast cancer.

Fibulin-1 functions as a prognostic factor in lung adenocarcinoma.

Science.gov (United States)

Cui, Yuan; Liu, Jian; Yin, Hai-Bing; Liu, Yi-Fei; Liu, Jun-Hua

2015-09-01

Fibulin-1 is a member of the fibulin gene family, characterized by tandem arrays of epidermal growth factor-like domains and a C-terminal fibulin-type module. Fibulin-1 plays important roles in a range of cellular functions including morphology, growth, adhesion and mobility. It acts as a tumor suppressor gene in cutaneous melanoma, prostate cancer and gastric cancer. However, whether fibulin-1 also acts as a tumor suppressor gene in lung adenocarcinoma remains unknown. We also determined the association of fibulin-1 expression with various clinical and pathological parameters, which would show its potential role in clinical prognosis. We investigated and followed up 140 lung adenocarcinoma patients who underwent lung resection without pre- and post-operative systemic chemotherapy at the Affiliated Hospital of Nantong University from 2009 to 2013. Western blot assay and immunohistochemistry were used to evaluate the expression of fibulin-1 in lung adenocarcinoma tissues. We then analyzed the correlations between fibulin-1 expression and clinicopathological variables as well as the patients' overall survival rate. Both western blot assay and immunohistochemistry demonstrated that the level of fibulin-1 was downregulated in human lung adenocarcinoma tissues compared with that of normal lung tissues. Fibulin-1 expression significantly correlated with histological differentiation (P = 0.046), clinical stage (P< 0.01), lymph node status (P = 0.038) and expression of Ki-67 (P = 0.013). More importantly, multivariate analysis revealed that fibulin-1 was an independent prognostic marker for lung adenocarcinoma, and high expression of fibulin-1 was significantly associated with better prognosis of lung adenocarcinoma patients. The results supported our hypothesis that fibulin-1 can act as a prognostic factor in lung adenocarcinoma progression. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Molecular cytogenetic evaluation of gastric cardia adenocarcinoma and precursor lesions

NARCIS (Netherlands)

H. van Dekken (Herman); J.C. Alers (Janneke); P.H.J. Riegman (Peter); C. Rosenberg; H.W. Tilanus (Hugo); K.J. Vissers (Kees)

2001-01-01

textabstractAnalyses of cancer incidence data in the United States and Western Europe revealed steadily rising rates over the past decades of adenocarcinomas of the esophagus and gastric cardia. Genetic information on gastric cardia adenocarcinoma and its preneoplasias

Clinicopathologic features of incidental prostatic adenocarcinoma in radical cystoprostatectomy specimens

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Vuruskan Hakan

2011-07-01

Full Text Available Abstract Background The aim of this study is to review all features of incidentally discovered prostate adenocarcinoma in patients undergoing radical cystoprostatectomy for bladder cancer. Methods The medical charts of 300 male patients who underwent radical cystoprostatectomy for bladder cancer between 1997 and 2005 were retrospectively reviewed. The mean age of the patients was 62 (range 51-75 years. Results Prostate adenocarcinoma was present in 60 (20% of 300 specimens. All were acinar adenocarcinoma. Of these, 40 (66.7% were located in peripheral zone, 20 (33.3% had pT2a tumor, 12 (20% had pT2b tumor, 22(36.7% had pT2c and, 6 (10% had pT3a tumor. Gleason score was 6 or less in 48 (80% patients. Surgical margins were negative in 54 (90% patients, and tumor volume was less than 0.5 cc in 23 (38.3% patients. Of the 60 incidentally detected cases of prostate adenocarcinoma 40 (66.7% were considered clinically significant. Conclusion Incidentally detected prostate adenocarcinoma is frequently observed in radical cystoprostatectomy specimens. The majority are clinically significant.

Cyclooxygenase-2 inhibitor induces apoptosis in breast cancer cells in an in vivo model of spontaneous metastatic breast cancer.

