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, complement C1r/C1s, Uegf, Bmp1 (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 with flCDCP1, induced a dramatic increase in phosphorylation of the migration-associated proteins: PKCδ, ERK1/2 and p38 mitogen-activated protein kinase in HEK 293T. In addition, only cCDCP1 induced migration of HEK 293T cells and rescued migration of the TNBC cell lines expressing short hairpin RNA 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. We found that ECC inhibited phosphorylation of PKCδ and migration of TNBC cells in two-dimensional culture. Furthermore, ECC decreased cell invasiveness, inhibited proliferation and stimulated apoptosis of TNBC cells in three-dimensional culture, indicating that the cCDCP1 dimer is an important contributor to TNBC aggressiveness. These studies have important implications for the development of a therapeutic to block CDCP1 activity and TNBC metastasis.
Subject(s)
Antigens, CD/genetics , Cell Adhesion Molecules/genetics , Neoplasm Proteins/genetics , Protein Isoforms/genetics , Triple Negative Breast Neoplasms/genetics , Antigens, CD/chemistry , Antigens, Neoplasm , Apoptosis , Cell Adhesion/genetics , Cell Adhesion Molecules/chemistry , Cell Movement/genetics , Dimerization , HEK293 Cells , Humans , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/chemistry , Phosphorylation , Protein Isoforms/biosynthesis , Signal Transduction/genetics , Triple Negative Breast Neoplasms/pathology , p38 Mitogen-Activated Protein Kinases/geneticsABSTRACT
In the title compound, C(9)H(10)O(4), the dihedral angle between the benzene ring and the -CO(2) unit is 11.93â (8)° and the conformation of the 2-hy-droxy-ethyl side chain is gauche [O-C-C-O = -71.91â (17)°]. In the crystal, mol-ecules are linked by O-Hâ¯O and C-Hâ¯O hydrogen bonds.
