Retinoic acid (RA), the bioactive derivative of Vitamin A, is a potent inhibitor of cell growth. RA action is mediated by the RA-receptors (RARs). We found that induction of RARB2 epigenetic silencing in RA-sensitive breast cancer cells make them susceptible to become growth-promoted by RA (Ren et al., Mol Cell Biol, 2005). Furthermore, we observed that this change is underlined by a switch in the sphingolipid rheostat (Somenzi et al., submitted). While RA-induced growth inhibition in RA-sensitive cells occurs in association with an increase of endogenous ceramide, which is an anti-proliferative sphingolipid, RA-induced growth promotion is associated with an increase of sphinosine-1-phosphate (S1P), the sphingolipid mediating cell proliferation. S1P expedites the transition of cells from G1 to the S phase. Consistently, flow cytometry and global gene expression analyses showed that upon induction of RARB2 epigenetic silencing, cells indeed undergo a significantly faster G1-S transition in response to RA, concomitantly with significant changes in cell cycle gene transcription. Moreover, when we grew these cells as xenograft tumors in nude mice, we observed that tumor growth was promoted by RA, including dietary RA. Apparently, RARB2 epigenetic silencing can lead to major biochemical and molecular changes, drastically changing the biological response to retinoic acid. This study was supported by the Roswell Park Alliance Foundation and the U.S. Army Medical Research and Materiel Command (DAMD17-02-1-0432) to NS.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]