The Nuclear Receptor, RORγ, Regulates Pathways Necessary for Breast Cancer Metastasis

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• RORγ (Retinoid-related Orphan Receptor gamma) expression is reduced in estrogen receptor-negative (ER-ve) breast cancer, with higher levels correlating with improved outcomes.
• The specific mechanisms by which RORγ suppresses breast carcinogenesis remain largely unknown.

Purpose of the Study:

• To elucidate the RORγ-dependent molecular mechanisms that repress breast cancer initiation and progression.
• To investigate the role of RORγ in regulating key oncogenic pathways and DNA repair in breast cancer.

Main Methods:

• Analysis of RORγ expression in breast cancer cohorts, correlating it with subtype, histological grade, and drivers of carcinogenesis.
• Integration of RNA-sequencing (RNA-seq) and Chromatin Immunoprecipitation-chip (ChIP-chip) data to identify RORγ-regulated genes.
• Pharmacological studies using RORγ agonists and inverse agonists in breast cancer cell lines.

Main Results:

• RORγ expression is decreased in basal-like breast cancers and inversely correlated with tumor grade.
• RORγ negatively regulates the transforming growth factor-beta (TGF-β)/epithelial-mesenchymal transition (EMT) and mammary stem cell (MaSC) pathways, while positively regulating DNA repair.
• RORγ regulates genes in TGF-β/EMT, DNA repair, and MaSC pathways, including the non-coding RNA LINC00511.
• RORγ agonist treatment suppressed breast cancer cell viability, migration, EMT, and mammosphere formation.
• RORγ inverse agonist treatment induced TGF-β/EMT signaling.

Conclusions:

• RORγ acts as a tumor suppressor in breast cancer by inhibiting critical oncogenic pathways and enhancing DNA repair.
• Pharmacological activation of RORγ demonstrates therapeutic potential for breast cancer treatment.