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 occurs in 73–75% of invasive breast cancers (Nadji et al. 2005; Rhodes et al. 2000).
- ER protein expression occurs in 40–76% of endometrial cancers (Merritt et al. 2010; Suthipintawong et al. 2008).
- ESR1 mutations are rare in primary breast cancers at the time of diagnosis (TCGA 2012).
- ESR1 mutations have been identified in up to 55% of ER-positive metastatic breast cancers that have been previously treated with antiestrogens in retrospective data sets (Jeselsohn et al. 2014; Merenbakh-Lamin et al. 2013; Robinson et al. 2013; Toy et al. 2013).
- Cases of ESR1 mutations in endometrial cancer have also been reported (TCGA 2013).