Kisspeptin/KISS1R System in Breast Cancer

Abstract

Kisspeptins (KP), peptide products of the kisspeptin-1 (KISS1) gene are the endogenous ligands for a G protein-coupled receptor (GPCR) - KP receptor (KISS1R). KISS1R couples to the Gαq/11 signaling pathway. KISS1 is a metastasis suppressor gene and the KP/KISS1R signaling has anti-metastatic and tumor-suppressant effects in numerous human cancers. On the other hand, recent studies indicate that KP/KISS1R pathway plays detrimental roles in breast cancer. In this review, we summarize recent developments in the understanding of the mechanisms regulating KP/KISS1R signaling in breast cancer metastasis.

Keywords: G protein-coupled receptor.; KISS1R; Kisspeptin; breast cancer; invasion; metastasis.

Fig 1

Established and putative signaling pathways coupled to KISS1R. KISS1R is a G_q/11-coupled receptor, resulting in the activation of the primary effector phospholipase C (PLC) and associated secondary effectors such as protein kinase C (PKC) and ERK1/2. KISS1R can also signal via G protein-independent (β-arrestin-dependent) pathway to also activate ERK1/2. KISS1R activates several secondary effectors including p38, phosphatidylinositol-3-kinase (PI3K) but it is not yet known through which pathway they are activated.

Fig 2

Novel KP/KISS1R signaling pathways in breast cancer cells lacking the estrogen receptor, ERα. ERα has been found to negatively regulates KISS1R expression. KISS1R activation in these cells leads to epidermal growth factor (EGFR) transactivation via β-arrestin 2- and IQGAP1-mediated pathways. KISS1R activation can induce epithelial-mesenchymal transition (EMT), resulting in a decrease in E-cadherin expression and acquisition of a mesenchymal phenotype, characterized by actin cytoskeleton re-organization and stress fiber formation. Expression of mesenchymal markers (Snail/slug, N-cadherin, Vimentin) also increases. KP/KISS1R pathway can also activate RhoA. Blue solid lines represent KISS1R interacting proteins; black dashed lines represent EGFR interacting proteins.

Fig 3

Proposed model for ERα-dependent KP/KISS1R signaling in breast epithelia. In normal healthy mammary epithelia, estrogen signaling through ERα is responsible for maintaining normal breast epithelial growth and function, keeping KP/KISS1R signaling in check through transcriptional regulation of KISS and/or KISS1R. However, in breast cancer, when ERα expression is lost or silenced, this results in increased transcription of KISS1 and/or KISS1R, and increased receptor signaling and the induction of EMT, allowing epithelial cells to acquire a more migratory and invasive phenotype.