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Basu, Gargi D; Pathangey, Latha B; Tinder, Teresa L; Lagioia, Michelle; Gendler, Sandra J; Mukherjee, Pinku

2004-11-01

Cyclooxygenase-2 (COX-2) inhibitors are rapidly emerging as a new generation of therapeutic drug in combination with chemotherapy or radiation therapy for the treatment of cancer. The mechanisms underlying its antitumor effects are not fully understood and more thorough preclinical trials are needed to determine if COX-2 inhibition represents a useful approach for prevention and/or treatment of breast cancer. The purpose of this study was to evaluate the growth inhibitory mechanism of a highly selective COX-2 inhibitor, celecoxib, in an in vivo oncogenic mouse model of spontaneous breast cancer that resembles human disease. The oncogenic mice carry the polyoma middle T antigen driven by the mouse mammary tumor virus promoter and develop primary adenocarcinomas of the breast. Results show that oral administration of celecoxib caused significant reduction in mammary tumor burden associated with increased tumor cell apoptosis and decreased proliferation in vivo. In vivo apoptosis correlated with significant decrease in activation of protein kinase B/Akt, a cell survival signaling kinase, with increased expression of the proapoptotic protein Bax and decreased expression of the antiapoptotic protein Bcl-2. In addition, celecoxib treatment reduced levels of proangiogenic factor (vascular endothelial growth factor), suggesting a role of celecoxib in suppression of angiogenesis in this model. Results from these preclinical studies will form the basis for assessing the feasibility of celecoxib therapy alone or in combination with conventional therapies for treatment and/or prevention of breast cancer.

Microparticles shed from multidrug resistant breast cancer cells provide a parallel survival pathway through immune evasion.

Science.gov (United States)

Jaiswal, Ritu; Johnson, Michael S; Pokharel, Deep; Krishnan, S Rajeev; Bebawy, Mary

2017-02-06

Breast cancer is the most frequently diagnosed cancer in women. Resident macrophages at distant sites provide a highly responsive and immunologically dynamic innate immune response against foreign infiltrates. Despite extensive characterization of the role of macrophages and other immune cells in malignant tissues, there is very little known about the mechanisms which facilitate metastatic breast cancer spread to distant sites of immunological integrity. The mechanisms by which a key healthy defense mechanism fails to protect distant sites from infiltration by metastatic cells in cancer patients remain undefined. Breast tumors, typical of many tumor types, shed membrane vesicles called microparticles (MPs), ranging in size from 0.1-1 μm in diameter. MPs serve as vectors in the intercellular transfer of functional proteins and nucleic acids and in drug sequestration. In addition, MPs are also emerging to be important players in the evasion of cancer cell immune surveillance. A comparative analysis of effects of MPs isolated from human breast cancer cells and non-malignant human brain endothelial cells were examined on THP-1 derived macrophages in vitro. MP-mediated effects on cell phenotype and functionality was assessed by cytokine analysis, cell chemotaxis and phagocytosis, immunolabelling, flow cytometry and confocal imaging. Student's t-test or a one-way analysis of variance (ANOVA) was used for comparison and statistical analysis. In this paper we report on the discovery of a new cellular basis for immune evasion, which is mediated by breast cancer derived MPs. MPs shed from multidrug resistant (MDR) cells were shown to selectively polarize macrophage cells to a functionally incapacitated state and facilitate their engulfment by foreign cells. We propose this mechanism may serve to physically disrupt the inherent immune response prior to cancer cell colonization whilst releasing mediators required for the recruitment of distant immune cells. These findings

Resistance Exercise and Inflammation in Breast Cancer Patients Undergoing Adjuvant Radiation Therapy: Mediation Analysis From a Randomized, Controlled Intervention Trial

Energy Technology Data Exchange (ETDEWEB)

Schmidt, Martina E., E-mail: m.schmidt@dkfz.de [Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg (Germany); Meynköhn, Anna; Habermann, Nina [Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg (Germany); Wiskemann, Joachim [Division of Medical Oncology, National Center for Tumor Diseases and University Hospital, Heidelberg (Germany); Oelmann, Jan; Hof, Holger; Wessels, Sabine [Department of Radiation Oncology, National Center for Tumor Diseases and University Hospital, Heidelberg (Germany); Klassen, Oliver [Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg (Germany); Debus, Jürgen; Potthoff, Karin [Department of Radiation Oncology, National Center for Tumor Diseases and University Hospital, Heidelberg (Germany); Steindorf, Karen; Ulrich, Cornelia M. [Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg (Germany)

