Abstract LB-280: Inhibition of SHP2 in basal-like and triple-negative breast cancer cells induces basal-to-luminal transition, suppresses tumorigenesis, and blocks metastasis.

Abstract

Abstract One of the factors that contribute to the disproportionately high mortalities in basal-like and triple-negative breast cancer (BTBC) is the lack of targeted therapies. Identifying and characterizing potential targets is therefore critical for future development of such therapies. In the current report, we show that silencing the expression of the Src homology phosphotyrosyl phosphatase 2 (SHP2) in BTBC cell lines (MDA-MB231 and MDA-MB468) suppresses cell proliferation, reverses transformation, and blocks invasiveness. Unexpectedly, we have discovered that inhibition of SHP2 induces basal-to-luminal transition (BLT) in BTBC cells as evidenced by a decrease in the expression of mesenchymal markers and/or drivers (vimentin, ZEB1, Snail, and alpha smooth muscle actin) and an increase in the expression of the luminal marker cytokeratin 18. Furthermore, we have discovered that inhibition of SHP2 induces the expression of the estrogen receptor alpha in otherwise triple-negative breast cancer cells. Intramammary transplantation studies in the NOD/SCID mice demonstrated that inhibition of SHP2 suppresses tumorigenesis and blocks metastasis. Analyses of total cell lysates prepared from cells grown in 3D matrigel cultures demonstrated that SHP2 mediates the activation of the Ras-ERK, the PI3K, and the β-catenin signaling pathways to promote the tumorigenic, invasive, and metastatic potential of BTBC cells. By and large, the results presented in this report suggest that SHP2 plays an essential role in the biology of BTBC. Citation Format: Fatimah Matalka, Hua Zhao, Yehenew M. Agazie. Inhibition of SHP2 in basal-like and triple-negative breast cancer cells induces basal-to-luminal transition, suppresses tumorigenesis, and blocks 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 LB-280. doi:10.1158/1538-7445.AM2013-LB-280