Abstract P4-08-07: CDCP1 cleavage is necessary for homodimerization-induced migration of triple-negative breast cancer

Abstract

Triple negative breast cancer (TNBC) is a highly aggressive and metastatic form of breast cancer that lacks the estrogen, progesterone, and HER2 receptors and is resistant to targeted and hormone therapies. TNBCs express high levels of the transmembrane glycoprotein, CUB-domain containing protein 1 (CDCP1), which has been correlated with the aggressiveness and poor prognosis of multiple carcinomas. Full-length CDCP1 (flCDCP1) can be proteolytically cleaved, resulting in a cleaved membrane-bound isoform (cCDCP1). CDCP1 is phosphorylated by Src family kinases in its full-length and cleaved states, which is important for its pro-metastatic signaling. We observed that cCDCP1, compared to flCDCP1, induced a dramatic increase in phosphorylation of the migration-associated proteins: PKCδ, ERK1/2, and p38 MAPK in HEK 293T. In addition, only cCDCP1 induced migration of HEK 293T cells and rescued migration of the TNBC cell line, MDA-MB-231, expressing shRNA against CDCP1. Importantly, we found that only cCDCP1 is capable of dimerization, which can be blocked by expression of the extracellular portion of cCDCP1 (ECC), indicating that dimerization occurs through CDCP1's ectodomain. Furthermore, we found that ECC inhibited phosphorylation of PKCδ by Src and migration of TNBC cells, indicating that the cCDCP1 dimer is an important contributor to TNBC aggressiveness. These studies have important implications for development of a therapeutic to block CDCP1 activity and TNBC metastasis. Citation Format: Wright H, Motazedi M, Nelson L, Aulmoli J, Flanagan L, Razorenova O. CDCP1 cleavage is necessary for homodimerization-induced migration of triple-negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-08-07.