2016-02-01

Purpose: To explore the mediating role of inflammatory parameters in the development of fatigue, pain, and potentially related depressive symptoms during radiation therapy for breast cancer and its mitigation by resistance exercise. Methods and Materials: Breast cancer patients scheduled for adjuvant radiation therapy were randomized to 12-week progressive resistance exercise training (EX) or a relaxation control group. Interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1ra) were measured in serum samples collected before, at the end, and 6 weeks after radiation therapy from 103 chemotherapy-naïve participants. Fatigue was assessed with the multidimensional Fatigue Assessment Questionnaire, pain with the European Organization for Research and Treatment of Cancer QLQ-C30, and depressive symptoms with the Center for Epidemiologic Studies Depression Scale. Analysis of covariance models, partial correlations, Freedman-Schatzkin tests, and R{sup 2} effect-size measures for mediation were calculated. Results: The analysis of covariance models revealed a significant intervention effect on IL-6 (P=.010) and the IL-6/IL-1ra ratio (P=.018), characterized by a marked increase during radiation therapy among controls, but no significant change in EX. Interleukin-1 receptor antagonist did not change significantly in either group (P=.88). Increased IL-6 and IL-6/IL-1ra levels at the end of radiation therapy were significantly associated with increased physical fatigue and pain 6 weeks after radiation. We observed significant partial mediation by IL-6 and IL-6/IL-1ra of the effect of resistance exercise on physical fatigue (Freedman-Schatzkin P=.023 and P<.001) and pain (both P<.001). Hereby IL-6 and IL-6/IL-1ra mediated between 15% and 24% of the variance of physical fatigue and pain explained by the intervention. Conclusions: This randomized, controlled trial showed a significantly increased proinflammatory cytokine level after adjuvant radiation therapy in breast

Resistance Exercise and Inflammation in Breast Cancer Patients Undergoing Adjuvant Radiation Therapy: Mediation Analysis From a Randomized, Controlled Intervention Trial

International Nuclear Information System (INIS)

Schmidt, Martina E.; Meynköhn, Anna; Habermann, Nina; Wiskemann, Joachim; Oelmann, Jan; Hof, Holger; Wessels, Sabine; Klassen, Oliver; Debus, Jürgen; Potthoff, Karin; Steindorf, Karen; Ulrich, Cornelia M.

2016-01-01

Purpose: To explore the mediating role of inflammatory parameters in the development of fatigue, pain, and potentially related depressive symptoms during radiation therapy for breast cancer and its mitigation by resistance exercise. Methods and Materials: Breast cancer patients scheduled for adjuvant radiation therapy were randomized to 12-week progressive resistance exercise training (EX) or a relaxation control group. Interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1ra) were measured in serum samples collected before, at the end, and 6 weeks after radiation therapy from 103 chemotherapy-naïve participants. Fatigue was assessed with the multidimensional Fatigue Assessment Questionnaire, pain with the European Organization for Research and Treatment of Cancer QLQ-C30, and depressive symptoms with the Center for Epidemiologic Studies Depression Scale. Analysis of covariance models, partial correlations, Freedman-Schatzkin tests, and R"2 effect-size measures for mediation were calculated. Results: The analysis of covariance models revealed a significant intervention effect on IL-6 (P=.010) and the IL-6/IL-1ra ratio (P=.018), characterized by a marked increase during radiation therapy among controls, but no significant change in EX. Interleukin-1 receptor antagonist did not change significantly in either group (P=.88). Increased IL-6 and IL-6/IL-1ra levels at the end of radiation therapy were significantly associated with increased physical fatigue and pain 6 weeks after radiation. We observed significant partial mediation by IL-6 and IL-6/IL-1ra of the effect of resistance exercise on physical fatigue (Freedman-Schatzkin P=.023 and P<.001) and pain (both P<.001). Hereby IL-6 and IL-6/IL-1ra mediated between 15% and 24% of the variance of physical fatigue and pain explained by the intervention. Conclusions: This randomized, controlled trial showed a significantly increased proinflammatory cytokine level after adjuvant radiation therapy in breast

Mucinous adenocarcinoma of the appendix: A case report and ...

