Abstract S6-10: Identification of a Novel Tumor Suppressor Network Reveals a Role for Proto-Oncogenic Receptor Tyrosine Kinases in Triple-Negative Breast Cancer

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 SECT21 as a core component in this network and a commonly inactivated tumor suppressor in TNBC. SECT21 is a potent suppressor of human mammary epithelial cell proliferation and transformation. SECT21 function is frequently compromised in human TNBCs by inactivating mutations, deletion, or loss of protein expression. Mechanistically, SECT21 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 SECT21-deficient TNBCs is severely impaired by restoring SECT21 function or by inhibiting kinase targets of SECT21, suggesting that TNBCs are dependent on the proto-oncogenic tyrosine kinases constrained by SECT21. Collectively, these data identify SECT21 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 Information: Cancer Res 2010;70(24 Suppl):Abstract nr S6-10.