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Esr1 mutation

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https://www.readbyqxmd.com/read/29666928/implications-of-esr1-mutations-in-hormone-receptor-positive-breast-cancer
#1
REVIEW
Tomás Reinert, Rodrigo Gonçalves, José Bines
Endocrine treatment resistance eventually develops during adjuvant and even more often during hormonal treatment for advanced breast cancer (ABC). An ESR1 gene mutation, which encodes for the estrogen receptor (ER) protein, is one of the potential mechanisms of therapy resistance. The ESR1 mutations result in conformational changes in the ER leading to subsequent estrogen-independent transcriptional activity. These mutations are found at a lower level in early stage when compared to metastatic BC, more often through selective pressure after aromatase inhibitor (AI) treatment...
April 17, 2018: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/29662653/plasma-thymidine-kinase-1-activity-predicts-outcome-in-patients-with-hormone-receptor-positive-and-her2-negative-metastatic-breast-cancer-treated-with-endocrine-therapy
#2
Martina Bonechi, Francesca Galardi, Chiara Biagioni, Francesca De Luca, Mattias Bergqvist, Magnus Neumüller, Cristina Guarducci, Giulia Boccalini, Stefano Gabellini, Ilenia Migliaccio, Angelo Di Leo, Marta Pestrin, Luca Malorni
The aim of this study was to investigate if thymidine kinase-1 (TK1), a well-known proliferation marker, could represent a valid circulating biomarker to identify hormone receptor positive (HR+)/HER2 negative (HER2neg) metastatic breast cancer (MBC) patients most likely to benefit from endocrine therapy (ET). We used the DiviTum™ assay to analyze TK1 activity in cell lysates of three HR+/HER2neg BC cell lines and in plasma of 31 HR+/HER2neg MBC patients receiving ET. Blood samples were collected at treatment initiation, after one month and at disease progression...
March 27, 2018: Oncotarget
https://www.readbyqxmd.com/read/29659014/single-cpg-hypermethylation-allele-methylation-errors-and-decreased-expression-of-multiple-tumor-suppressor-genes-in-normal-body-cells-of-mutation-negative-early-onset-and-high-risk-breast-cancer-patients
#3
Julia Böck, Silke Appenzeller, Larissa Haertle, Tamara Schneider, Andrea Gehrig, Jörg Schröder, Simone Rost, Beat Wolf, Claus R Bartram, Christian Sutter, Thomas Haaf
To evaluate the role of constitutive epigenetic changes in normal body cells of BRCA1/BRCA2-mutation negative patients, we have developed a deep bisulfite sequencing assay targeting the promoter regions of 8 tumor suppressor (TS) genes (BRCA1, BRCA2, RAD51C, ATM, PTEN, TP53, MLH1, RB1) and the estrogene receptor gene (ESR1), which plays a role in tumor progression. We analyzed blood samples of two breast cancer (BC) cohorts with early onset (EO) and high risk (HR) for a heterozygous mutation, respectively, along with age-matched controls...
April 16, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29600986/molecular-genetic-models-for-prognosis-of-development-of-tumors-of-reproductive-system-in-women-with-family-history-of-cancer
#4
O V Paliychuk, L Z Polishchuk, Z I Rossokha, V F Chekhun
AIM: To develop a prognostic molecular genetic model for assessing the risk of development of benign and malignant tumors of female reproductive organs (FRO) in patients from cancer-affected families. PATIENTS AND METHODS: The work presents the data on a comprehensive clinical examination of 210 women (90 patients with FRO cancer with aggregation of tumor pathology in families, 65 patients with benign pathology of FRO from cancer-affected families, 55 women - control group of healthy women without family history of cancer)...
