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

Abstract

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.

Estrogen-dependent activation of NCOA3 couples with p300 and NF-κB to mediate antiapoptotic genes in ER-positive breast cancer cells

“…ER signaling mediates gene expression through classical and non-classical pathways [ 14 ]. In the classical pathway, β-estradiol (also called E2) binds to the ER, causing the conformational change of the ER and enabling its release from the heat shock protein complex [ 14 ].…”

“…ER signaling mediates gene expression through classical and non-classical pathways [ 14 ]. In the classical pathway, β-estradiol (also called E2) binds to the ER, causing the conformational change of the ER and enabling its release from the heat shock protein complex [ 14 ]. The ER translocates from the cytoplasm to the nucleus, where it coordinates with transcriptional coactivators or corepressors to regulate gene expression by binding to the estrogen response elements (ERE) [ 14 ].…”

“…In the classical pathway, β-estradiol (also called E2) binds to the ER, causing the conformational change of the ER and enabling its release from the heat shock protein complex [ 14 ]. The ER translocates from the cytoplasm to the nucleus, where it coordinates with transcriptional coactivators or corepressors to regulate gene expression by binding to the estrogen response elements (ERE) [ 14 ]. Moreover, the ER can also mediate gene expression by coordinating with different transcription factors, such as Activating Protein 1 (AP1), Specificity Protein 1 (SP1), and Nuclear Factor Kappa B (NF-κB) [ 14 ].…”

“…The ER translocates from the cytoplasm to the nucleus, where it coordinates with transcriptional coactivators or corepressors to regulate gene expression by binding to the estrogen response elements (ERE) [ 14 ]. Moreover, the ER can also mediate gene expression by coordinating with different transcription factors, such as Activating Protein 1 (AP1), Specificity Protein 1 (SP1), and Nuclear Factor Kappa B (NF-κB) [ 14 ]. Among the five antiapoptotic genes, three ( BCL2, BCL2A1, and MCL1 ) can be regulated by NF-κB in different types of cancer cells [ 15 – 17 ].…”

Design, Synthesis, and Biological Evaluation of Novel Amyl Ester Tethered Dihydroartemisinin‐Isatin Hybrids as Potent Anti‐Breast Cancer Agents

“…[5,6] Estrogen receptor (ER)-positive breast cancer is a major breast cancer subtype that comprises about two-thirds of breast cancer occurrences, and almost 20 % might relapse within 10-years after treatment. [7,8] Triple-negative breast cancer suffers from comparatively high rate of relapse, high rate of distant metastasis, and poor overall survival. [9,10] Chemotherapy plays an important role in fighting against breast cancer since application of chemotherapy generally reduces the risk of recurrence by about 30 % in patients with ER-positive breast cancer and triplenegative breast cancer.…”