Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer

Holst, Frederik; Stahl, Phillip; Ruiz, Christian; Hellwinkel, Olaf; Jehan, Zeenath; Wendland, Marc; Lebeau, Annette; Terracciano, Luigi; Al‐Kuraya, Khawla S.; Jänicke, F.; Sauter, Guido; Simon, Ronald

doi:10.1038/ng2006

Cited by 333 publications

(355 citation statements)

References 18 publications

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“…This analysis identified numerous genes previously shown to be involved in breast cancer development and progression. It should be noted ESR1 expression levels did not correlate with copy number and no amplification of ESR1 gene was found, corroborating previous studies by our group [23] and others [48][49][50] and calling into question the results by Holst et al [51], who described ESR1 gene amplification in [20% of all breast cancers.…”

Section: Discussionsupporting

confidence: 86%

A high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines

Mackay

Tamber

Fenwick

et al. 2009

Breast Cancer Res Treat

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Section: Discussionsupporting

confidence: 86%

A high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines

Mackay

Tamber

Fenwick

et al. 2009

Breast Cancer Res Treat

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“…ESR1 locus gain, and its relevance in prognosis or prediction of response to endocrine therapies, is an area of open scientific debate. Two studies described a 11-20% frequency of amplification and improved prognosis for tumors showing this alteration, substantiating the importance of this biologic event on resistance to tamoxifen (Holst et al, 2007;Tomita et al, 2009). Nevertheless, other reports appear to contradict these findings (Adelaide et al, 2008;Brown et al, 2008;Horlings et al, 2008;Reis-Filho et al, 2008;Vincent-Salomon et al, 2008).…”

Section: Effect Of 17be2 Through Eramentioning

confidence: 87%

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

et al. 2010

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Endocrine therapies targeting the proliferative effect of 17b-estradiol through estrogen receptor a (ERa) are the most effective systemic treatment of ERa-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through molecular mechanisms that are not yet fully understood. The longterm estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERa. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were predicted to be influenced by transcription factors known to be involved in acquired resistance or cell proliferation (for example, interferon regulatory transcription factor 1 and E2F1, respectively) but, notably, not by canonical ERa transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)-to pS167-ERa were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERa-negative status, early response to letrozole and tamoxifen, and recurrence after tamoxifen treatment. In accordance with these profiles, MCF7-LTED cells showed increased sensitivity to inhibition of FGFR-mediated signaling with PD173074. This study provides mechanistic insight into acquired resistance to endocrine therapies of breast cancer and highlights a potential therapeutic strategy.

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“…41 A variety of mechanisms enhance ERa levels, including amplification of the ERa gene, although almost half of breast tumors with high ERa do not show such an amplification. 42 Mutation of caveolin-1 (ref. 43) and loss of expression of miR206 (ref.…”

Section: Discussionmentioning

confidence: 99%

RASSF1A inhibits estrogen receptor alpha expression and estrogen-independent signalling: implications for breast cancer development

et al. 2012

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The Ras association domain family 1 isoform A (RASSF1A) is a tumor suppressor whose inactivation is implicated in the development of many human cancers, including breast carcinomas. Little is known about the tumor-suppressive function of RASSF1A in breast tissue and whether its inactivation is mechanistically involved in the initiation and progression of breast tumors. Here, we show that RASSF1A inhibits breast cancer growth in vivo, and suppresses estrogen receptor (ERa) expression and function. Reconstitution of RASSF1A in MCF7 cells led to decreased ERa levels and reduced sensitivity to estrogen (E2). Concomitantly, we observed decreased expression of Id1 as well as the E2-responsive genes Bcl-2 and c-Myc that cooperatively contribute to the immortalization and transformation of breast epithelial cells. This downregulation was associated with induction of cell-cycle arrest and senescence that constitute early barriers to cancer initiation and progression. Knockdown of ERa showed that downregulation of ERa suffices to increase senescence and inhibit expression of Bcl-2, c-Myc and Id1. However, enforced expression of ERa only partially rescued RASSF1A-mediated growth inhibition and senescence, suggesting that suppression of ERa expression and activity is not the only mechanism by which RASSF1A inhibits growth and survival of breast cancer cells. Ectopic expression of Bcl-2, c-Myc and Id1 had little or no effect on RASSF1A-mediated growth arrest, indicating that RASSF1A acts dominantly over these oncogenes. Mechanistically, RASSF1A was found to suppress ERa expression through Akt1. It also transiently inhibited ERa-induced Ras-MAPK activity after exposure of cells to E2. Together, our data show that RASSF1A acts as a tumor suppressor in ERa þ mammary epithelial cells, in part through inhibiting ERa expression and activity. These findings suggest that RASSF1A has a key role in suppressing the transformation of human breast epithelial cells and ERa þ breast cancer initiation.

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Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer

Cited by 333 publications

References 18 publications

A high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines

A high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

RASSF1A inhibits estrogen receptor alpha expression and estrogen-independent signalling: implications for breast cancer development

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