Identification of estrogen receptor dimer selective ligands reveals growth-inhibitory effects on cells that...

Area of Science:

• Endocrinology
• Molecular Biology
• Oncology

Background:

• Estrogen receptors ERα and ERβ have opposing roles in cell proliferation, with ERα being proliferative and ERβ anti-proliferative.
• ERβ's anti-proliferative effects in ERα-positive cancers suggest potential for ERα/β heterodimer formation to oppose ERα's actions.
• The specific biological roles of ERα/β heterodimers remain largely uncharacterized.

Purpose of the Study:

• To identify compounds that selectively activate ERα/β heterodimers.
• To elucidate the biological function of ERα/β heterodimers in cancer cells.
• To investigate the co-expression of ERα and ERβ in human breast tumors.

Main Methods:

• A two-step, high-throughput small molecule screen was employed to identify ER transcriptional activity and ER dimer selectivity.
• Cell-based assays were used to test the effects of identified phytoestrogens on ERα/β heterodimer activation.
• Automated Quantitative Analysis (AQUA) was utilized to assess nuclear co-expression of ERα and ERβ in human breast tissue microarrays.

Main Results:

• Two phytoestrogens were identified that selectively activate ERα/β heterodimers at specific concentrations.
• ERα/β heterodimer-selective ligands demonstrated growth-inhibitory effects in breast and prostate cancer cells co-expressing ERα and ERβ.
• Human breast tumors exhibit co-expression of ERα and ERβ within the same cells, supporting the physiological relevance of heterodimer formation.

Conclusions:

• ERα/β heterodimers are growth-inhibitory in cancer cells that co-express both estrogen receptor isoforms.
• The co-expression of ERα and ERβ in tumors suggests that ERα/β heterodimer formation can occur under physiological and pathological conditions.
• Targeting ERα/β heterodimers represents a potential novel therapeutic strategy for cancers characterized by ERα and ERβ co-expression.