March 2018: Experimental Oncology
https://www.readbyqxmd.com/read/29546395/uterine-function-in-the-mouse-requires-speckle-type-poz-protein
#5
Lan Hai, Maria M Szwarc, Bin He, David M Lonard, Ramakrishna Kommagani, Francesco J DeMayo, John P Lydon
Speckle-type poz protein (SPOP) is an E3-ubiquitin ligase adaptor for turnover of a diverse number of proteins involved in key cellular processes from chromatin remodeling, transcriptional regulation to cell signaling. Genomic analysis revealed that SPOP somatic mutations are found in a subset of endometrial cancers, suggesting that these mutations act as oncogenic drivers of this gynecologic malignancy. These studies also raise the question as to the role of wild type SPOP in normal uterine function. To address this question, we generated a mouse model (Spopd/d) in which SPOP is ablated in uterine cells that express the PGR...
March 13, 2018: Biology of Reproduction
https://www.readbyqxmd.com/read/29531247/high-sensitivity-assay-for-monitoring-esr1-mutations-in-circulating-cell-free-dna-of-breast-cancer-patients-receiving-endocrine-therapy
#6
Laura Lupini, Anna Moretti, Cristian Bassi, Alessio Schirone, Massimo Pedriali, Patrizia Querzoli, Roberta Roncarati, Antonio Frassoldati, Massimo Negrini
Approximately 70% of breast cancers (BCs) express estrogen receptor alpha (ERα) and are treated with endocrine therapy. However, the effectiveness of this therapy is limited by innate or acquired resistance in approximately one-third of patients. Activating mutations in the ESR1 gene that encodes ERα promote critical resistance mechanisms. Here, we developed a high sensitivity approach based on enhanced-ice-COLD-PCR for detecting ESR1 mutations. The method produced an enrichment up to 100-fold and allowed the unambiguous detection of ESR1 mutations even when they consisted of only 0...
March 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29522117/esr1-and-endocrine-therapy-resistance-more-than-just-mutations
#7
S Piscuoglio, C K Y Ng, B Weigelt, S Chandarlapaty, J S Reis-Filho
No abstract text is available yet for this article.
March 7, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29497091/early-circulating-tumor-dna-dynamics-and-clonal-selection-with-palbociclib-and-fulvestrant-for-breast-cancer
#8
Ben O'Leary, Sarah Hrebien, James P Morden, Matthew Beaney, Charlotte Fribbens, Xin Huang, Yuan Liu, Cynthia Huang Bartlett, Maria Koehler, Massimo Cristofanilli, Isaac Garcia-Murillas, Judith M Bliss, Nicholas C Turner
CDK4/6 inhibition substantially improves progression-free survival (PFS) for women with advanced estrogen receptor-positive breast cancer, although there are no predictive biomarkers. Early changes in circulating tumor DNA (ctDNA) level may provide early response prediction, but the impact of tumor heterogeneity is unknown. Here we use plasma samples from patients in the randomized phase III PALOMA-3 study of CDK4/6 inhibitor palbociclib and fulvestrant for women with advanced breast cancer and show that relative change in PIK3CA ctDNA level after 15 days treatment strongly predicts PFS on palbociclib and fulvestrant (hazard ratio 3...
March 1, 2018: Nature Communications
https://www.readbyqxmd.com/read/29492198/ubash3b-promotes-tamoxifen-resistance-and-could-be-negatively-regulated-by-esr1
#9
Ketao Jin, Huanrong Lan, Junyu Zhang, Jieqing Lv, Yuan Chen, Kang Yu, Wei Wang
Purpose: To explore the prognostic value of UBASH3B in ER+ breast cancer patients and explore potential molecular mechanisms. Materials and Methods: Datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were re-analyzed to explore the association between UBASH3B and the progression of ER+ breast cancer. Kaplan-Meier plot analysis with a total of 734 ER+ samples and Gene Set Enrichment Analysis with 632 samples were used in the study. Results: High expression of UBASH3B is negatively correlated with distant metastasis free survival (DMFS, P = 0...
