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ESR1 and breast

Nikiana Simigdala, Sunil Pancholi, Ricardo Ribas, Elizabeth Folkerd, Gianmaria Liccardi, Joanna Nikitorowicz-Buniak, Stephen R Johnston, Mitch Dowsett, Lesley-Ann Martin
BACKGROUND: Resistance to endocrine therapy remains a major clinical problem in the treatment of oestrogen-receptor positive (ER+) breast cancer. Studies show androgen-receptor (AR) remains present in 80-90% of metastatic breast cancers providing support for blockade of AR-signalling. However, clinical studies with abiraterone, which blocks cytochrome P450 17A1 (CYP17A1) showed limited benefit. METHODS: In order to address this, we assessed the impact of abiraterone on cell-viability, cell-death, ER-mediated transactivation and recruitment to target promoters...
July 11, 2018: British Journal of Cancer
Kendra Hodgkinson, Laura A Forrest, Nhung Vuong, Kenneth Garson, Bojana Djordjevic, Barbara C Vanderhyden
Estrogenic hormone replacement therapy increases the risk of developing ovarian cancer, and estrogen promotes tumour initiation and growth in mouse models of this disease. GREB1 (Growth regulation by estrogen in breast cancer 1) is an ESR1 (estrogen receptor 1)-upregulated protein which may mediate estrogen action. GREB1 knockdown prevents hormone-driven proliferation of several breast and prostate cancer cell lines and prolongs survival of mice engrafted with ovarian cancer cells, but its mechanism of action remains unclear...
July 4, 2018: Oncogene
Deisi L Braga, Sara T S Mota, Mariana A P Zóia, Paula M A P Lima, Priscila C Orsolin, Lara Vecchi, Júlio C Nepomuceno, Cristina R Fürstenau, Yara C P Maia, Luiz Ricardo Goulart, Thaise G Araújo
Breast Cancer (BC) encompasses numerous entities with different biological and behavioral characteristics, favored by tumor molecular complexity. Azadirachta indica (neem) presents phenolic compounds, indicating its potential as an antineoplastic compound. The present study aimed to evaluate the cellular response of MCF10, MCF7, and MDA-MB-231 breast cell lines to ethanolic extracts of neem leaves (EENL) obtained by dichloromethane (DCM) and ethyl acetate (EA) solvent. Extracts’ antiproliferative activities were evaluated against MCF 10A, MCF7, and MDA-MB-231 for 24 and 48 h using MTT assay...
June 26, 2018: International Journal of Molecular Sciences
Weijie Zhang, Mingming Wu, Qing-Yun Chong, Min Zhang, Xiao Zhang, Lan Hu, Yanghao Zhong, Pengxu Qian, Xiang Jun Kong, Sheng Tan, Gaopeng Li, Keshuo Ding, Peter E Lobie, Tao Zhu
The dysregulation of miRNAs has been increasingly recognized as a critical mediator of cancer development and progression. Here we show that frequent deletion of the MIR135A1 locus is associated with poor prognosis in primary breast cancer. Forced expression of miR-135a decreased breast cancer progression, whilst inhibition of miR-135a with a specific miRNA sponge elicited opposing effects, suggestive of a tumor suppressive role of miR-135a in breast cancer. Estrogen receptor alpha (ERα) bound the promoter of MIR135A1 for its transcriptional activation, whereas tamoxifen treatment inhibited expression of miR-135a in ERα+ breast cancer cells...
June 26, 2018: Cancer Research
Nur Izyani Kamaruzman, Snigdha Tiash, Maeirah Ashaie, Ezharul Hoque Chowdhury
Breast cancer, the second leading cause of female deaths worldwide, is usually treated with cytotoxic drugs, accompanied by adverse side-effects, development of chemoresistance and relapse of disease condition. Survival and proliferation of the cancer cells are greatly empowered by over-expression or over-activation of growth factor receptors and anti-apoptotic factors. Identification of these key players that cross-talk to each other, and subsequently, knockdown with their respective siRNAs in a synchronous manner could be a promising approach to precisely treat the cancer...
