It was recently discovered by this laboratory that Yippie-like 3 (YPEL3) is a novel p53 regulated gene that when induced triggers premature senescence in primary and tumor cell lines. Initial screens of human tumor samples uncovered significant decreases in YPEL3 gene expression in ER- verses ER+ breast cancers leading us to believe that estrogen may have a regulatory effect on YPEL3 expression. Using ER+ MCF7 cells, we determined that estrogen is a significant inhibitor of YPEL3 gene expression in cells grown in media with 10% serum verses cells grown in media with charcoal stripped serum (CSS) from which estrogen has been removed. The increase in YPEL3 mRNA expression demonstrated in CSS can be blocked by the addition of estrogen, and as expected tamoxifen competes with this estrogen repressive effect. The effects of estrogen on YPEL3 expression are not observed in MCF10A mammary epithelial cells which are ER negative demonstrating the requirement for the estrogen receptor in the observed effect. Given our observation that YPEL3 induction triggers senescence in breast cancer cells, we employed beta-galactosidase activity as a measurement of senescence and observed an 8-fold increase in senescence in MCF7 cells grown in CSS media. The increase is reduced to less than 3.5-fold with the addition of estrogen to the CSS media, and the increase in cellular senescence is blocked in MCF7 cells stably selected for the loss of YPEL3 (MCF7-shYPEL3) suggesting the need for the absence of estrogen and the presence of YPEL3 in senescence induction. We are currently testing the effects of estrogen on MCF7 cells where p53 has been knocked down using RNAi approaches and are planning to test the effects of RNAi targeting ER-alpha. We believe estrogen is inhibiting YPEL3 expression through its association with the estrogen receptor and their association with p53 thereby inhibiting p53 transactivation of YPEL3. These findings suggest that modulation of YPEL3 by estrogen and its growth suppressive effects may provide a target for future breast cancer therapies.

Note: First two authors contributed equally.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3066.