Regulation of Bcl-2 Family Proteins in Estrogen Receptor-Positive Breast Cancer and Their Implications in Endocrine Therapy.

Abstract

Simple SummaryBreast cancer is the leading cause of cancer-related deaths in the female population, with estrogen receptor (ER)-positive breast cancer accounting for two-third of incidents. Endocrine therapy has proven beneficial in treating ER-positive breast cancer. However, resistance acquired toward therapy remains a drawback in treatment. The activation of signaling pathways regulated by estrogen receptors has been linked with the evasion of cell death and drug resistance. An important role in regulating signals determining cell survival or death is assigned to the Bcl-2 family of proteins. Since the upregulation of anti-survival Bcl-2 proteins has been associated with decreased endocrine therapy efficacy and resistance, this review focuses on the molecular regulation of this group of proteins in ER-positive breast cancer and their implications in endocrine therapy treatment. Furthermore, advancements in the development of agents targeting the Bcl-2 family proteins have been overviewed, and their application in ER-positive breast cancer is presented.Estrogen receptor (ER)-positive breast cancer accounts for around two-thirds of breast cancer occurrences, with endocrine therapy serving as first-line therapy in most cases. Targeting estrogen signaling pathways, which play a central role in regulating ER+ breast cell proliferation and survival, has proven to improve patient outcomes. However, despite the undeniable advantages of endocrine therapy, a subset of breast cancer patients develop acquired or intrinsic resistance to ER-targeting agents, limiting their efficacy. The activation of downstream ER signaling pathways upregulates pro-survival mechanisms that have been shown to influence the response of cells to endocrine therapy. The Bcl-2 family proteins play a central role in cell death regulation and have been shown to contribute to endocrine therapy resistance, supporting the survival of breast cancer cells and enhancing cell death evasion. Due to the overexpression of anti-apoptotic Bcl-2 proteins in ER-positive breast cancer, the role of these proteins as potential targets in hormone-responsive breast cancer is growing in interest. In particular, recent advances in the development of BH3 mimetics have enabled their evaluation in preclinical studies with ER+ breast cancer models, and BH3 mimetics have entered early ER+ breast cancer clinical trials. This review summarizes the molecular mechanisms underlying the regulation of Bcl-2 family proteins in ER+ breast cancer. Furthermore, an overview of recent advances in research regarding the efficacy of BH3 mimetics in ER+ breast cancer has been provided.