A Repressive Epigenetic Domino Effect Confers Susceptibility to Breast Epithelial Cell Transformation: Implications for Predicting Breast Cancer Risk

Abstract

Retinoic acid (RA) is a master epigenetic regulator that plays a pivotal role in both breast morphogenesis and development. Here, we show for the first time that RA, via the RA receptor α (RARα), epigenetically regulates in a concerted fashion the transcription of two RA-responsive genes, the RA receptor β2 (RARβ2) and the cellular retinol-binding protein 1 (CRBP1). Specifically, an impaired RA signal through RARα in human breast epithelial cells triggers a repressive epigenetic domino effect, involving first RARβ2 and second CRBP1. The phenotype acquired by breast epithelial cells clearly implies that the resistance to RA-mediated growth inhibition precedes the acquisition of morphological epithelial transformation, thus supporting the occurrence of sequential transcriptional silencing of first RARβ2 and second CRBP1. The identification of this epigenetic network mechanistically linking RARβ2 and CRBP1 transcription provides the basis for devising more accurate epigenetic tests for the prediction of breast cancer risk.(Cancer Res 2006; 66(21): 10308-14)