Abstract LB-236: Differential regulation of STAT3 in mammary gland involution as well as in mammary tumorigeneis

Abstract

Abstract STAT3 (Signal Transducer and Activator of Transcription 3) is persistently activated in many human primary tumors as well as in cancer cell lines, including breast cancer. This activated STAT3 is associated with cell survival and proliferation, inhibition of apoptosis, activation of angiogenesis and suppression of immune surveillance. Thus, STAT3 is generally considered as a growth-promoting factor. However, STAT3 activation also plays an important role in initiation of apoptotic signaling, especially, in mammary epithelial cells during mammary gland involution. Conditional deletion of STAT3 is associated with delayed involution mainly due to inadequate induction of apoptosis in mammary epithelial cells. Additionally, STAT3 activation is associated with induction of growth arrest and apoptosis in mouse mammary epithelial cells, myeloid cells and granulocyte. Thus, STAT3 plays dual role as a growth promoter as well as a growth inhibitor. However, the molecular switch that is responsible for switching the STAT3- associated pro-oncogenic signal to pro-apoptotic signal is not known. In order to identify this molecular switch we screened for signaling molecules that regulate STAT3 as well as those that are regulated by STAT3 during mammary gland involution, in human primary breast tumor tissues, and in human breast cancer cell lines. Our results show that early in the onset of mammary gland involution there is a significant up regulation of STAT3 and SLC5A8, a Na+-coupled transporter for monocarboxylates, including butyrate an inhibitor of histone deacetylases (HDACs). Further, STAT3 expression during mammary gland involution was found to be predominantly acetylated and phosphorylated. However, in human breast cancer cell lines we found an increase in phosphorylated STAT3 with almost undetectable expression of SLC5A8 and significantly decreased expression of acetylated STAT3 expression. Heterologous expression of SLC5A8 in human mammary tumor cell lines resulted in a butyrate-dependent induction of apoptosis with an increase in acetylated forms of STAT3. These results suggest that SLC5A8 is the molecular switch that converts the pro-oncogenic STAT3 signal to a pro-apoptotic signal by mediating the butyrate entry into mammary epithelial cells and thus it activates death receptor signaling by inhibiting HDACs and activation of STAT3 acetylation during mammary gland involution. However, in cancer cells the expression of SLC5A8 is silenced and thus it no longer able to inhibits HDACs and activates Ac-Stat3 and death receptor signaling. Thus, our studies provide a molecular link between the STAT3-associated pro-apoptotic and pro-oncogenic signaling that observed in normal mammary epithelium and in human breast cancer, respectively. 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 LB-236.