African Journals Online (AJOL)

Primary adenocarcinoma of the appendix is a rare disease as compared with cancer of the colon. It is common in patients in the middle age. Mucinous adenocarcinoma is one of the histological types seen. The usual presentation of patients is acute appendicitis or peri –appendicular abscess. Diagnosis is often made after ...

Urachal adenocarcinoma: a rare case report

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Bo Bao

2017-03-01

Full Text Available Urachal carcinoma is a rare and aggressive form of bladder cancer involving the urachus, a fibrous remnant of the allantois that extends from the bladder to the umbilicus. We report this case of a 49-year-old women with primary urachal adenocarcinoma treated with partial cystectomy who relapsed 5 years after surgery with lung metastases. This patient with unremarkable medical history presented with abdominal discomfort and a palpable pelvic mass. Follow-up imaging reveals a large mass on the dome of the bladder extending from the urachus. Subsequent ultrasound-guided biopsy result was suggestive of an urachal mucinous adenocarcinoma. The patient was treated surgically with a partial cystectomy.

An Exceptional Adenocarcinoma in a Girl

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Bangaly Traore

2018-01-01

Full Text Available Anal adenocarcinoma is very rare and usually occurs in the elderly. We present a case of a 12-year-old girl with an anal margin painful tumor infiltrating the lower rectum, with perineal and vulvar permeation nodules and bilateral fixed inguinal and iliac lymph nodes. Histology showed anal adenocarcinoma with mucosecreting component and independent cells. She had no extra pelvic metastasis on CT scan. She underwent a colostomy and palliative care. This exceptional case challenges us on the diversity of forms of anal cancers that require a multidisciplinary approach. The precarious social context and the age of onset make it difficult to manage this rare cancer.

Increasing trend of metronidazole resistance in the treatment of ...

African Journals Online (AJOL)

Helicobacter pylori are gram negative spiral bacteria that colonize the human stomach. Infection with H. pylori is associated with chronic gastritis, peptic ulcer, gastric adenocarcinoma and gastric mucosaassociated lymphoid tissue (MALT) lymphoma. Antibiotic resistance is an ever increasing problem with the treatment of ...

Intrinsic mechanism of estradiol-induced apoptosis in breast cancer cells resistant to estrogen deprivation.

Science.gov (United States)

Lewis, Joan S; Meeke, Kathleen; Osipo, Clodia; Ross, Eric A; Kidawi, Noman; Li, Tianyu; Bell, Eric; Chandel, Navdeep S; Jordan, V Craig

2005-12-07

We previously developed an estrogen receptor (ER)-positive breast cancer cell line (MCF-7:5C) that is resistant to long-term estrogen deprivation and undergoes rapid and complete apoptosis in the presence of physiologic concentrations of 17beta-estradiol. Here, we investigated the role of the mitochondrial apoptotic pathway in this process. Apoptosis in MCF-7:5C cells treated with estradiol, fulvestrant, or vehicle (control) was investigated by annexin V-propidium iodide double staining and 4',6-diamidino-2-phenylindole (DAPI) staining. Apoptosis was also analyzed in MCF-7:5C cells transiently transfected with small interfering RNAs (siRNAs) to apoptotic pathway components. Expression of apoptotic pathway intermediates was measured by western blot analysis. Mitochondrial transmembrane potential (psim) was determined by rhodamine-123 retention assay. Mitochondrial pathway activity was determined by cytochrome c release and cleavage of poly(ADP-ribose) polymerase (PARP) protein. Tumorigenesis was studied in ovariectomized athymic mice that were injected with MCF-7:5C cells. Differences between the treatment groups and control group were determined by two-sample t test or one-factor analysis of variance. All statistical tests were two-sided. MCF-7:5C cells treated with estradiol underwent apoptosis and showed increased expression of proapoptotic proteins, decreased psim, enhanced cytochrome c release, and PARP cleavage compared with cells treated with fulvestrant or vehicle. Blockade of Bax, Bim, and p53 mRNA expression by siRNA reduced estradiol-induced apoptosis relative to control by 76% [95% confidence interval (CI) = 73% to 79%, P estradiol-induced apoptosis in long-term estrogen-deprived breast cancer cells. Physiologic concentrations of estradiol could potentially be used to induce apoptosis and tumor regression in tumors that have developed resistance to aromatase inhibitors.

