Master of Science
Dr. Moshmi Bhattacharya
Kisspeptins (KP), peptide products of the kisspeptin-1 (KISS1) gene are the endogenous ligands for a G protein-coupled receptor (KISS1R). KISS1 acts as a metastasis suppressor in numerous human cancers. However, recent studies have demonstrated that an increase in KISS1 and KISS1R expression in human breast tumors correlates with higher tumor grade and metastatic potential. We have previously shown that KP-10, the most potent KP, stimulates invasion of estrogen receptor (ER)-negative breast cancer cells via transactivation of the epidermal growth factor receptor (EGFR). Here, I report that KP-10 treatment of the ER-negative non-malignant mammary epithelial MCF10A cells, or stable expression of KISS1R in MCF10A and SKBR3 breast cancer cells stimulated cell invasiveness. KISS1R expression in these cells induced a partial epithelial-to-mesenchymal transition (EMT)-like phenotype. However, KP-10 had no effect on migration and invasion of the ER-positive T47D and MCF7 breast cancer cells. Furthermore, KP-10 stimulated EGFR transactivation in the ER-negative, but not in the ER-positive cells. KP-10-stimulated cell migration, invasion and EGFR transactivation were ablated upon stable expression of ERα in the ER-negative MDA-MB-231 cells. Lastly, I found that KISS1R was localized at the leading edge of motile cells, where it co-localized with the actin scaffolding protein, IQGAP1. Furthermore, I identified IQGAP1 as a novel binding partner of KISS1R and have demonstrated that KISS1R regulates breast cancer cell migration and invasion in an IQGAP1-dependent manner. Overall, these data reveal for the first time that the ER status of mammary cells may dictate whether KISS1R signaling pathway may be a novel target for breast cancer metastasis.
Cvetkovic, Donna, "KISS1R Induces Human Mammary Epithelial Cell Invasiveness and Promotes Breast Cancer Cell Migration and Invasion via IQGAP1" (2012). Electronic Thesis and Dissertation Repository. 684.