Abstract 4296: STAT3 is required for proliferation and tumor growth of breast cancer stem cells

Abstract

Abstract Breast cancer is the leading type of cancer affecting women. It is estimated that breast cancer accounts for over a quarter of all newly diagnosed cancer cases in women. Despite advances in chemotherapy and hormonal treatment, at the present time, metastatic breast cancer remains an incurable disease. Although a large number of chemotherapeutic agents have been developed that are able to cause the regression of metastatic breast cancers, these tumors almost always recur following chemotherapy treatment. It is possible that breast cancer stem cells or breast cancer initiating cells are responsible for the drug-resistance, metastasis, and recurrence of cancer. Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) signaling is frequently detected in many types of cancers, including breast cancer, and has emerged as an attractive molecular target for cancer treatment. However, whether or not STAT3 is activated in breast cancer stem cells and what role STAT3 signaling plays in cancer stem cells is still unknown. If STAT3 is activated in breast cancer stem cells, targeting STAT3 may offer a promising opportunity to eliminate breast cancer stem cells and prevent the recurrence of cancer. We examined STAT3 activation in breast cancer stem cells, which are characterized by an aldehyde dehydrogenase (ALDH)-positive (ALDH+) and ALDH+/CD44+/CD24− subpopulations. Interestingly, we observed that the ALDH+ and ALDH+/CD44+/CD24− subpopulations of breast cancer cells expressed higher levels of phosphorylated STAT3, an active form of STAT3, as compared to the ALDH− and ALDH−/CD44+/CD24+ subpopulations and un-separated breast cancer cells, suggesting that STAT3 is activated in breast cancer stem cells. We also demonstrated that a novel STAT3 inhibitor, LLL12, inhibited STAT3 phosphorylation, cell viability, STAT3 downstream target gene expression, and induced apoptosis in breast cancer stem cells. In addition, the STAT3 inhibitors Stattic and LLL12 inhibited the tumorsphere forming capacity of breast cancer stem cells. Furthermore, in a mouse tumor model using breast cancer stem cells, we demonstrated that LLL12 can suppress tumor growth in vivo. This is the first report to demonstrate that persistent STAT3 phosphorylation is expressed in breast cancer stem cells and that this subpopulation of breast cancer stem cells is sensitive to STAT3 inhibitors. Our results suggest that STAT3 is a novel therapeutic target in breast cancer stem cells and inhibition of activated STAT3 in cancer stem cells may offer a more effective treatment for breast cancer. 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 4296.