SIRT1 expression is associated with poor prognosis of lung adenocarcinoma

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Li C

2015-04-01

Full Text Available Chong Li,1,2,* Lingling Wang,3,* Liang Zheng,4 Xianghong Zhan,4 Bin Xu,1,2 Jingting Jiang,1,2 Changping Wu1,2 1Department of Tumor Biological Treatment, the Third Affiliated Hospital, Soochow University, Changzhou, 2Cancer Immunotherapy Engineering Research Center of Jiangsu Province, Changzhou, 3Department of Medical Education, Jinling Hospital, Medical School of Nanjing University, Nanjing, 4Department of Thoracic Surgery, the Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu, People’s Republic of China *These authors contributed equally to this work Abstract: Several studies have reported that the overexpression of Sirtuin 1 (SIRT1 was associated with poor prognosis in various human cancers. However, little is known regarding the prognostic value of SIRT1 in lung adenocarcinoma. Therefore, the aim of this study is to evaluate the role of SIRT1 in the prognosis of lung adenocarcinoma patients. Using a tissue microarray, we detected SIRT1 expression by immunohistochemistry in lung adenocarcinoma tissue, as well as in corresponding noncancerous tissues (NCTs. A high expression level of SIRT1 was observed in 74.7% (56/75 of patients with lung adenocarcinoma and 6.7% (5/75 of NCTs (P<0.001. SIRT1 expression was significantly associated with high pathological stage. Importantly, we found that SIRT1 expression was associated with worse overall survival in these lung adenocarcinoma patients (67.0 months vs 104.5 months; P=0.005. In addition, anaplastic lymphoma kinase, epidermal growth factor receptor, vascular endothelial growth factor (VEGF, and Survivin expression were evaluated by fluorescent in situ hybridization or immunohistochemistry, respectively. We found that VEGF and Survivin were both highly expressed in the lung adenocarcinoma tissues, as compared to NCTs. Moreover, the SIRT1 and VEGF expression statuses were significantly positively correlated (r=0.238, P=0.039, while SIRT1 and Survivin expression status were not

Prostatic adenocarcinoma with osseous metastases in a dog

International Nuclear Information System (INIS)

Lee-Parritz, D.E.; Lamb, C.R.

1988-01-01

Bone scintigraphy was used to diagnose osseous metastasis of prostatic adenocarcinoma in a 10-year-old dog with neck pain and ataxia and a large, sensitive prostate gland. Although radiography revealed a normal spine, prostatic fluid cytologic and ultrasonographic findings were compatible with prostatitis or neoplasia. Scintigraphic hot spots were seen in the axial skeleton, ribs, pelvis, humerus, and femur and corresponded to sites of metastatic prostatic adenocarcinoma

Technetium-99m sestamibi uptake in human breast carcinoma cell lines displaying glutathione-associated drug-resistance

International Nuclear Information System (INIS)

Kabasakal, L.; Oezker, K.; Hayward, M.; Akansel, G.; Griffith, O.; Isitman, A.T.; Hellman, R.; Collier, D.

