Abstract SY01-04: Tackling breast cancer: from genetic screens to new therapeutic strategies

Abstract

Abstract Breast cancer is a collection of diseases with distinct clinical behaviors and underlying genetic causes. Triple-negative breast cancer (TNBC) is a common subtype of breast cancer that confers a particularly poor prognosis and is refractory to current targeted therapies. Unfortunately, the molecular determinants driving this aggressive malignancy are poorly understood. Using an unbiased genetic screen, we have identified a novel tumor suppressor network that governs proliferation and transformation of TNBCs in vitro and in vivo. We define PTPN12 as a core component in this network and a commonly inactivated tumor suppressor in TNBC. PTPN12 is a potent suppressor of human mammary epithelial cell proliferation and transformation. PTPN12 function is frequently compromised in human TNBCs by inactivating mutations, deletion, or loss of protein expression. Mechanistically, PTPN12 is a tyrosine phosphatase that suppresses cellular transformation by interacting with and inhibiting several oncogenic receptor tyrosine kinases including HER2, EGFR, and PDGFR. Notably, the tumorigenic and metastatic potential of PTPN12-deficient TNBCs is severely impaired by restoring PTPN12 function or by inhibiting kinase targets of PTPN12, suggesting that TNBCs are dependent on the proto-oncogenic tyrosine kinases constrained by PTPN12. Collectively, these data identify PTPN12 as a commonly inactivated tumor suppressor and provide a rationale for combinatorially targeting tyrosine kinases in TNBC and other cancers based on their profile of tyrosine phosphatase activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY01-04. doi:10.1158/1538-7445.AM2011-SY01-04