CIP4 promotes metastasis in triple-negative breast cancer and is associated with poor patient prognosis

// Otto L.D. Cerqueira 1 , Peter Truesdell 2 , Tomas Baldassarre 2 , Santiago A. Vilella-Arias 1 , Kathleen Watt 2 , Jalna Meens 2 , Harish Chander 2 , Cynthia A.B. Osório 3 , Fernando A. Soares 3, 4 , Eduardo M. Reis 1, 4 , Andrew W.B. Craig 2 1 Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil 2 Department of Biomedical and Molecular Sciences, Queen's University, and Division of Cancer Biology & Genetics, Queen's Cancer Research Institute, Kingston, ON, Canada 3 Department of Anatomic Pathology, A.C. Camargo Hospital, São Paulo, SP, Brazil 4 Instituto Nacional de Ciência e Tecnologia em Oncogenômica, São Paulo, SP, Brazil Correspondence to: Andrew W. Craig, e-mail: andrew.craig@queensu.ca Eduardo M. Reis, e-mail: emreis@iq.usp.br Keywords: metastasis, triple-negative breast cancer, CIP4 Received: October 22, 2014 Accepted: February 10, 2015 Published: March 19, 2015 ABSTRACT 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.