1996-01-01

An in vitro study was designed to evaluate the uptake of sestamibi (MIBI) in P-glycoprotein (Pgp) and glutathione-associated (GSH) multidrug-resistant (MDR) cell lines. MIBI uptake was studied in various human breast carcinoma cell lines, i.e. in wild-type (MCF7/wt) cells, in adriamycin-resistant (MCF7/adr) cells which express Pgp and in melphalan-resistant (MCF7/mph) cells with increased levels of GSH. The effects of buthiomine sulphoximine (BSO) and verapamil on MIBI uptake were also studied in the MCF7/mph and MCF7/adr cells respectively. The cells were incubated for 1 h with a dose of 0.1 MBq thallium-201 and technetium-99m MIBI. Both BIBI and 201 Tl uptakes were higher for MCF7/mph cells than for the other cells studied. The mean MIBI uptake in MCF7/adr cells was significantly lower than that in MCF7/wt cells (1.9%±0.5% vs 3.1%.0.6%; P 0.1). This study suggests that the uptake of MIBI is not diminished by glutathione-associated drug resistance and that MIBI uptake in a tumour sample does not necessarly indicate that a cancer is sensitive to drugs. (orig.)

Management of Adenocarcinoma In Situ of Cervix in Pregnancy

Directory of Open Access Journals (Sweden)

Alireza Abidi

2008-03-01

Full Text Available Adenocarcinoma in situ is one of the premalignant lesions of the cervix and its incidence is believed to be increasing while the pathogenesis of the disease is not clearly understood. Management of Adenocarcinoma in situ (AIS unlike carcinoma in situ (CIS has not been clearly described in the current literature. Here we describe conservative management and serial colposcopy of two pregnant women with adenocarcinoma in situ of the cervix. Both of the cases were diagnosed initially with abnormal Pap smears and were confirmed by colposcopic directed biopsy. None of the patients agreed with any invasive procedure during pregnancy and both of them were followed with serial colposcopy. None of the lesions showed any evidence of progression. All cases underwent cold knife cone biopsies in their postpartum period. Hysterectomy as the final treatment has been done in both cases with no evidence of progression of the disease during pregnancy. We concluded that adenocarcinoma in situ of the cervix during pregnancy could be managed conservatively with definite treatment postponed till after delivery.

Nanomedicine applications in the treatment of breast cancer: current state of the art

Directory of Open Access Journals (Sweden)

Wu D

2017-08-01

Full Text Available Di Wu, Mengjie Si, Hui-Yi Xue, Ho-Lun Wong Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, USA Abstract: Breast cancer is the most common malignant disease in women worldwide, but the current drug therapy is far from optimal as indicated by the high death rate of breast cancer patients. Nanomedicine is a promising alternative for breast cancer treatment. Nanomedicine products such as Doxil® and Abraxane® have already been extensively used for breast cancer adjuvant therapy with favorable clinical outcomes. However, these products were originally designed for generic anticancer purpose and not specifically for breast cancer treatment. With better understanding of the molecular biology of breast cancer, a number of novel promising nanotherapeutic strategies and devices have been developed in recent years. In this review, we will first give an overview of the current breast cancer treatment and the updated status of nanomedicine use in clinical setting, then discuss the latest important trends in designing breast cancer nanomedicine, including passive and active cancer cell targeting, breast cancer stem cell targeting, tumor microenvironment-based nanotherapy and combination nanotherapy of drug-resistant breast cancer. Researchers may get insight from these strategies to design and develop nanomedicine that is more tailored for breast cancer to achieve further improvements in cancer specificity, antitumorigenic effect, antimetastasis effect and drug resistance reversal effect. Keywords: nanomedicine, breast cancer, targeted delivery, drug therapy, drug resistance, tumor microenvironment 

Obesity-associated Breast Cancer: Analysis of risk factors.

Science.gov (United States)

