Abstract 18: Slc5a8 inactivation is associated with mammary gland involution delay, early onset of mammary tumorigenesis and accelerated lung metastasis

Abstract

Abstract Accumulation of milk during mammary gland involution induces apoptosis in mammary epithelium, but the underlying molecular mechanism is not known. Slc5a8, a plasma membrane transporter and a candidate tumor suppressor, is silenced in many human cancers, including breast and colon cancers. The tumor-suppressive function of Slc5a8 is believed to be due to its ability to mediate the entry of butyrate and pyruvate into cells in a Na+-coupled manner. Butyrate and pyruvate are inhibitors of histone deacetylases (HDACs), and Slc5a8-mediated concentrative entry of these compounds into cells causes HDAC inhibition. Normal cells possess low HDAC activity, and inhibition of HDACs does not induce apoptosis. In contrast, tumor cells possess high HDAC activity, and these cells are propelled into apoptosis by HDAC inhibition. This probably explains why tumor cells silence this transporter. Breast milk contains significant amounts of butyrate. We postulated that Slc5a8 might play an important role not only in normal mammary gland but also in breast cancer by transporting butyrate into mammary epithelial cells and consequently causing HDAC inhibition. Here we have shown that milk stasis-associated mechanical stretching, which occurs in early onset of mammary gland involution, dramatically induced Slc5a8 expression in luminal epithelium. Deletion of Slc5a8 in mouse is associated with mammary gland hyperplasia, stem cell and progenitor cell proliferation, and delayed mammary gland involution. We hypothesize that the mammary gland hyperplasia and involution delay in Slc5a8-null mice are due to lack of butyrate-induced HDAC inhibition because the absence of the transporter prevents the entry of butyrate into mammary epithelial cells. In wild type mice, mammary gland involution was associated with decreased expression of HDAC1/3, and exogenous administration of butyrate accelerated the involution process. Further, deletion of Slc5a8 predisposed mice to early onset of mammary tumorigenesis in two different mammary tumor models (MMTV-Neu and MMTV-HRas), accelerated lung metastasis, and reduced disease-free survival. Mammary gland-specific overexpression of Slc5a8 (Slc5a8-MMTV-Tg mouse) induced early onset mammary gland involution, reduced mammary tumor incidence, delayed mammary tumor formation, and reduced lung metastasis. Induction of Slc5a8 with a DNA methyltransferase inhibitor (5-azacytidine), coupled with exogenous administration of butyrate, dramatically reduced mammary tumor incidence, delayed mammary tumorigenesis, and increased disease-free survival. We conclude that Slc5a8 functions as a tumor suppressor in mammary gland and that induction of Slc5a8 with DNA methyltransferase inhibitors coupled with butyrate administration might represent a novel approach to breast cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 18. doi:1538-7445.AM2012-18