CIP4 promotes metastasis in triple-negative breast cancer and is associated with poor patient prognosis
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Otto L.D. Cerqueira1, Peter Truesdell2, Tomas Baldassarre2, Santiago A. Vilella-Arias1, Kathleen Watt2, Jalna Meens2, Harish Chander2, Cynthia A.B. Osório3, Fernando A. Soares3,4, Eduardo M. Reis1,4, Andrew W.B. Craig2
1Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil
2Department of Biomedical and Molecular Sciences, Queen's University, and Division of Cancer Biology & Genetics, Queen's Cancer Research Institute, Kingston, ON, Canada
3Department of Anatomic Pathology, A.C. Camargo Hospital, São Paulo, SP, Brazil
4Instituto Nacional de Ciência e Tecnologia em Oncogenômica, São Paulo, SP, Brazil
Andrew W. Craig, e-mail: [email protected]
Eduardo M. Reis, e-mail: [email protected]
Keywords: metastasis, triple-negative breast cancer, CIP4
Received: October 22, 2014 Accepted: February 10, 2015 Published: March 19, 2015
Signaling via epidermal growth factor receptor (EGFR) and Src kinase pathways promote triple-negative breast cancer (TNBC) cell invasion and tumor metastasis. Here, we address the role of Cdc42-interacting protein-4 (CIP4) in TNBC metastasis in vivo, and profile CIP4 expression in human breast cancer patients. In human TNBC cells, CIP4 knock-down (KD) led to less sustained activation of Erk kinase and impaired cell motility compared to control cells. This correlated with significant defects in 3D invasion of surrounding extracellular matrix by CIP4 KD TNBC cells when grown as spheroid colonies. In mammary orthotopic xenograft assays using both human TNBC cells (MDA-MB-231, HCC 1806) and rat MTLn3 cells, CIP4 silencing had no overt effect on tumor growth, but significantly reduced the incidence of lung metastases in each tumor model. In human invasive breast cancers, high CIP4 levels was significantly associated with high tumor stage, TNBC and HER2 subtypes, and risk of progression to metastatic disease. Together, these results implicate CIP4 in promoting metastasis in TNBCs.
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