TY - JOUR
T1 - A repressive epigenetic domino effect confers susceptibility to breast epithelial cell transformation
T2 - Implications for predicting breast cancer risk
AU - Bistulfi, Gala
AU - Pozzi, Silvia
AU - Ren, Ming Qiang
AU - Rossetti, Stefano
AU - Sacchi, Nicoletta
PY - 2006/11/1
Y1 - 2006/11/1
N2 - 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 α2 (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 RARβS 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.
AB - 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 α2 (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 RARβS 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.
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U2 - 10.1158/0008-5472.CAN-06-1052
DO - 10.1158/0008-5472.CAN-06-1052
M3 - Article
C2 - 17079450
AN - SCOPUS:33751288955
SN - 0008-5472
VL - 66
SP - 10308
EP - 10314
JO - Cancer Research
JF - Cancer Research
IS - 21
ER -