Preferential estrogen receptor β ligands reduce Bcl-2 expression in hormone-resistant breast cancer cells to increase...

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Acquired resistance to SERM and SERD is a major clinical issue in ER(+) breast cancer treatment.
• Estrogen receptor (ER) subtypes ERα and ERβ have opposing roles in breast cancer proliferation.
• SERM resistance is linked to increased relative ERβ expression.

Purpose of the Study:

• To investigate the therapeutic potential of ERβ agonists in SERM/SERD-resistant breast cancer.
• To elucidate the molecular mechanisms underlying ERβ agonist activity in resistant cells.

Main Methods:

• Utilized SERM/SERD-resistant breast cancer cell lines.
• Administered ERβ agonists (WAY-20070, L17) and measured cell cycle progression (G2-M phase), protein/mRNA expression (cyclin D1, cyclin E, Bcl-2), and autophagy markers (LC3-I/II).
• Investigated the role of ERα, ERβ, and RIP140 recruitment to gene enhancers/promoters.
• Assessed the impact of combining ERβ agonists with autophagy inhibitors (chloroquine) and caspase inhibitors (Z-VAD-FMK).

Main Results:

• ERβ agonists significantly reduced G2-M phase and altered cyclin D1/E expression.
• ERβ agonists promoted ERα and ERβ recruitment to the Bcl-2 E2-response element, decreasing Bcl-2 expression in an ERβ-dependent manner.
• L17 recruited RIP140 to the Bcl-2 promoter in ERβ-overexpressing cells.
• ERβ agonists enhanced autophagic flux, indicated by increased LC3-I to LC3-II processing.
• Combined ERβ agonist and chloroquine treatment led to sub-G1 DNA accumulation, blocked by Z-VAD-FMK.

Conclusions:

• ERβ agonists can overcome SERM/SERD resistance in breast cancer by modulating cell cycle and apoptosis.
• ERβ-dependent mechanisms involving Bcl-2 regulation and enhanced autophagy are key to this effect.
• Combined therapy with ERβ agonists and autophagy inhibitors presents a novel treatment strategy for resistant breast cancers.