February 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29462880/benzothiophenone-derivatives-targeting-mutant-forms-of-estrogen-receptor-%C3%AE-in-hormone-resistant-breast-cancers
#10
Kriti Singh, Ravi S N Munuganti, Nada Lallous, Kush Dalal, Ji Soo Yoon, Aishwariya Sharma, Takeshi Yamazaki, Artem Cherkasov, Paul S Rennie
Estrogen receptor-α positive (ERα⁺) breast cancers represent 75% of all invasive breast cancer cases, while de novo or acquired resistance to ER-directed therapy is also on the rise. Numerous factors contribute to this phenomenon including the recently-reported ESR1 gene mutations such as Y537S, which amplifies co-activator interactions with ERα and promotes constitutive activation of ERα function. Herein, we propose that direct targeting of the activation function-2 (AF2) site on ERα represents a promising alternative therapeutic strategy to overcome mutation-driven resistance in breast cancer...
February 15, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29438694/allele-specific-chromatin-recruitment-and-therapeutic-vulnerabilities-of-esr1-activating-mutations
#11
Rinath Jeselsohn, Johann S Bergholz, Matthew Pun, MacIntosh Cornwell, Weihan Liu, Agostina Nardone, Tengfei Xiao, Wei Li, Xintao Qiu, Gilles Buchwalter, Ariel Feiglin, Kayley Abell-Hart, Teng Fei, Prakash Rao, Henry Long, Nicholas Kwiatkowski, Tinghu Zhang, Nathanael Gray, Diane Melchers, Rene Houtman, X Shirley Liu, Ofir Cohen, Nikhil Wagle, Eric P Winer, Jean Zhao, Myles Brown
Estrogen receptor α (ER) ligand-binding domain (LBD) mutations are found in a substantial number of endocrine treatment-resistant metastatic ER-positive (ER+ ) breast cancers. We investigated the chromatin recruitment, transcriptional network, and genetic vulnerabilities in breast cancer models harboring the clinically relevant ER mutations. These mutants exhibit both ligand-independent functions that mimic estradiol-bound wild-type ER as well as allele-specific neomorphic properties that promote a pro-metastatic phenotype...
February 12, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29383109/landscape-of-genome-wide-age-related-dna-methylation-in-breast-tissue
#12
Min-Ae Song, Theodore M Brasky, Daniel Y Weng, Joseph P McElroy, Catalin Marian, Michael J Higgins, Christine Ambrosone, Scott L Spear, Adana A Llanos, Bhaskar V S Kallakury, Jo L Freudenheim, Peter G Shields
Despite known age-related DNA methylation (aDNAm) changes in breast tumors, little is known about aDNAm in normal breast tissues. Breast tissues from a cross-sectional study of 121 cancer-free women, were assayed for genome-wide DNA methylation. mRNA expression was assayed by microarray technology. Analysis of covariance was used to identify aDNAm's. Altered methylation was correlated with expression of the corresponding gene and with DNA methyltransferase protein DNMT3A, assayed by immunohistochemistry. Publically-available TCGA-BRCA data were used for replication...
December 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29344954/mixed-ductal-lobular-carcinomas-evidence-for-progression-from-ductal-to-lobular-morphology
#13
Amy E McCart Reed, Jamie R Kutasovic, Katia Nones, Jodi M Saunus, Leonard Da Silva, Felicity Newell, Stephen Kazakoff, Lewis Melville, Janani Jayanthan, Ana Cristina Vargas, Lynne E Reid, Jonathan Beesley, Xiao Qing Chen, Anne Marie Patch, D David Clouston, Alan Porter, Elizabeth Evans, John V Pearson, Georgia Chenevix-Trench, Margaret C Cummings, Nic Waddell, Sunil R Lakhani, Peter T Simpson
Mixed ductal-lobular carcinomas (MDL) display both ductal and lobular morphology, and are an archetypal example of intra-tumour morphological heterogeneity. The mechanisms underlying coexistence of these different morphologic entities are poorly understood, although theories include that these components either represent 'collision' of independent tumours or evolve from a common ancestor. We performed comprehensive clinico-pathological analysis of a cohort of 82 MDLs and found: i) MDLs more frequently co-exist with ductal carcinoma in situ (DCIS) than lobular carcinoma in situ (LCIS); ii) the E-cadherin-catenin complex was normal in the ductal component in 77...
