An update of estrogen receptors on human disease

Estrogen receptors: how much do we know?

Key Points

Importance:

• Many physiological processes are influenced by estrogens and its receptors which includes ERα and ERβ. Given its widespread role in normal human physiology, estrogen is also associated with the development of a number of diseases.

Highlight:

• Estrogen is implicated in some diseases including breast cancer, ovarian cancer, colon cancer, prostate cancer, endometrial cancer, endometriosis, uterine leiomyomas and cardiovascular disease.

What's done here:

• This review provides a 5-year update of the studies regarding the influence of estrogens on some human cancers, endometriosis, fibroids, and cardiovascular disease.

Data:

• ERα status is a significant predictor of breast cancer prognosis, but the role of ERβ is less clear.
• In ovarian cancer, ERα expression is associated with progression-free survival, while the loss of ERβ expression correlates with shorter overall survival.
• Patient survival is associated with ERα expression in endometrial cancer.
• Both alterations of ERα and ERβ have roles in endometriosis pathogenesis.
• ERα appears vital in fibroids, but more studies are needed to understand the exact role.

Lay Summary

Estrogens and its receptors influence numerous human physiological processes. Two estrogen receptors exist, including estrogen receptor α (ERα) and ERβ. Hence, it is essential to elucidate the functions of these receptors in healthy and diseased states. This is particularly important for developing relevant therapeutics. This review highlights the more recent (5-year update) regarding the influence of estrogens on some human cancers (breast, ovarian, colon, prostate, endometrial), endometriosis, fibroids, and cardiovascular disease.

Breast cancer: ERα has been long determined as a prognostic marker for breast cancer, where anti-estrogen therapy can improve the survival. The role of ERβ in breast cancer is less clear and most likely independent of ERα.

Ovarian cancer: ERα expression is associated with progression-free survival and an indicator to select patients suitable for anti-hormonal therapy. Intriguingly, the loss of ERβ expression associates with shorter overall survival and suggests that its loss may be a feature of malignant transformation. Ovarian cancer risk is slightly related to ERα or ERβ single nucleotide polymorphism (SNPs) or altered methylation status.

Endometrial cancer: ERα expression is associated with patient survival. In uterine carcinosarcoma, the expression of ERα is suppressed while ERβ is elevated. Depending on ERα SNPs intronic variation, this may confer risk or protection to endometrial cancer.

Colon cancer: Both ERα and ERβ have been implicated, but ERβ is most likely a critical mediator. In the non-cancerous condition such as endometriosis, the alterations in both ERs have; thus with endometriosis pathogenesis. In fibroids, ERα appears to be the primary factor, although SNPs and methylation status data are needed to conclude.

While these clinical data on ERs are available, continual studies in ERs are essential to understanding the clinical response of endocrine therapy such ER agonists and antagonists for hormone-positive cancers and endometriosis. The currently available ER antagonists can have off-target effects, thus future research to define tissue-specific selective ER modulators will be useful. Specifically, information on the underlying mechanisms of selective ER modulators, their tissue selectivity and responses to estrogen may yield more effective therapeutics. Future detailed analyses on ERs interacting partners and post-translational modification may someday improve treatment strategies.