Activating ESR1 mutations in hormone-resistant metastatic breast cancer
Dan R. Robinson,Yi-Mi Wu,Pankaj Vats,Fengyun Su,Robert J. Lonigro,Xuhong Cao,Shanker Kalyana-Sundaram,Rui Wang,Yu Ning,Lynda Hodges,Amy Gursky,Javed Siddiqui,Scott A. Tomlins,Sameek Roychowdhury,Kenneth J. Pienta,Scott Y. H. Kim,J. Scott Roberts,James M. Rae,Catherine Van Poznak,Daniel F. Hayes,Rashmi Chugh,Lakshmi P. Kunju,Moshe Talpaz,Anne F. Schott,Arul M. Chinnaiyan +24 more
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Five new LBD-localized ESR1 mutations identified here were shown to result in constitutive activity and continued responsiveness to anti-estrogen therapies in vitro, suggesting that activating mutations in E SR1 are a key mechanism in acquired endocrine resistance in breast cancer therapy.Abstract:
Arul Chinnaiyan and colleagues report the results of prospective clinical sequencing of 11 estrogen receptor–positive metastatic breast cancers. They identify ESR1 mutations affecting the ligand-binding domain in six hormone-resistant metastatic breast cancers and show that the mutant estrogen receptors are constitutively active and continue to be responsive to anti-estrogen therapies in vitro. Breast cancer is the most prevalent cancer in women, and over two-thirds of cases express estrogen receptor-α (ER-α, encoded by ESR1). Through a prospective clinical sequencing program for advanced cancers, we enrolled 11 patients with ER-positive metastatic breast cancer. Whole-exome and transcriptome analysis showed that six cases harbored mutations of ESR1 affecting its ligand-binding domain (LBD), all of whom had been treated with anti-estrogens and estrogen deprivation therapies. A survey of The Cancer Genome Atlas (TCGA) identified four endometrial cancers with similar mutations of ESR1. The five new LBD-localized ESR1 mutations identified here (encoding p.Leu536Gln, p.Tyr537Ser, p.Tyr537Cys, p.Tyr537Asn and p.Asp538Gly) were shown to result in constitutive activity and continued responsiveness to anti-estrogen therapies in vitro. Taken together, these studies suggest that activating mutations in ESR1 are a key mechanism in acquired endocrine resistance in breast cancer therapy.read more
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FOXA1 levels are decreased in pleural breast cancer metastases after adjuvant endocrine therapy, and this is associated with poor outcome.
Willemijne A. M. E. Schrijver,Karianne Schuurman,Annelot van Rossum,Marjolein Droog,Carmen Jerónimo,Sofia Salta,Rui Henrique,Jelle Wesseling,Cathy B. Moelans,Sabine C. Linn,Sabine C. Linn,Michel M. van den Heuvel,Paul J. van Diest,Wilbert Zwart,Wilbert Zwart +14 more
TL;DR: Divergent clinical correlations are shown of the two ERα pioneer factors FOXA1 and GATA3 in metastatic breast cancer, where endocrine therapy resistance was associated with decreased FoxA1 levels in pleural metastases.
Journal ArticleDOI
A guide to PIN1 function and mutations across cancers
Maguie El Boustani,Lucia De Stefano,Isabella Caligiuri,Nayla Mouawad,Carlotta Granchi,Vincenzo Canzonieri,Tiziano Tuccinardi,Antonio Giordano,Flavio Rizzolio +8 more
TL;DR: The role ofPIN1 in cancer and the regulation of PIN1 expression is reviewed, and the single nucleotide polymorphisms, and mutations in PIN1 gene associated with cancer are cataloged and a 3D model of the protein is provided to localize the mutated residues.
Journal ArticleDOI
The deubiquitinating enzyme USP15 stabilizes ERα and promotes breast cancer progression.
Xiaohong Xia,Chuyi Huang,Yuning Liao,Yuan Liu,Jinchan He,Zhenlong Shao,Tumei Hu,Cuifu Yu,Lili Jiang,Jinbao Liu,Hongbiao Huang +10 more
TL;DR: In this paper, the deubiquitinase USP15 was identified as a novel protector for preventing ERα degradation and a critical driver for breast cancer progression, which not only provided a novel treatment for overcoming resistance to endocrine therapy, but also represent a therapeutic strategy on ERα protein degradation by targeting USP 15-ERα axis.
Journal ArticleDOI
Early Enrichment of ESR1 Mutations and the Impact on Gene Expression in Presurgical Primary Breast Cancer Treated with Aromatase Inhibitors.
Mariana Ferreira Leal,Mariana Ferreira Leal,Ben P. Haynes,Eugene Schuster,Belinda Yeo,M Afentakis,Lila Zabaglo,Lila Zabaglo,Vera Martins,Richard Buus,Andrew Dodson,Maggie C.U. Cheang,Ian E. Smith,Ian E. Smith,Lesley-Ann Martin,Mitch Dowsett,Mitch Dowsett +16 more
TL;DR: Ligand-independent ER signaling, as a result of ESR1 mutation or reduced ER dependence, identified after extended NAI therapy, can guide early selection of patients who would benefit from combination therapy.
Journal ArticleDOI
Biomarkers of Everolimus Sensitivity in Hormone Receptor-Positive Breast Cancer
Zongbi Yi,Fei Ma +1 more
TL;DR: Large-scale clinical studies are needed to identify biomarkers of efficacy and resistance to everolimus, a mTOR inhibitor shown to increase the efficacy of endocrine therapy and overcome resistance to endocrine therapies.
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