Abstract B22: Novel dual regulation of epithelial-mesenchymal transition and anoikis resistance prevents metastases of triple negative breast cancer

Abstract

Abstract Triple negative breast cancers (TNBC) are associated with a higher rate of metastatic recurrence and poorer prognosis due to intrinsic biological aggressiveness and lack of targeted therapies. Novel strategies to prevent metastasis are needed to improve outcomes for patients diagnosed with TNBC. Epithelial-mesenchymal transition (EMT) and anoikis resistance are processes recognized as contributing to treatment resistance and enhanced metastatic potential. In a functional genomic screen, we identified several candidates as novel dual regulators of EMT and anoikis sensitivity of triple negative breast cancer cells, that can be pharmacologically targeted to prevent metastases. One highly validated candidate, PTK6/Brk, specifically enhances anoikis resistance and metastatic potential of triple negative breast cancer cells via E-cadherin regulation. Overexpression of PTK6 in non-transformed immortalized breast epithelial cells is sufficient to promote an EMT, whereas PTK6 inhibition (either PTK6 shRNA or kinase inhibitor treatment) enhances E-cadherin expression and suppresses migration and lung colonization of TNBC cells. PTK6-dependent E-cadherin regulation and anoikis resistance is specifically dependent on levels of SNAIL, a transcriptional repressor. SNAIL down-regulation by PTK6 inhibition is directly responsible for modulation of anoikis sensitivity, which is in turn causally linked to lung colonization potential. PTK6 inhibition promotes the degradation of SNAIL via a novel mechanism independent of GSK3β and Fbox proteins known to regulate Snail ubiquitination. Using an siRNA screening approach, we identified novel E3 ligase candidates responsible for SNAIL ubiquitination and degradation downstream of PTK6 inhibition. PTK6 is a representative novel regulator of EMT and anoikis resistance that can be targeted to prevent metastases of patient triple negative tumors. Citation Format: Koichi Ito, Sun Hee Park, Anupma Nayak, Hanna Y. Irie. Novel dual regulation of epithelial-mesenchymal transition and anoikis resistance prevents metastases of triple negative breast cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B22.