June 22, 2018: Biomedicines
Samantha M Carlisle, David W Hein
The expression levels of estrogen receptor 1 (ESR1), arylamine N‑acetyltransferase 1 (NAT1), and arylamine N‑acetyltransferase 2 (NAT2) are implicated in breast cancer; however, their co-expression profiles in normal breast tissue, primary breast tumors and established breast cancer cell lines are undefined. NAT1 expression is widely reported to be associated with ESR1 expression and is frequently investigated in breast cancer etiology. Furthermore, the NAT2 phenotype has been reported to modify breast cancer risk in molecular epidemiological association studies...
August 2018: International Journal of Oncology
Mónica Sierra-Martinez, Leticia Hernández-Cadena, José Rubén García-Sánchez, Gustavo Acosta-Altamirano, Carmen Palacios-Reyes, Patricia García Alonso-Themann, Liliana García-Ortiz, Laura Itzel Quintas-Granados, Octavio Daniel Reyes-Hernández
Context: Several factors contribute to the increase in breast cancer (BC) incidence, such as lifetime exposure to estrogen, early menarche and older ages at first birth, menopause, and the increased prevalence of postmenopausal obesity. In fact, there is an association between an increased BC risk and elevated estrogen levels, which may be involved in carcinogenesis via the estrogen receptor alpha (ERα) encoded by the ESR1 gene. Interestingly, there is an antagonistic relationship between ERα and the aryl hydrocarbon receptor (AhR) in BC cells...
April 2018: Journal of Cancer Research and Therapeutics
Ricardo Ribas, Sunil Pancholi, Aradhana Rani, Eugene Schuster, Stephanie K Guest, Joanna Nikitorowicz-Buniak, Nikiana Simigdala, Allan Thornhill, Francesca Avogadri-Connors, Richard E Cutler, Alshad S Lalani, Mitch Dowsett, Stephen R Johnston, Lesley-Ann Martin
BACKGROUND: Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER+ ) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed...
June 8, 2018: Breast Cancer Research: BCR
Swati Gupta, Navin R Mani, Daniel E Carvajal-Hausdorf, Veerle Bossuyt, Kenneth Ho, Jodi Weidler, Wendy Wong, Brian Rhees, Michael Bates, David L Rimm
An on-demand, closed RT-qPCR, the GeneXpert (GX) system, has the potential to provide biomarker information in low-resourced settings and elsewhere. We used this system with a research use only version of the Breast Cancer STRAT4 cartridge that measures the mRNA expression levels of ERBB2, ESR1, PGR, and MKi67. Here we evaluated the impact of non-macrodissected (non m-d) versus macrodissected (m-d) samples using STRAT4 on formalin-fixed, paraffin-embedded (FFPE) core needle biopsies. Two cohorts were assessed: (1) 60 FFPE infiltrating ductal carcinoma (IDCA) cases and (2) 20 FFPE IDCA cases with ductal carcinoma in situ (DCIS) with a range of HER2 expression as determined by clinical immunohistochemistry and fluorescence in situ hybridization (IHC/FISH)...
June 1, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
Phoebe Ann, Brandon-Luke L Seagle, Arunima Shilpi, Manoj Kandpal, Shohreh Shahabi
Objective: Tumor expression of Anterior Gradient 2 ( AGR2 ), an endoplasmic reticulum protein disulfide isomerase, was associated with decreased breast cancer survival. We aimed to validate the association of tumor AGR2 mRNA expression with disease-specific survival (DSS) and identify differentially expressed signaling pathways between high and low AGR2 expression tumor groups. Methods: Primary tumor mRNA expression data from the METABRIC study was used to evaluate AGR2 expression as a prognostic factor for DSS while adjusting for survival-determining confounders using Cox proportional-hazards regression...
