SIRT1, a NAD+-dependent deacetylase, first emerged as a potential anti-aging factor by controlling senescence, but now it is also implicated in tumor development and cancer cell survival. SIRT1 is overexpressed and/or catalytically activated in a variety of human cancers, suggesting a potential role for SIRT1 in tumor promotion. SIRT1 promotes oncogenic signaling, in part, by deacetylating the tumor suppressor protein p53 resulting in its inactivation. Similarly, estrogen receptor alpha (ERα) also promotes the development and progression of hormone-dependent cancers such as breast cancer, in part, by inactivating p53 function. It is not known whether ERα and SIRT1 functionally cooperate to elicit their biologic effects. Thus, we hypothesized that there could be a functional link between ERα and SIRT1 and that this link could play a role in cellular immortalization and tumor formation in mammary epithelial cells. Using a series of coimmunoprecipitation and immunofluorescence assays, we demonstrated that ERα physically interacts and functionally cooperates with SIRT1 in breast cancer cells and that SIRT1 is necessary for ERα-induced p53 inactivation. This interaction requires active estrogen-ERα (E2-ERα) complex and catalytically active SIRT1. Functional disruption of either E2-ERα or SIRT1 dramatically reduces this interaction. Further, ERα binds to SIRT1 promoter and increases SIRT1 transcription whereas SIRT1 does not affect the expression and acetylation status of ERα. In breast cancer cells, SIRT1 inactivation or knockdown decreases E2-induced cell growth, and this process is associated with prevention of ERα-induced p53 inactivation and induction of antioxidant enzymes. Finally, mouse xenograft studies of human ER-positive breast cancer cells provide in vivo evidence for the importance of the ERα-SIRT1 complex in breast cancer growth in which deletion of SIRT1 abrogates the tumor-promoting activity of estrogen completely. These studies show that SIRT1 is essential for the promotion of E2/ERα-associated breast cancer growth and that a combination of SIRT1 inhibitors and anti-estrogens could offer a novel approach for breast cancer management.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4032. doi:10.1158/1538-7445.AM2011-4032

©2011 American Association for Cancer Research
2011