Engin, Atilla

2017-01-01

Several studies show that a significantly stronger association is obvious between increased body mass index (BMI) and higher breast cancer incidence. Furthermore, obese women are at higher risk of all-cause and breast cancer specific mortality when compared to non-obese women with breast cancer. In this context, increased levels of estrogens due to excessive aromatization activity of the adipose tissue, overexpression of pro-inflammatory cytokines, insulin resistance, hyperactivation of insulin-like growth factors (IGFs) pathways, adipocyte-derived adipokines, hypercholesterolemia and excessive oxidative stress contribute to the development of breast cancer in obese women. While higher breast cancer risk with hormone replacement therapy is particularly evident among lean women, in postmenopausal women who are not taking exogenous hormones, general obesity is a significant predictor for breast cancer. Moreover, increased plasma cholesterol leads to accelerated tumor formation and exacerbates their aggressiveness. In contrast to postmenopausal women, premenopausal women with high BMI are inversely associated with breast cancer risk. Nevertheless, life-style of women for breast cancer risk is regulated by avoiding the overweight and a high-fat diet. Estrogen-plus-progestin hormone therapy users for more than 5 years have elevated risks of both invasive ductal and lobular breast cancer. Additionally, these cases are more commonly node-positive and have a higher cancer-related mortality. Collectively, in this chapter, the impacts of obesity-related estrogen, cholesterol, saturated fatty acid, leptin and adiponectin concentrations, aromatase activity, leptin and insulin resistance on breast cancer patients are evaluated. Obesity-related prognostic factors of breast cancer also are discussed at molecular basis.

Boron absorption imaging in rat lung colon adenocarcinoma metastases

Energy Technology Data Exchange (ETDEWEB)

Altieri, S [Dipartimento di Fisica Nucleare e Teorica Universita degli Studi di Pavia (Italy); Bortolussi, S [Dipartimento di Fisica Nucleare e Teorica Universita degli Studi di Pavia (Italy); Bruschi, P [Dipartimento di Fisica Nucleare e Teorica Universita degli Studi di Pavia (Italy); Fossati, F [Dipartimento di Fisica Nucleare e Teorica Universita degli Studi di Pavia (Italy); Vittor, K [Dipartimento di Fisica Nucleare e Teorica Universita degli Studi di Pavia (Italy); Nano, R [Dipartimento di Biologia Animale Universita degli Studi di Pavia (Italy); Facoetti, A [Dipartimento di Biologia Animale Universita degli Studi di Pavia (Italy); Chiari, P [Dipartimento di Fisica Nucleare e Teorica Universita degli Studi di Pavia (Italy); Bakeine, J [Dipartimento di Scienze Biomediche e Biotecnologie Universita degli Studi di Brescia (Italy); Clerici, A [Dipartimento di Chirurgia Universita degli Studi di Pavia (Italy); Ferrari, C [Dipartimento di Chirurgia Universita degli Studi di Pavia (Italy); Salvucci, O [Dipartimento di Scienze Biomediche e Biotecnologie Universita degli Studi di Brescia (Italy)

2006-05-15

Given the encouraging results from our previous work on the clinical application of BNCT on non-resectable, chemotherapy resistant liver metastases, we explore the possibility to extend our technique to lung metastases. A fundamental requirement for BNCT is achieving higher {sup 10}B concentrations in the metastases compared to those in healthy tissue. For this reason we developed a rat model with lung metastases in order to study the temporal distribution of {sup 10}B concentration in tissues and tumoral cells. Rats with induced lung metastases from colon adenocarcinoma were sacrificed two hours after intraperitoneal Boronphenylalanine infusion. The lungs were harvested, frozen in liquid nitrogen and subsequently histological sections underwent neutron autoradiography in the nuclear reactor Triga Mark II, University of Pavia. Our findings demonstrate higher Boron uptake in tumoral nodules compared to healthy lung parenchyma 2 hours after Boronphenylalanine infusion.

Heavy resistance training and lymphedema

DEFF Research Database (Denmark)

Bloomquist, Kira; Karlsmark, Tonny; Christensen, Karl Bang

2014-01-01

BACKGROUND: There is limited knowledge regarding progressive resistance training during adjuvant chemotherapy and the risk of developing breast cancer-related lymphedema (BCRL). Furthermore, no studies have investigated the safety of resistance training with heavy loads (> 80% 1 repetition maximum......) in this population. 'Body and Cancer' is a six-week, nine-hour weekly, supervised, multimodal exercise intervention utilizing progressive resistance training with heavy loads for cancer patients undergoing chemotherapy. The purpose of the present study was to estimate the prevalence of BCRL in former participants......, and identify associations between progressive resistance training with heavy loads, and the development of BCRL. MATERIAL AND METHODS: This was a descriptive study. POPULATION: Women treated for breast cancer (n = 149), who had participated in the 'Body and Cancer' exercise intervention between 1 January 2010...