RETINOIC ACID RECEPTOR ALPHA MUTATIONS IN BREAST FIBROEPITHELIAL TUMORS: STRUCTURAL MECHANISMS AND DRUG DISCOVERY

Abstract

Breast fibroepithelial tumours are a heterogenous group of neoplasms which includes the highly common benign fibroadenomas to the rarer but malignant phyllodes tumours. Currently, there are limited treatment options for patients with these tumours. Recently, molecular profiling of these tumours have revealed high frequencies of retinoic acid receptor alpha mutations (RARA) across the fibroadenoma-phyllodes spectrum, indicating an emerging role of RARα aberrations in tumorigenesis that currently lacked understanding. RARΑ encodes for RARα, a nuclear receptor involved in retinoic acid signalling. Using extensive biochemical analyses, we observed that clinically-associated mutant RARα possess altered biochemical properties, rendering them ineffective transcriptional activators. Phyllodes tumour cells that express mutant RARα were unresponsive to retinoic acid treatment. Additionally, evidence suggesting that mutant RARα may confer a growth advantage to cells were observed. Taken together, this study contribute significantly to our current understanding of the mechanistic and biological mechanisms of mutant RARα in tumorigenesis.