Abstract 5128: Upregulation of epsin in breast cancer and critical role of epsin in promoting cancer growth and metastasis.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC We have previously demonstrated that deficiency of epsins, a family of endocytic clathrin adaptor proteins, decreases tumor growth by enhancing VEGF signaling in endothelial cells and causing dysfunctional tumor angiogenesis. However, the role of epsin in cancer cells is unclear. Our preliminary data indicate that epsins are upregulated in various human cancers, including breast cancer, prostate cancer, ovary cancer, cervix cancer, bladder cancer, and esophagus cancer. Here, we determined the role of epsin in cancer cells in regulating breast cancer growth and metastasis. Increased epsin level was found in ER(+/-) and/or PR(+/-) human breast cancer cell lines including MDA-MB-231, BT-20, ZR751, MCF7 and T47D, and in mouse breast cancer cell lines, such as 168FARN and 4T1. The level of epsins was also considerably augmented in tumors derived from MMTV-PyMT spontaneous breast cancer mouse model at different progressive stages. We observed a correlative increase in epsin expression with cancer progression in MMTV-PyMT mice. We also generated stable epsin-deficient MDA-MB-231 and 4T1 cells. Epsin deficiency markedly inhibited cell proliferation and migration in vitro. Xenograft mouse models of epsin-deficient breast cancer cells revealed striking reduction in tumorigenesis and lung metastasis. Lung metastasis by tail-vein injection of epsin-deficient MDA-MB-231 cells was also decreased compared to controls. Mechanistically, we showed that epsin-deficiency induced morphological change from mesenchamal-like to epitheial-like in MDA-MB-231 cells, indicating a reversal of Epithelial-Mesenchymal Transition (EMT) to Mesenchymal-Epithelial-Transition (MET). Moreover, epsin-deficiency increased E-cadherin expression but decreased vimentin, and EMT inducing genes snail/slug expression in MDA-MB-231 cells. Epsin-deficiency also dramatically reduced cyclin D1 expression and Rb activation. Accordingly, elevated E-cadherin but attenuated vimentin, slug and cyclin D1 were observed in tumor tissues or lung tissues isolated from epsin-deficient MDA-MB-231 and 4T1 tumor models. Conversely, overexpression of epsin in MDA-MB-231 cells enhanced cyclin D1 and vimentin expression. Collectively, epsin promotes breast tumor growth and metastasis through coordinated regulation of cell cycle and EMT. Our study provides a basis for novel therapeutic targets for anti-cancer treatments. Citation Format: Xiaofeng Cai, Satish Pasula, Baojun Chang, Scott Hahn, John McManus, Hong Chen. Upregulation of epsin in breast cancer and critical role of epsin in promoting cancer growth and metastasis. [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 5128. doi:10.1158/1538-7445.AM2013-5128