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

Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, New York

Requests for reprints: Nicoletta Sacchi, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-1053; Fax: 716-845-1741; E-mail: nicoletta.sacchi{at}roswellpark.org.

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 (RAR), epigenetically regulates in a concerted fashion the transcription of two RA-responsive genes, the RA receptor ß2 (RARß2) and the cellular retinol-binding protein 1 (CRBP1). Specifically, an impaired RA signal through RAR in human breast epithelial cells triggers a repressive epigenetic domino effect, involving first RARß2 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 RARß2 and second CRBP1. The identification of this epigenetic network mechanistically linking RARß2 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)