title: A tumor suppressor role for srGAP3 in mammary epithelial cells.
abstract: srGAP3, a member of the Slit-Robo sub-family of Rho GTPase-activating proteins (Rho GAPs), controls actin and microtubule dynamics through negative regulation of Rac. Here, we describe a potential role for srGAP3 as a tumor suppressor in mammary epithelial cells. We show that RNAi-mediated depletion of srGAP3 promotes Rac dependent, anchorage-independent growth of partially transformed human mammary epithelial cells (HMECs). Furthermore, srGAP3 expression is absent, or significantly reduced in 7/10 breast cancer cell lines compared with normal HMECs. Re-expression of srGAP3 in a subset of these cell lines inhibits both anchorage-independent growth and cell invasion in a GAP-dependent manner, and this is accompanied by an increase in phosphorylation of the ezrin/radixin/moesin (ERM) family proteins and myosin light chain 2 (MLC2). Inhibition of the Rho regulated kinase, ROCK, reduces ERM and MLC2 phosphorylation and restores invasion. We conclude that srGAP3 has tumor suppressor-like activity in HMECs, likely through its activity as a negative regulator of Rac1.
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Lahoz
authors.forename: A
authors.initials: A
authors.lastname: Hall
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D005260:Female; D020690:GTPase-Activating Proteins / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology
chemical_list: D020690:GTPase-Activating Proteins; C465659:SRGAP3 protein, human