• What is ESR1?
  • ESR1 in Breast Cancer
  • Clinical Trials

ER (ESR1)

Gene and Protein Description

Estrogen receptor 1 (ESR1; also known as ER) is a gene that encodes an estrogen receptor protein, estrogen receptor α (ERα). ESR1 is located on chromosome 6 (Gosden et al. 1986). Estrogen receptor β (ERβ) is a second estrogen receptor that plays a separate role in cancer biology and is encoded by a different gene (Thomas and Gustafsson 2011). The symbol ER generally refers to ERα. The protein functions in hormone binding. Estrogen receptors are important for sexual development and reproductive function. Missense mutations, nonsense mutations, silent mutations, frameshift deletions, and in-frame deletions are observed in cancers such as endometrial cancer, intestinal cancer, and stomach cancer.

Steroid Signaling Pathway

ER is a member of the steroid hormone signaling pathway, a cell signaling pathway that functions in transcriptional activation and gene expression. The pathway includes, but is not limited to, the following proteins: androgen receptor (AR), estrogen receptor 1 (ESR1), progesterone receptor (PGR), LRP1B, and TSHR. The steroid hormone signaling pathway may be activated by steroid hormones, such as estrogen and progesterone, which bind to a steroid binding protein.

Estrogen is a steroid hormone that controls cellular processes such as cell division, growth, differentiation, and proliferation. Estrogen is converted from androgen precursors by the aromatase enzyme. Aromatase converts androgens to estrogens. Estrogen acts as a ligand and binds to the estrogen receptor (ER), which results in changes in gene expression and the activation of signaling pathways that regulate cell growth processes, such as the cell cycle control signaling pathway.

Oncogenic Alterations in ESR1

ER Expression

ESR1 Mutations

Related Pathways

Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2015. ER (ESR1). My Cancer Genome https://www.padiracinnovation.org/content/disease/breast-cancer/esr1/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

ER (ESR1) in Breast Cancer

Both ER expression and ESR1 mutations are observed in breast cancer. ER expression is common in primary breast cancers and occurs in 73–75% of invasive breast cancers (Nadji et al. 2005; Rhodes et al. 2000). ESR1 mutations are observed primarily in breast cancers that have developed resistance to antiestrogen therapy (Jeselsohn et al. 2014; Merenbakh-Lamin et al. 2013; Robinson et al. 2013; Toy et al. 2013).

ER-Positive Breast Cancer Sensitive to Endocrine Therapy

Endocrine therapies are a class of agents that target the estrogen receptor pathway. ER expression has been demonstrated to be predictive of benefit from tamoxifen, a member of the class of endocrine therapies known as selective estrogen receptor modulators (SERMs; Davies et al. 2012; EBCTCG 2011). Multi-year adjuvant treatment is currently the standard of care for early stage ER-positive breast cancer patients (NCCN 2013). For patients with ER-positive metastatic breast cancer, standard-of-care endocrine therapies include SERMs, estrogen agonists/antagonists, and aromatase inhibitors (NCCN 2013).

However, despite the demonstrated benefit, up to 50% of patients on first-line tamoxifen will eventually experience progressive disease (Nabholtz et al. 2000). In the first-line setting, a third of metastatic ER-positive breast cancer patients do not respond to aromatase inhibitors and the remainder will experience progression after an initial period of clinical response (Mouridsen et al. 2003; Nabholtz et al. 2000).

ER-Positive Breast Cancer Resistant to Endocrine Therapy

Resistance to endocrine therapy in ER-positive breast cancer is defined clinically as either primary or acquired (Bachelot et al. 2012).

Primary resistance is defined as

  • Recurrence either within adjuvant therapy or within 6–12 months of completion of adjuvant therapy
  • Disease progression < 6 months after treatment in the metastatic setting

Acquired resistance is defined as

  • Recurrence at least 6–12 months after completion of adjuvant therapy
  • Disease progression > 6 months after endocrine therapy initiated in the metastatic setting

A variety of mechanisms have been implicated in primary and acquired resistance to endocrine agents. Recently, there has been an increase in the number of clinical trials using novel targeted therapeutic strategies in endocrine resistant ER-positive breast cancer, with varying levels of evidence for improvement in outcomes (Table 1).


Table 1. Mechanisms of Resistance to Endocrine Agents.

