A repressive epigenetic domino effect confers susceptibility to breast epithelial cell transformation: implications for predicting breast cancer risk

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 alpha (RAR alpha), epigenetically regulates in a concerted fashion the transcription of two RA-responsive genes, the RA receptor 2 (RAR beta 2) and the cellular retinol-binding protein 1 (CRBP1). Specifically, an impaired RA signal through RAR alpha in human breast epithelial cells triggers a repressive epigenetic domino effect, involving first RAR beta 2 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 RAR beta 2 and second CRBP1. The identification of this epigenetic network mechanistically linking RAR beta 2 and CRBP1 transcription provides the basis for devising more accurate epigenetic tests for the prediction of breast cancer risk.