Abstract 518: Kisspeptin stimulates invasiveness of ERα -negative human mammary epithelial and breast cancer cells.

Abstract

Recently, we have shown that KP-10 stimulates invasion of estrogen receptor (ERα)-negative breast cancer cells via transactivation of the epidermal growth factor receptor (EGFR) [Zajac et al. (2011) PLoS ONE 6(6): e21599]. Here we report that KP-10 stimulated cell motility and invasiveness of ERα-negative non-malignant mammary epithelial MCF10A cells that endogenously expressing KISS1R, and MCF10A cells stably expressing KISS1R using three-dimensional (3D) Matrigel cultures. Additionally, exogenous expression of KISS1R in ERα-negative SKBR3 breast cancer cells stimulated invasion in 3D cultures and induced extravasation in vivo using chorioallantoic membrane (CAM) assays. Exogenous KISS1R expression in MCF10A and SKBR3 cells also induced a partial epithelial-to-mesenchymal transition like phenotype as evidenced by the acquisition of a spindle-shaped morphology, intracellular localization of the epithelial marker E-cadherin, increased stress fibre formation and elevated levels of the mesenchymal markers, Snail/Slug, vimentin and N-cadherin. In contrast, KP-10 had no effect on migration and invasion of the ERα-positive T47D and MCF7 breast cancer cells and failed to transactivate EGFR in the ERα-positive cells. This suggested that ERα negatively regulates KISS1R-dependent breast cancer cell migration, invasion and EGFR transactivation. In support of this, we found KP-10-stimulated cell migration, invasion and EGFR transactivation were ablated upon stably expressing ERα in the ERα-negative MDA-MB-231 cells. Lastly, we found that KISS1R was localized at the leading edge of motile cells, where it co-localized with the actin scaffolding protein, IQGAP1. We have identified IQGAP1 as a novel binding partner of KISS1R and have demonstrated 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 will dictate whether the KISS1R signaling pathway may be a novel clinical target for the treatment of breast cancer metastasis. Citation Format: Moshmi M. Bhattacharya, Dragana Cvetkovic, Magdalena Dragan, Hon Sing Leong, Andy Babwah. Kisspeptin stimulates invasiveness of ERα -negative human mammary epithelial and breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 518. doi:10.1158/1538-7445.AM2013-518