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Biomarkers and Early Detection: Premalignant Lesions

Concerted silencing of vitamin A genes in breast epithelial cells: Implications for cancer prevention.

Roswell Park Cancer Institute, Buffalo, NY

Abstract

A3

Genes with different biological functions become aberrantly hypermethylated in breast cancer (Widschwendter et al, Oncogene, 2002). Some of these hypermethylated genes are currently used for early detection of breast epithelial cell transformation (Fackler et al, Cancer Res, 2004), as well as for prediction of cancer risk in non-neoplastic breast tissue (Bean et al, Cancer Epidemiol Biomarkers Prev, 2005). Our recent work showed that development of resistance to the tumor suppressive action of retinoic acid (RA), the bioactive derivative of vitamin A, would precede morphological changes of breast epithelial cell transformation thus providing a way to predict breast cancer risk. Apparently, an impairment of RA-signal in breast epithelial cells leads first to RA-resistance, due to silencing of the RA-receptor beta 2 (RARß2), which, in turn, can trigger the silencing of its target, the cellular retinol binding protein 1 (CRBP1), critical for the transport of vitamin A as well as normal breast epithelial cell morphology. Silencing of both genes is marked by epigenetic changes, including DNA hypermethylation, readily detectable in breast samples with current technology. The discovery of this epigenetic network opens the way for devising an ad hoc panel of hypermethylated markers for clinical applications. Further, maintenance of the integrity of RA-signal in breast tissue might prevent the occurrence of the epigenetic "domino effect" involving RA-responsive genes and consequently breast tumorigenesis.