Abstract PS4-42: Kiss1, the kiss1 receptor (kiss1r) and the protein kinase c (pkc) family identifies patients with clinical outcome in clinical breast cancer

Abstract

Abstract Background: Kiss1, also known as Kisspeptin-1 and metastin, is a protein coded by the KISS1 gene (1). The receptor for KISS1, KISS1R (also known as G-protein coupled receptor 54 or GPR54 is coded by the KISS1R gene. Kiss1 and Kiss1R have been indicated in a number of pathophysiological conditions, including metabolic and reproductive abnormalities and the protein complex has been well indicated in the development and progression of a number of solid cancers including the metastatic potential of cancer cells (1) and in clinical cancers including breast cancer (2). Here, the intracellular events associated with KISS1/KISS1R signalling have been explored, including focal adhesion kinase and phospholipase-C (PLC) pathways where we employed a protein kinase platform together with a clinical breast cohort in order to explore protein kinases that are involved in KISS1 signalling and the clinical significance. Methods: A protein kinase microarray (Kinexus850) was employed to detect the cellular kinase responses to exogenous Kisspeptin stimulation. Kiss1, Kiss1 receptor (KISS1R or GPR54) and the prospective members of the protein kinase C (PKC) family members were assessed for the expression in a Cardiff breast cancer cohort and were analysed against the pathological and clinical outcomes of the patients. Results. Using the Kinexus protein kinase platform, we identified that some key members of the protein kinase C family were upregulated in response to treatment with exogenous Kisspeptin. These members include Protein kinase C (PKC)-gamma, PKC-iota, PKC-zeta and PKC-delta, which are potential downsteam targets of KISS1/KISS1R. In our clinical cohort, KISS1 was significantly correlated with the expression levels of PKC-iota (p=0.01) and PKC-gamma (p<0.001). Similarly, KISS1 receptor (KISS1R) was also significantly correlated with both PKC-gamma and PKC-iota. Neither PKC-delta nor PKC-zeta showed a correlation with KISS1 and KISS1R in the clinical cohort. When KISS1, KISS1R, PKC-gamma and PKC-iota were collectively analysed against clinical outcome of the patients, the four molecules identified a subset of the patients who had all survived the ten year followup period (OS) and with no breast cancer related incidence (DFS). The subgroup consisted of all Her-2 negative tumours but with variable nodal and disease stages. Multivariate analyses indicate that the collective expression pattern of KISS1, KISS1R, PKC-gamma and PKC-iota is an independent prognostic factor for disease free survival in breast cancer patients. Discussion: Protein kinase C (PKC) family members, including PKC-gamma and PKC-iota, are important downstream intracellular events in response to KISS1/KISS1R activation. These protein kinase C members together with KISS1/KISS1R protein complex identify a subset of patients with breast cancer who have favourable prognosis.