Abstract 2445: Cucurbitacin B suppresses breast cancer growth by inhibiting TGFβ-mediated integrin-HER2 signaling.

Abstract

Abstract Integrins have recently been shown to play an important role in promotion of cell motility and survival in various cancers through cooperative signaling with EGFRs. Integrins transmit cell survival signals through ILK-Paxillin complex and further play role in activating AKT signaling. Curcubitacin B (CuB) is a steroidal class of chemical present in the plants belonging to cucurbitaceae family. CuB has shown cytotoxic potential in several cancers by causing G2/M cell cycle arrest and inhibition of JAK/STAT3 pathway. However, the exact mechanism of CuB and its role in metastasis and cell survival is not known. Our results show that CuB significantly suppressed the growth of MDA-MB-231, SKBR3, MCF-7, MDA-MB-231 (HER2) and MCF-7 (HER2), five different breast cancer cells in a concentration and time-dependent manner. CuB also induced apoptosis and down-regulated Integrin linked kinase 1(ILK1) expression. In addition, CuB down-regulated Integrin β4 (ITGB4) and Integrin α 6 (ITGA6) protein expression and suppressed the phosphorylation of AKT at Ser473, paxillin at Tyr118. Previous studies have shown that Transforming growth factor β (TGFβ) mediates crosstalk between ITGB4 and HER2, through Src kinase to enhance cell survival and motility. Interestingly we observed significant downregulation of Src, EGFR and HER2 in various breast cancer cells, suggesting that CuB suppresses cooperative signaling of Integrins and HER2. We also observed that TGFβ pretreatment imparted protection against CuB induced cytotoxic effects, indicating that CuB modulates TGFβ mediated Integrin signaling. Taken together our results indicate the anti-cancer effects of CuB in breast cancer cells by targeting ITGB4/ITGA6, Src, ILK and TGFβ. Further detailed mechanistic work is in progress. [Supported in part by R01 grants CA129038 (to S.K.S) awarded by the National Cancer Institute]. Citation Format: Parul Gupta, Sanjay K. Srivastava. Cucurbitacin B suppresses breast cancer growth by inhibiting TGFβ-mediated integrin-HER2 signaling. [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 2445. doi:10.1158/1538-7445.AM2013-2445