Activating ESR1 mutations in hormone-resistant metastatic breast cancer

被引：871

作者：

Robinson, Dan R. ^{[1
,2
]}

Wu, Yi-Mi ^{[1
,2
]}

Vats, Pankaj ^{[1
,2
]}

Su, Fengyun ^{[1
,2
]}

Lonigro, Robert J. ^{[1
,3
]}

Cao, Xuhong ^{[1
,4
]}

Kalyana-Sundaram, Shanker ^{[1
,2
]}

Wang, Rui ^{[1
,2
]}

Ning, Yu ^{[1
,2
]}

Hodges, Lynda ^{[1
]}

Gursky, Amy ^{[1
,2
]}

Siddiqui, Javed ^{[1
,2
]}

Tomlins, Scott A. ^{[1
,2
]}

Roychowdhury, Sameek ^{[5
]}

Pienta, Kenneth J. ^{[6
]}

Kim, Scott Y. ^{[7
]}

Roberts, J. Scott ^{[8
]}

Rae, James M. ^{[3
,9
]}

Van Poznak, Catherine H. ^{[9
]}

Hayes, Daniel F. ^{[9
]}

Chugh, Rashmi ^{[9
]}

Kunju, Lakshmi P. ^{[1
,2
]}

Talpaz, Moshe ^{[9
]}

Schott, Anne F. ^{[9
]}

Chinnaiyan, Arul M. ^{[1
,2
,3
,4
,10
,11
]}

机构：

[1] Univ Michigan, Sch Med, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA

[3] Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI USA

[4] Univ Michigan, Sch Med, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA

[5] Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA

[6] Johns Hopkins Univ, Sch Med, Brady Urol Inst, Baltimore, MD USA

[7] Univ Michigan, Ctr Bioeth & Social Sci Med, Ann Arbor, MI 48109 USA

[8] Univ Michigan, Dept Hlth Behav & Hlth Educ, Ann Arbor, MI 48109 USA

[9] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA

[10] Univ Michigan, Sch Med, Dept Urol, Ann Arbor, MI USA

[11] Univ Michigan, Ctr Computat Med & Biol, Ann Arbor, MI 48109 USA

来源：

NATURE GENETICS | 2013年 / 45卷 / 12期

关键词：

ESTROGEN-RECEPTOR; LIGAND-BINDING; AROMATASE INHIBITION; SOMATIC MUTATION; THERAPY; TAMOXIFEN; GENE; IDENTIFICATION; CONFORMATION; EXPRESSION;

D O I：

10.1038/ng.2823

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Breast cancer is the most prevalent cancer in women, and over two-thirds of cases express estrogen receptor-alpha (ER-alpha, 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 antiestrogen 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.

引用

页码：1446 / U197

页数：8

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