Abstract A19: Identification of epigenetic hits can predict breast cancer risk

A19

RARB2 is a master tumor suppressor that mediates the growth-inhibitory action of retinoic acid (RA). Homozygosis for epigenetically silent RARB2 alleles, which results into loss of RARB2 tumor suppressor activity, leads to RA-resistance, and apparently precedes the acquisition of morphological transformation of breast epithelial cells (Bistulfi et al., Cancer Research, 2006). RARB2 epigenetic silencing is marked by chromatin repressive changes, including DNA methylation of the RARB2 CpG island (Sirchia et al., Oncogene, 2000). In a mechanistic study, we demonstrated that methylation arises at a specific epicenter in the RARB2 CpG island, which we call the RARB2 methylation epicenter (RME) (Ren et al., MCB, 2005). Here we show that RME methylation is detectable in both benign and ductal carcinoma in situ within the same patient tissue sample. This finding implies sequential epigenetic silencing of RARB2 alleles. Timely identification of the first epigenetic hit in breast tissue of women at risk of breast cancer could prevent progression to RME methylation homozygosity, the consequent loss of RARB2-mediated tumor suppressor function, RA-resistance, and morphological epithelial cell transformation.

This work was supported by the Roswell Park Alliance Foundation Award (NS), the Breast Cancer Coalition of Rochester (NS), the Susan Komen Foundation (SR).

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A19.