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 (RARalpha), epigenetically regulates in a concerted fashion the transcription of two RA-responsive genes, the RA receptor beta2 (RARbeta2) and the cellular retinol-binding protein 1 (CRBP1). Specifically, an impaired RA signal through RARalpha in human breast epithelial cells triggers a repressive epigenetic domino effect, involving first RARbeta2 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 RARbeta2 and second CRBP1. The identification of this epigenetic network mechanistically linking RARbeta2 and CRBP1 transcription provides the basis for devising more accurate epigenetic tests for the prediction of breast cancer risk.
Bistulfi
Gaia
G
Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, New York 14263, USA.
Pozzi
Silvia
S
Ren
MingQiang
M
Rossetti
Stefano
S
Sacchi
Nicoletta
N
D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics*; D002471:Cell Transformation, Neoplastic; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D006801:Humans; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000235:genetics; D012177:Retinol-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D054840:Retinol-Binding Proteins, Cellular; D012306:Risk; D014212:Tretinoin / Q000494:pharmacology
C518456:RBP1 protein, human; D018168:Receptors, Retinoic Acid; D012177:Retinol-Binding Proteins; D054840:Retinol-Binding Proteins, Cellular; C082925:retinoic acid receptor beta; D014212:Tretinoin