Abstract 3151: Muc1/Cin85 complex is a new molecular target for control of cancer invasion and metastasis

Abstract

Abstract MUC1 is a transmembrane glycoprotein abnormally expressed in all stages of human adenocarcinomas as well as sites of chronic inflammation. The extracellular domain of MUC1 contains a variable number of tandem repeats (VNTR) region that is extensively O-glycosylated in normal epithelia and underglycosylated in tumor cells. Lack of sugars on the VNTR increases the accessibility of the peptide backbone to more efficient or completely new protein-protein interactions that can profoundly change intracellular signaling in tumors compared to normal cells. We recently identified CIN85 (Cbl-interacting protein 85 KDa), as a new protein that associates with MUC1 in human and mouse cancer cell lines. Immunohistochemistry and confocal immunofluorescence on breast and colon human tissue microarray (TMA) composed of cancer samples and their adjacent normal tissues revealed that hypoglycosylated MUC1 and CIN85 are both over-expressed in early as well as advanced clinical stages of breast and colon cancer and co-localize on invadopodia-like structures implicated in cell invasion. When tested in vivo in a tumor metastasis model of B16 melanoma, mice injected with CIN85-depleted melanoma cells exhibited few or no lung metastasis and overexpression of MUC1 recovered the shCIN85-reduced metastatic process. MUC1-CIN85 complex may represent a promising target for invasion inhibition and an effective alternative or complementary therapy for metastatic cancer. To that end, we are generating novel MUC1 analogs and testing their anti-metastatic activity in vitro and in vivo. CIN85 contains three SH3 domains that recognize a consensus sequence PXXXP that corresponds to the PDTRP sequences found in the VNTR of MUC1 and the PVTRP sequences adjacent to the VNTR region. Molecular dynamics simulations predict that CIN85 would bind MUC1 as a dimer. To test this, we synthesized a MUC1 peptide agonist capable of inducing CIN85 dimerization and enhancing the binding between MUC1 and CIN85. Upon addition of the peptide, the interaction between MUC1 and CIN85 was two times higher than in its absence. Based on this peptide sequence, we designed several drug compounds that can mimic MUC1 binding site for CIN85. Preliminary results revealed that some of them are able to modulate the interaction between CIN85 and MUC1. Interestingly, they also regulate MUC1 phosphorylation, essential step for MUC1-associatated signaling. Based on these preliminary results, we hypothesize that some of these drug compounds will inhibit tumor metastasis in in vivo, which we are currently testing. Citation Format: Sandra Cascio, Joshua Sciurba, Rebecca Hughey, Carlos Camacho, Olivera Finn. Muc1/Cin85 complex is a new molecular target for control of cancer invasion and metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3151. doi:10.1158/1538-7445.AM2014-3151