January 18, 2018: Journal of Pathology
https://www.readbyqxmd.com/read/29306943/clinically-observed-estrogen-receptor-alpha-mutations-within-the-ligand-binding-domain-confer-distinguishable-phenotypes
#14
Shanhang Jia, Mark T Miedel, Marilyn Ngo, Ryan Hessenius, Ning Chen, Peilu Wang, Amir Bahreini, Zheqi Li, Zhijie Ding, Tong Ying Shun, Daniel M Zuckerman, D Lansing Taylor, Shannon L Puhalla, Adrian V Lee, Steffi Oesterreich, Andrew M Stern
OBJECTIVE: Twenty to fifty percent of estrogen receptor-positive (ER+) metastatic breast cancers express mutations within the ER ligand-binding domain. While most studies focused on the constitutive ER signaling activity commonly engendered by these mutations selected during estrogen deprivation therapy, our study was aimed at investigating distinctive phenotypes conferred by different mutations within this class. METHODS: We examined the two most prevalent mutations, D538G and Y537S, employing corroborative genome-edited and lentiviral-transduced ER+ T47D cell models...
2018: Oncology
https://www.readbyqxmd.com/read/29278418/aberrant-dna-methylation-is-associated-with-aggressive-clinicopathological-features-and-poor-survival-in-cutaneous-melanoma
#15
B de Unamuno Bustos, R Murria Estal, G Pérez Simó, J Simarro Farinos, C Pujol Marco, M Navarro Mira, V Alegre de Miquel, R Ballester Sánchez, V Sabater Marco, M Llavador Ros, S Palanca Suela, R Botella Estrada
BACKGROUND: Promoter methylation of tumor suppressor genes (TSGs) has recently been implicated in the pathogenesis of several types of cancer. Regarding melanoma, over a hundred genes that contribute to its pathogenesis have been identified to be aberrantly hypermethylated. This is a retrospective observational study that aims to analyze the prevalence of CpG island methylation in a series of primary melanoma, to identify the associations with the main clinicopathological features, and to explore the prognostic significance of methylation in melanoma survival...
December 26, 2017: British Journal of Dermatology
https://www.readbyqxmd.com/read/29248526/significant-alterations-of-the-novel-15-gene-signature-identified-from-macrophage-tumor-interactions-in-breast-cancer
#16
Rajshri Singh, Priya Dagar, Shyama Pal, Bhakti Basu, Bhavani S Shankar
BACKGROUND: Tumor microenvironment is composed of a largely altered extracellular matrix with different cell types. The complex interplay between macrophages and tumor cells through several soluble factors and signaling is an important factor in breast cancer progression. METHODS: We have extended our earlier studies on monocyte and macrophage conditioned medium (MϕCM) and have carried out proteomic analysis to identify its constituents as well as validation. The 8-gene signature identified through macrophage-breast cancer cell interactions was queried in cBioportal for bioinformatic analyses...
March 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29234250/are-we-ready-to-use-esr1-mutations-in-clinical-practice
#17
REVIEW
Rinath Jeselsohn
The recurrent ligand-binding domain ESR1 mutations are an important mechanism of endocrine resistance in estrogen receptor-positive (ER+) metastatic breast cancer. These mutations evolve under the selective pressure of endocrine treatments and are rarely found in treatment-naïve ER+ breast cancers. Preclinical studies showed that these mutations lead to ligand-independent activity facilitating resistance to aromatase inhibitors and relative resistance to tamoxifen and fulvestrant. Retrospective analyses of ESR1 mutations in baseline plasma circulating tumor DNA from clinical trials suggest that these mutations are prognostic of poor overall survival and predictive of resistance to aromatase inhibitors in metastatic disease...