May 1, 2018: Oncotarget
Fritz F Parl, Philip S Crooke, W Dale Plummer, William D Dupont
BACKGROUND: Estrogens are a prime risk factor for breast cancer yet their causal relation to tumor formation remains uncertain. A recent study of 560 breast cancers identified 82 genes with 916 point mutations as drivers in the genesis of this malignancy. Since estrogens play a major role in breast cancer development and are also known to regulate the expression of numerous genes, we hypothesize that the 82 driver genes are likely to be influenced by estrogens, such as 17ß-estradiol (E2), and the estrogen receptor, ESR1 (ERα)...
May 22, 2018: Cancer Epidemiology, Biomarkers & Prevention
Azadeh Nasrazadani, Roby A Thomas, Steffi Oesterreich, Adrian V Lee
In recent decades, breast cancer has become largely manageable due to successes with hormone receptor targeting. Hormone receptor-positive tumors have favorable outcomes in comparison to estrogen receptor (ESR1, ER)/progesterone receptor-negative tumors given the targetable nature of these tumors, as well as their inherently less aggressive character. Nonetheless, treatment resistance is frequently encountered due to a variety of mechanisms, including ESR1 mutations and loss of ER expression. A new era of precision medicine utilizes a range of methodologies to allow real-time analysis of individual genomic signatures in metastases and liquid biopsies with the goal of finding clinically actionable targets...
2018: Frontiers in Oncology
Violette Allouchery, Ludivine Beaussire, Anne Perdrix, David Sefrioui, Laetitia Augusto, Cécile Guillemet, Nasrin Sarafan-Vasseur, Frédéric Di Fiore, Florian Clatot
BACKGROUND: Detection of circulating ESR1 mutations is associated with acquired resistance to aromatase inhibitor (AI) in metastatic breast cancer. Until now, the presence of circulating ESR1 mutations at the end of adjuvant treatment by AI in early breast cancer had never been clearly established. In this context, the aim of the present study was to evaluate the circulating ESR1 mutation frequency at the end of adjuvant treatment and after relapse. METHODS: This monocentric retrospective study was based on available stored plasmas and included all early breast cancer patients who completed at least 2 years of AI adjuvant treatment and experienced a documented relapse after the end of their treatment...
May 16, 2018: Breast Cancer Research: BCR
Sandra Lettlova, Veronika Brynychova, Jan Blecha, David Vrana, Magdalena Vondrusova, Pavel Soucek, Jaroslav Truksa
BACKGROUND/AIMS: MiRNA-301a-3p is an oncogenic miRNA whose expression is associated with tumor development, metastases and overall poor prognosis. Estrogen receptor α (ERα) is one of the estrogen hormone-activated transcription factors, which regulates a large number of genes and is involved in the mammary gland development. Expression of ERα is considered to be a good indicator for endocrine therapy and breast cancer survival. Loss of ERα in breast cancer patients indicates invasiveness and poor prognosis...
2018: Cellular Physiology and Biochemistry
Vincent Hanoux, Judith Eguida, Emmanuelle Fleurot, Jérôme Levallet, Pierre-Jacques Bonnamy
The loss of estrogen receptor α (ERα) expression in breast cancer constitutes a major hallmark of tumor progression to metastasis and is generally correlated to a strong increase in Hyaluronic Acid (HA) turnover. The aim of our study was to search for a putative link between these two major events of breast cancer progression in the estrogen receptor-positive (ER+) MCF7 breast cancer cell line. The increase in HA turnover was performed by stable overexpression of the standard CD44 (CD44S) isoform and also by treatment with exogenous Hyaluronidase (Hyal) to allow an increase in HA catabolism...
