A Closer Look at Estrogen Receptor Mutations in Breast Cancer and Their Implications for Estrogen and Antiestrogen Responses

Abstract

Breast cancer (BC) is the most common cancer among women worldwide. More than 70% of BC cases express estrogen receptor alpha (ERα), a central transcription factor that stimulates the proliferation of breast cancer cells, usually in the presence of estrogen. While most cases of ER-positive BC initially respond to antiestrogen therapies, a high percentage of cases develop resistance to treatment over time. The recent discovery of mutated forms of ERα that result in constitutively active forms of the receptor in the metastatic-resistance stage of BC has provided a strong rationale for the development of new antiestrogens. These molecules targeting clinically relevant ERα mutants and a combination with other pharmacological inhibitors of specific pathways may constitute alternative treatments to improve clinical practice in the fight against metastatic-resistant ER-positive BC. In this review, we summarize the latest advances regarding the particular involvement of point mutations of ERα in endocrine resistance. We also discuss the involvement of synonymous ERα mutations with respect to co-translational folding of the receptor and ribosome biogenesis in breast carcinogenesis.

Keywords: breast cancer; endocrine resistance; estrogen receptor; mutation; receptor folding.

Figure 1

ERα activity through genomic and nongenomic actions. Genomic activity: ERα activation upon estrogen binding (E2) or after its phosphorylation by cellular kinases following growth factor (GF) receptor stimulation allows its release from heat shock proteins (HSPs). Then, ERα translocates into the nucleus, where it binds DNA by direct (through estrogen responsive elements, EREs) or indirect mechanisms (upon binding to other transcription factors, such as AP1 or SP1, that bind DNA through serum responsive elements, SREs). Nongenomic activity: Activated ERα interacts with cellular kinases (e.g., PI3K and Src), leading to signaling pathway stimulation involving AKT or MAPK, for example, eventually resulting in transcription factor (TF) activation. All these mechanisms induce transcriptional activation or repression of the regulation of cell fate.

Figure 2

(A) ERα is composed of 595 amino acids forming 6 domains, from A to F. Transcriptional activation function 1 (AF1) is localized in the N-terminal region of the receptor, whereas a second transactivation function (AF2) is generated at the C-terminus when conformational rearrangements take place. The C and E domains contain the DNA- and ligand-binding domains, respectively (DBD, LBD). Finally, the D domain is called the hinge region, which participates in conformational changes and protein/protein interactions and contains nuclear localization signals (NLS) [11]. (B) A schematic representation of ERα LBD (from the crystal structure 1GWR deposited in the Protein Data Bank) with the ligand-binding pocket (LBP) depicted.

Figure 3

Synonymous mutations (represented by a star) can modify translational speed by impacting various parameters, such as the mRNA structure and the stability or availability of cognate tRNAs. This can ultimately result in the alteration of protein conformation, affecting its expression, stability and function.