October 2017: Breast Care
https://www.readbyqxmd.com/read/29233927/comprehensive-mutation-and-copy-number-profiling-in-archived-circulating-breast-cancer-tumor-cells-documents-heterogeneous-resistance-mechanisms
#18
Costanza Paoletti, Andi K Cani, Jose M Larios, Daniel H Hovelson, Kimberly Aung, Elizabeth P Darga, Emily M Cannell, Paul J Baratta, Chia-Jen Liu, David Chu, Maryam Yazdani, Allen R Blevins, Valeria Sero, Nahomi Tokudome, Dafydd G Thomas, Christina Gersch, Anne F Schott, Yi-Mi Wu, Robert Lonigro, Dan R Robinson, Arul M Chinnaiyan, Farideh Z Bischoff, Michael D Johnson, Ben H Park, Daniel F Hayes, James M Rae, Scott A Tomlins
Addressing drug resistance is a core challenge in cancer research, but the degree of heterogeneity in resistance mechanisms in cancer is unclear. In this study, we conducted next-generation sequencing (NGS) of circulating tumor cells (CTC) from patients with advanced cancer to assess mechanisms of resistance to targeted therapy and reveal opportunities for precision medicine. Comparison of the genomic landscapes of CTCs and tissue metastases is complicated by challenges in comprehensive CTC genomic profiling and paired tissue acquisition, particularly in patients who progress after targeted therapy...
February 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29192207/discovery-of-naturally-occurring-esr1-mutations-in-breast-cancer-cell-lines-modelling-endocrine-resistance
#19
Lesley-Ann Martin, Ricardo Ribas, Nikiana Simigdala, Eugene Schuster, Sunil Pancholi, Tencho Tenev, Pascal Gellert, Laki Buluwela, Alison Harrod, Allan Thornhill, Joanna Nikitorowicz-Buniak, Amandeep Bhamra, Marc-Olivier Turgeon, George Poulogiannis, Qiong Gao, Vera Martins, Margaret Hills, Isaac Garcia-Murillas, Charlotte Fribbens, Neill Patani, Zheqi Li, Matthew J Sikora, Nicholas Turner, Wilbert Zwart, Steffi Oesterreich, Jason Carroll, Simak Ali, Mitch Dowsett
Resistance to endocrine therapy remains a major clinical problem in breast cancer. Genetic studies highlight the potential role of estrogen receptor-α (ESR1) mutations, which show increased prevalence in the metastatic, endocrine-resistant setting. No naturally occurring ESR1 mutations have been reported in in vitro models of BC either before or after the acquisition of endocrine resistance making functional consequences difficult to study. We report the first discovery of naturally occurring ESR1Y537C and ESR1Y537S mutations in MCF7 and SUM44 ESR1-positive cell lines after acquisition of resistance to long-term-estrogen-deprivation (LTED) and subsequent resistance to fulvestrant (ICIR)...
November 30, 2017: Nature Communications
https://www.readbyqxmd.com/read/29166868/prevalence-of-esr1-e380q-mutation-in-tumor-tissue-and-plasma-from-japanese-breast-cancer-patients
#20
Takashi Takeshita, Yutaka Yamamoto, Mutsuko Yamamoto-Ibusuki, Aiko Sueta, Mai Tomiguchi, Keiichi Murakami, Yoko Omoto, Hirotaka Iwase
BACKGROUND: ESR1 mutations have attracted attention as a potentially important marker and treatment target in endocrine therapy-resistant breast cancer patients. The E380Q mutation, which is one of the ESR1 mutations, is associated with estradiol (E2) hypersensitivity, increased DNA binding to the estrogen response element, and E2-independent constitutive trans-activation activity, but its frequency in ESR1 mutations remains unknown. The present study aimed to investigate the E380Q mutation in comparison with the other representative ESR1 mutations...
November 22, 2017: BMC Cancer
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