Prolylcarboxypeptidase Promotes IGF1R/HER3 Signaling and Is a Potential Target to Improve Endocrine Therapy Response in Estrogen Receptor Positive Breast Cancer

Background Prolylcarboxypeptidase (PRCP) is a lysosomal serine protease that cleaves peptide substrates when the penultimate amino acid is proline. Previous studies have linked PRCP to blood-pressure and appetite control through its ability to cleave peptide substrates such as angiotensin II and a-MSH. A potential role for PRCP in cancer has to date not been widely appreciated. Endocrine therapy resistance in breast cancer is an enduring clinical problem mediated in part by aberrant receptor tyrosine kinase (RTK) signaling. We previously found PRCP overexpression promoted tamoxifen (TAM) resistance in estrogen receptor-positive (ER+) breast cancer cells. Currently we tested the potential association between PRCP with breast cancer patient outcome and RTK signaling, and tumor responsiveness to endocrine therapy. Methods We analyzed PRCP protein expression by IHC staining of ER+ breast cancer samples and PRCP gene expression in clinical databases and used Kaplan-Meier survival curves to determine the significance of PRCP expression correlation with recurrence free survival and overall survival. We analyzed PRCP-regulated IGF1R/HER3 signaling using immunoblotting in the ER+ MCF7 cell line. We analyzed the therapeutic effect of a PRCP specific inhibitor (PRCPi) and/or endoxifen on tumor growth of ER+ PDX tumors and MCF7 tumors in immunocompromised mice. ResultsWe found high PRCP protein levels in tumors associates with worse outcome and earlier recurrence in breast cancer patients, including patients treated with TAM. Analyses of clinical databases showed that PRCP expression correlates with IGF1 and NRG1 expression and their target genes and earlier recurrence in endocrine-treated ER+/HER2- breast cancer patients. Overexpression of PRCP increased IGF1R/HER3 signaling. PRCPi blocked IGF1R/HER3 signaling and enhanced the response of ER+ breast cancer tumors in mice to endoxifen, the active metabolite of TAM. ConclusionsPRCP is an adverse prognostic marker in breast cancer and a potential target to improve endocrine therapy in ER+ breast cancers.