Mechanism of Resistance Implications for Targeted Therapeutics
Primary Resistance
Receptor Tyrosine Kinase/Growth Factor Signaling Pathway
FGFR amplification Unknown at this timea
EGFR/ERBB2 mutations Unknown at this time
Cell Cycle Control Signaling Pathway
Cyclin D1 amplification or expression FDA approvedb
MYC amplification and overexpression Unknown at this time
Hormone Signaling Pathway
Loss of ERα Unknown at this time
Post-translational modification of ERα Unknown at this time
Expression of ER coactivation/corepression factors Unknown at this time
ESR1 mutations Unknown at this timec
Acquired Resistance
PI3K/AKT1/MTOR Signaling Pathway
PI3K/AKT/mTOR pathway activation FDA approvedd
Mitogen-Activated Protein (MAP) Kinase Pathway
MAPK/ERK pathway activation Unknown at this time
Hormone Signaling Pathway
ESR1 mutations Unknown at this timee
Other
Changes in the tumor microenvironment Unknown at this time

 

a Turner et al. (2010) showed in preclinical studies that FGFR amplification promoted resistance to endocrine therapies. FGFR-inhibitors dovitinib (NCT01528345) and nintedanib (NCT01658462) phase 2 trials are ongoing in patients with ER-positive and/or HER2-negative breast cancer.

b Alterations that cause the secondary signals in the ESR1 and CDK4/6 pathway to become activated include cyclin D1 amplification and CDK4/6 gain. Cyclin D1 is a transcriptional target of the estrogen receptor and is involved in regulating entry into the synthesis phase (S phase) of the cell cycle. Cyclin D1 binds to cyclin dependent kinases 4 and 6 (CDK4/6), and this complex phosphorylates the retinoblastoma (RB1) tumor suppressor protein. The RB1 protein releases the transcription factors required for S phase entry in the cell cycle. Frequencies of genetic alterations have been described in cyclin D1 (14%), CDK4/6 (3%), and RB1 (5%) in primary untreated ER-positive breast cancer samples (Cerami et al. 2012; Gao et al. 2013). Palbociclib is a kinase inhibitor targeting cyclin-dependent kinase 4 (CDK4) and 6 (CDK6) granted accelerated approval in combination with letrozole for the treatment of postmenopausal women with HER2-negative hormone receptor positive breast cancer for first-line or initial endocrine therapy. Accelerated approval of the drug combination was based on the results of the randomized phase 2 trial PALOMA-I. In this study, 84 patients received combination therapy. The study showed an improvement in progression-free survival by 10 months (FDA 2015; Finn et al. 2015).

c ESR1 mutations are less common in primary breast cancers at the time of diagnosis (TCGA 2012), but they have been identified in up to 55% of ER-positive metastatic breast cancers that have been previously treated with antiestrogens in retrospective data sets. In vitro laboratory studies suggest that breast tumor cells harboring ESR1 mutations may not be as sensitive to antiestrogen therapy as wild type ER-positive breast tumor cells (Jeselsohn et al. 2014; Merenbakh-Lamin et al. 2013; Robinson et al. 2013; Toy et al. 2013).

d Hyper-activation of PI3K signaling occurs in 28-47% of ER-positive breast cancer samples, and leads to estrogen-dependent or estrogen-independent ER activity (Miller et al. 2010, 2011). Dual inhibition of the ER signaling pathway and the PIK3CA/mTOR pathway is a parallel targeting strategy that has been supported clinically. The mTOR inhibitor everolimus combined with endocrine therapy exemestane is an FDA-approved strategy for ER-positive metastatic breast cancer resistant to letrozole or anastrozole. Approval of the drug combination was based on the results of the randomized phase 3 trial BOLERO-2. In this study, 485 patients received combination therapy. The study showed an improvement in progression-free survival by 4.6 months; however, there was no change in overall survival (Baselga et al. 2012; FDA 2012; Piccart et al. 2014; Yardley et al. 2013).

e Several different ESR1 mutations in the ligand-binding domain of ESR1 have been identified in tumor samples from patients with ER-positive metastatic breast cancer after treatment with antiestrogen therapy, but these are rare in primary untreated tumors (Robinson et al. 2013; Toy et al. 2013). In functional modeling studies, these mutations confer constitutive ligand-independent activation of ER transcription and ERα expression and may mediate antiestrogen resistance (Jeselsohn et al. 2014; Merenbakh-Lamin et al. 2013; Robinson et al. 2013; Toy et al. 2013).

Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2017. ER (ESR1) in Breast Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/breast-cancer/esr1/ (Updated February 16).

Last Updated: February 16, 2017

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