Abstract LB-082: Targeted inactivation of STAT3 inhibits proliferation and invasion of breast cancer cells and enhances antitumor activity of doxorubicin through reversion of EMT

Abstract

Abstract Breast cancer is one of the most common malignant diseases in women. Epithelial-mesenchymal transition (EMT) has been documented to play an important role in proliferation, invasion and metastasis of tumor cells as well as drug resistance. Even though the signal transducer and activator of transcription 3 (STAT3) is not a master transcription factor of EMT, STAT3 is involved in the regulation of EMT-related gene expression. However, it remains unclear whether targeted inhibitors of STAT3 affect EMT-mediated proliferation, migration, invasion and drug resistance of tumor cells. In this paper, we investigated the effects of STAT3 and its interaction with Twist, a master transcription factor, in EMT program and subsequent changes in proliferation, migration and invasion of breast cancer cells by interfering STAT3 signaling pathway with different strategies such as STAT3 inactivation and STAT3 silencing. Furthermore, we explored the role of inhibiting STAT3 phosphorylation in the EMT regulation of the sensitivity of tumor cells response to doxorubicin. The results showed that the expression and activation of STAT3 correlated with cell phenotype and invasive ability of breast cancer cells. IL-6 induced phosphorylation of STAT3 can promote the EMT of breast cancer cells. WP1066 completely inhibited STAT3 autophosphorylation and IL-6-induced phosphorylation in breast cancer cells. WP1066 reversed EMT to MET through inhibiting the phosphorylation of STAT3 in breast cancer cells and significantly inhibited the proliferation and invasion in breast cancer cells. Silence STAT3 with siRNA also reversed EMT to MET in breast cancer cells. The expression of EMT transcription factor Twist1 was positively correlated with the activation of STAT3 but not with the expression of STAT3. WP1066 increased doxorubicin antitumor activity through inhibiting the STAT3 phosphorylation. These data provide a proof of concept that targeted inactivation of STAT3 can inhibit proliferation and invasion of breast cancer cells and reduce the resistance of Doxorubicin through reversion of EMT. Support by Natural Science Foundation of China (No.81472489) and Science and Technology Development Plan of Shandong (No.2014GSF118040) Citation Format: Yi Ding, Yu Jiang, Wenqing Li, Shurong Liu, Zhong Lu, Lihong Shi, Xuejian Wang, Jian Zhang, Lihua Wang. Targeted inactivation of STAT3 inhibits proliferation and invasion of breast cancer cells and enhances antitumor activity of doxorubicin through reversion of EMT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-082. doi:10.1158/1538-7445.AM2017-LB-082