Abstract 1681: Autophagy-regulation of STAT3 phosphorylation determines subtype differences in autophagy addiction and breast cancer cell survival.

Autophagy is a long-lived protein and organelle degradation pathway in which cytoplasmic material is engulfed in a double membrane structure known as the autophagosome and later delivered to the lysosome for its degradation. Macroautophagy (referred herein as autophagy) has been extensively studied in recent years, increasing our understanding of the major constituents of the autophagic pathway. Most importantly, defects in the autophagic pathway have been involved in diverse diseases including cancer. In this regard, some cancers, like pancreatic cancer and some Ras transformed tumors, are thought to be “autophagy addicted” since they require a functional autophagic pathway for survival. Although breast cancer has been considered to be an autophagy-independent type of cancer, most studies have not considered the high heterogeneity of this disease. Here, we found that different subtypes of breast cancer vary in their dependence on autophagy with cell lines from two particular subtypes, basal-like and claudin-low displaying particular sensitivity to autophagy inhibition by Atg gene knockdown or chloroquine treatment when compared to luminal and non-transformed cell lines. STAT3 constitutive activation and dependence for survival is known to be important for triple negative breast cancers which are mostly comprised by the basal-like and claudin-low subtypes. We found a strong correlation between STAT3 constitutive activity and autophagy-dependence for survival in a panel of breast cancer cell lines. Importantly, autophagy inhibition by Atg gene knockdown or chloroquine treatment significantly decreased STAT3 phosphorylation in the autophagy-dependent cell lines. Moreover, treatment with Stattic, a STAT3 inhibitor, showed a similar effect on cell death than chloroquine treatment or Atg gene knockdown, suggesting targeting of the same pathway. Finally, a constitutively active form of STAT3 decreased cell death induced by inhibition of the autophagic pathway in “autophagy-addicted” cell lines. Our results suggest that autophagy addiction in breast cancer is caused by autophagy regulation of STAT3 activation and that autophagy inhibition might be a potential therapeutic strategy for hard-to-treat triple negative breast cancers by blocking STAT3 activation. Currently these types of breast cancer lack effective and targeted treatment strategies and have the worst prognosis among breast cancers. Moreover, screening of STAT3 activation in tumors could serve as a selection strategy for treatment with autophagy inhibitors like chloroquine. Funding: NIH grants #R01CA150925 and RO1CA111421. Citation Format: Paola Maycotte, Michael J. Morgan, Andrew Thorburn. Autophagy-regulation of STAT3 phosphorylation determines subtype differences in autophagy addiction and breast cancer cell survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1681. doi:10.1158/1538-7445.AM2013-1681