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 A (RARA), epigenetically regulates in a concerted fashion the transcription of two RA-responsive genes, the RA receptor B2 (RARb2) and the cellular retinol-binding protein 1 (CRBP1). Specifically, an impaired RA signal through RARA in human breast epithelial cells triggers a repressive epigenetic domino effect, involving first RARb2 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 RARb2 and second CRBP1. The identification of this epigenetic network mechanistically linking RARb2 and CRBP1 transcription provides the basis for devising more accurate epigenetic tests for the prediction of breast cancer risk.

A distinct epigenetic signature at targets of a leukemia protein

“…One of these genes is Tcfec , whose human counterpart encodes a transcription factor that induces the granulocyte colony stimulating factor receptor G-CSFR [23,24]. Remarkably, Tcfec downregulation in A16 cells is paralleled by a significant downregulation of G-csfr (data not shown), indicating that AML1-MTG16 might have triggered a coordinated cascade of transcriptional downregulation, as we observed in other differentiation model systems [37,38]. The second gene is Mgmt , encoding the DNA repair enzyme O6-Methylguanine-DNA-methyltransferase, which is frequently silenced and hypermethylated in leukemia [39].…”

Disruption of Retinoic Acid Receptor Alpha Reveals the Growth Promoter Face of Retinoic Acid

“…RA, after binding the nuclear receptor RARα, triggers the transcription of other downstream RARs, including the RA-receptor and tumor suppressor, RARβ2 [6]. RARβ2 autoregulates its own transcription and, in turn, the transcription of a multitude of downstream RA-responsive target genes [7], [8].…”

ATRA transcriptionally induces nSMase2 through CBP/p300-mediated histone acetylation

“…Furthermore, a loss of ATRA signaling can result in repressive methylation of downstream target genes (29,30). This, together with the lack of effect of ATRA on promoter activity, led us to explore epigenetic mechanisms of regulation, and our data clearly indicate that ATRA primarily regulates nSMase2 through directly modulating histone acetylation, which is most likely through CBP/p300.…”

“…Previous studies have reported that loss of ATRA signaling can lead to hypermethylation of downstream genes in breast epithelial cells (29,30). Moreover, the Smpd3 gene (nSMase2) is reported to be hypermethylated in some breast cancer and hepatocellular carcinoma (HCC) cells (31,32).…”