Investigating the mechanism of CDCP1 activation to block CDCP1-driven metastasis

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 DESCRIPTION (provided by applicant) Triple negative breast cancer (TNBC) is a highly aggressive and metastatic form of breast cancer that is characterized by a lack of the estrogen, progesterone, and HER2 receptor, which renders it resistant to targeted and hormone therapies. TNBC patients tend to be young, thus, the need to develop effective targeted therapies for this subgroup of patients is particularly urgent. The molecular basis for the high metastatic potential of TNBC is unknown. TNBC expresses high levels of a metastasis-inducing protein, CUB-domain containing protein 1 (CDCP1), which has been correlated with the aggressive nature of many forms of cancer, including TNBC. CDCP1 can be proteolytically processed from a full-length, 135 kDa (flCDCP1), to a cleaved, 70 kDa (cCDCP1), isoform by trypsin, matriptase, and plasmin. Recent reports have highlighted the unique signaling cascades induced by 70 kDa cCDCP1, which include degradation of adherens junctions, evasion of PARP1 mediated apoptosis, and enhancement of PKCδ, Akt, and FAK signaling. Furthermore, we and others have observed that CDCP1 exists mostly in the cleaved state in multiple TNBC cell lines. Our lab and others have shown that CDCP1 is phosphorylated by Src family kinase (SFKs), which stimulates the recruitment of PKCδ to the CDCP1/SFK complex, resulting in PKCδ phosphorylation. PKCδ activation results in migration of cells in vitro. It is not clear if phosphorylation and cleavage are the only steps in activation of CDCP1 and its downstream signaling. The objective of this project is to dissect the mechanism of CDCP1 activation and determine a strategy to block it and inhibit CDCP1-induced migration. My recent work in HEK 293T cells shows a dramatic increase PKCδ, p38 MAPK, ERK1/2, and Akt phosphorylation in cCDCP1 transfected HEK 293T cells, as opposed to flCDCP1 transfected cells. These findings support the necessity of CDCP1 cleavage for its activation. Furthermore, I found that only cCDCP1 can form a dimer, which we propose to occur through its CUB domains known to be involved in protein-protein interactions. The importance for this dimer in CDCP1 pro-migratory signaling remains to be investigated. These studies aim to determine the role of the CDCP1 dimer in CDCP1-mediated metastasis. I propose that inhibiting CDCP1 dimerization is a rationale therapeutic to inhibit CDCP1-mediated metastasis as some current FDA approved anti-cancer therapies inhibit dimerization of their respective targets; Herceptin, Pertuzumab, and Cetuximab.