Estrogen Receptor Mutations in Human Disease

Abstract

As early as the 1800s, the actions of estrogen have been implicated in the development and progression of breast cancer. The estrogen receptor (ER) was identified in the late 1950s and purified a few years later. However, it was not until the 1980s that the first ER was molecularly cloned, and in the mid 1990s, a second ER was cloned. These two related receptors are now called ERalpha and ERbeta, respectively. Since their discovery, much research has focused on identifying alterations within the coding sequence of these receptors in clinical samples. As a result, a large number of naturally occurring splice variants of both ERalpha and ERbeta have been identified in normal epithelium and diseased or cancerous tissues. In contrast, only a few point mutations have been identified in human patient samples from a variety of disease states, including breast cancer, endometrial cancer, and psychiatric diseases. To elucidate the mechanism of action for these variant isoforms or mutant receptors, experimental mutagenesis has been used to analyze the function of distinct amino acid residues in the ERs. This review will focus on ERalpha and ERbeta alterations in breast cancer.

Calmodulin-independent, agonistic properties of a peptide containing the calmodulin binding site of estrogen receptor α

“…The basic ε-amino group in these amino acids may be taken as responsible for their capacity to attract CaM. In this view, a missense point mutation causing the substitution of an arginine (R) for K 303 has been detected in hyperplastic and neoplastic breast lesions (Fuqua et al, 2000;Herynk and Fuqua, 2004;Conway et at lower E 2 concentration than the wild type receptor (Fuqua et al, 2000). Since arginine is more basic than lysine, one may surmise that the hyperactivity of the K303R mutant may be relevant to a higher ability to attract CaM, with as a consequence a facilitated conversion of the receptor into its activated form.…”

ERβ in breast cancer—Onlooker, passive player, or active protector?

“…The human ERα and ERβ genes have been isolated and each contains eight exons [1,5]. For both genes, alternative mRNA splicing, in which one or more coding exons are deleted, results in proteins with altered functional domains and either dominant-negative, dominant-positive, or null biological activity [reviewed in 5].…”

“…It has been hypothesized that dysregulated ER signaling may lead to abnormal cellular proliferation and survival, thus impacting development and progression of breast cancer. In breast tumors, ERα expression increases several-fold compared to normal tissue, with 75% of the cells expressing high levels of ERα in low-grade ductal carcinoma in situ (DCIS) and 30% of the cells expressing low levels of ERα in high-grade DCIS [5,62]. DCIS lesions have reduced ERβ expression compared with normal epithelium, with high-grade DCIS showing the most significant reduction [61].…”

“…For many years the presence of immunopositive ERα, alone or with expression of the E2-stimulated progesterone receptor (PR), was used as a criterion for treatment of patients with adjuvant antiestrogen therapy such as tamoxifen (TAM) or ICI 182,780 (fulvestrant/faslodex) [2][3][4][5], or recently, aromatase inhibitors that prevent E2 biosynthesis [6]. ERα is present in 40-70% of breast tumors; with ER+/PR+ tumors accounting for approximately 30-50% and ER +/PR-representing approximately 10-20% of all breast tumors [2][3][4].…”

E-cadherin mediates the aggregation of breast cancer cells induced by tamoxifen and epidermal growth factor

“…Thus, tamoxifen resistance occurs frequently in breast cancer patients and seriously limits treatment efficacy [42,44]. Multiple mechanisms have been proposed to contribute to the failure of tamoxifen therapy, including changes in the uptake or metabolism of tamoxifen, presence of ER mutants and ligand-independent ER activation, loss of expression of ER and/or cofactors and modification of the estrogen response element [42,45].…”