title: KISS1R induces invasiveness of estrogen receptor-negative human mammary epithelial and breast cancer cells.
abstract: Kisspeptins (KPs), peptide products of the KISS1 metastasis-suppressor gene, are 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 patient breast tumors correlates with higher tumor grade and metastatic potential. We have shown that KP-10 stimulates invasion of estrogen receptor α (ERα)-negative MDA-MB-231 breast cancer cells via transactivation of the epidermal growth factor receptor (EGFR). Here, we report that either KP-10 treatment of ERα-negative nonmalignant mammary epithelial MCF10A cells or expression of KISS1R in MCF10A cells induced a mesenchymal phenotype and stimulated invasiveness. Similarly, exogenous expression of KISS1R in ERα-negative SKBR3 breast cancer cells was sufficient to trigger invasion and induced extravasation in vivo. In contrast, KP-10 failed to transactivate EGFR or stimulate invasiveness in the ERα-positive MCF7 and T47D breast cancer cells. This suggested that ERα negatively regulates KISS1R-dependent breast cancer cell migration, invasion, and EGFR transactivation. In support of this, we found that these KP-10-induced effects were ablated upon exogenous expression of ERα in the MDA-MB-231 cells, by down-regulating KISS1R expression. Lastly, we have identified IQGAP1, an actin cytoskeletal binding protein as a novel binding partner of KISS1R, and have shown that KISS1R regulates EGFR transactivation in breast cancer cells in an IQGAP1-dependent manner. Overall, our data strongly suggest that the ERα status of mammary cells dictates whether KISS1R may be a novel clinical target for treating breast cancer metastasis.
authors.affiliation: Department of Physiology, The University of Western Ontario, London, Ontario, Canada, N6A 5C1.
authors.forename: Donna
authors.initials: D
authors.lastname: Cvetkovic
authors.forename: Magdalena
authors.initials: M
authors.lastname: Dragan
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Leith
authors.forename: Zuhaib M
authors.initials: ZM
authors.lastname: Mir
authors.forename: Hon S
authors.initials: HS
authors.lastname: Leong
authors.forename: Macarena
authors.initials: M
authors.lastname: Pampillo
authors.forename: John D
authors.initials: JD
authors.lastname: Lewis
authors.forename: Andy V
authors.initials: AV
authors.lastname: Babwah
authors.forename: Moshmi
authors.initials: M
authors.lastname: Bhattacharya
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D002642:Chick Embryo; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D059648:Kisspeptins / Q000494:pharmacology; D061986:MCF-7 Cells; D042361:Mammary Glands, Human; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D000074502:Receptors, Kisspeptin-1; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; C101203:IQ motif containing GTPase activating protein 1; D007295:Inositol Phosphates; C106628:KISS1 protein, human; C118688:KISS1R protein, human; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D020703:ras GTPase-Activating Proteins; D066246:ErbB Receptors