May 15, 2018: Molecular and Cellular Endocrinology
Leah A Gates, Guowei Gu, Yue Chen, Aarti D Rohira, Jonathan T Lei, Ross A Hamilton, Yang Yu, David M Lonard, Jin Wang, Shu-Ping Wang, David G Edwards, Philip F Lavere, Jiangyong Shao, Ping Yi, Antrix Jain, Sung Yun Jung, Anna Malovannaya, Shunqiang Li, Jieya Shao, Robert G Roeder, Matthew J Ellis, Jun Qin, Suzanne A W Fuqua, Bert W O'Malley, Charles E Foulds
Approximately 75% of breast cancers are estrogen receptor alpha (ERα)-positive and are treatable with endocrine therapies, but often patients develop lethal resistant disease. Frequent mutations (10-40%) in the ligand-binding domain (LBD) codons in the gene encoding ERα (ESR1) have been identified, resulting in ligand-independent, constitutively active receptors. In addition, ESR1 chromosomal translocations can occur, resulting in fusion proteins that lack the LBD and are entirely unresponsive to all endocrine treatments...
May 11, 2018: Oncogene
Sasha M Pejerrey, Derek Dustin, Jin-Ah Kim, Guowei Gu, Yassine Rechoum, Suzanne A W Fuqua
After nearly 20 years of research, it is now established that mutations within the estrogen receptor (ER) gene, ESR1, frequently occur in metastatic breast cancer and influence response to hormone therapy. Though early studies presented differing results, sensitive sequencing techniques now show that ESR1 mutations occur at a frequency between 20 and 40% depending on the assay method. Recent studies have focused on several "hot spot mutations," a cluster of mutations found in the hormone-binding domain of the ESR1 gene...
May 7, 2018: Hormones & Cancer
Piera Rizzolo, Valentina Silvestri, Virginia Valentini, Veronica Zelli, Ines Zanna, Giovanna Masala, Simonetta Bianchi, Domenico Palli, Laura Ottini
Male breast cancer (MBC) is a rare disease. Due to its rarity, MBC research and clinical approach are mostly based upon data derived from female breast cancer (FBC). Increasing evidence indicate that on molecular level MBC may be an heterogeneous disease different from FBC. In order to investigate whether epigenetic signatures could define molecular subgroups of MBCs, we performed promoter methylation analysis of genes involved in signal transduction and hormone signalling in BRCA1/2 mutation-positive and -negative MBCs...
April 13, 2018: Oncotarget
G N Hortobagyi, S M Stemmer, H A Burris, Y S Yap, G S Sonke, S Paluch-Shimon, M Campone, K Petrakova, K L Blackwell, E P Winer, W Janni, S Verma, P Conte, C L Arteaga, D A Cameron, S Mondal, F Su, M Miller, M Elmeliegy, C Germa, J O'Shaughnessy
Background: The phase III MONALEESA-2 study demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for first-line ribociclib plus letrozole versus placebo plus letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Here we report updated efficacy and safety data, together with exploratory biomarker analyses, from the MONALEESA-2 study. Patients and methods: A total of 668 postmenopausal women with HR+, HER2- recurrent/metastatic breast cancer were randomized (1:1; stratified by presence/absence of liver and/or lung metastases) to ribociclib (600 mg/day; 3-weeks-on/1-week-off; 28-day treatment cycles) plus letrozole (2...
April 27, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Zhengyan Kan, Ying Ding, Jinho Kim, Hae Hyun Jung, Woosung Chung, Samir Lal, Soonweng Cho, Julio Fernandez-Banet, Se Kyung Lee, Seok Won Kim, Jeong Eon Lee, Yoon-La Choi, Shibing Deng, Ji-Yeon Kim, Jin Seok Ahn, Ying Sha, Xinmeng Jasmine Mu, Jae-Yong Nam, Young-Hyuck Im, Soohyeon Lee, Woong-Yang Park, Seok Jin Nam, Yeon Hee Park
Breast cancer (BC) in the Asia Pacific regions is enriched in younger patients and rapidly rising in incidence yet its molecular bases remain poorly characterized. Here we analyze the whole exomes and transcriptomes of 187 primary tumors from a Korean BC cohort (SMC) enriched in pre-menopausal patients and perform systematic comparison with a primarily Caucasian and post-menopausal BC cohort (TCGA). SMC harbors higher proportions of HER2+ and Luminal B subtypes, lower proportion of Luminal A with decreased ESR1 expression compared to TCGA...
April 30, 2018: Nature Communications
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