Prolyl Carboxypeptidase Maintains Receptor Tyrosine Kinase Signaling and Is a Potential Therapeutic Target in Triple Negative Breast Cancer.

Lei Duan,Paolo Gattuso,Virgilia Macias,Sarah Calhoun,Jeffrey A Borgia,Melissa R Pergande,Fatima Mir,Carl G Maki,Ricardo E Perez

doi:10.3390/cancers14030739

Lei Duan, Paolo Gattuso + Show 7 more

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https://doi.org/10.3390/cancers14030739

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Abstract

Simple SummaryTriple negative breast cancer (TNBC) is an aggressive cancer type with limited treatment options and poor prognosis. Our research has revealed that a protein called prolylcarboxypeptidase (PRCP) is a potential therapy target for TNBC. We found that high levels of PRCP in tumors coincides with worse prognosis in TNBC patients. Inhibition of PRCP with a small molecule inhibitor blocked TNBC cell and tumor growth and inhibited the activity of several receptor tyrosine kinases (RTKs), proteins that are located on the surface of cells and that are important for cancer development and progression. Our findings suggest that PRCP is a novel prognostic factor for TNBC and that specific inhibitors of PRCP could be developed for TNBC treatment.TNBC is an aggressive cancer sub-type with limited treatment options and poor prognosis. New therapeutic targets are needed to improve outcomes in TNBC patients. PRCP is a lysosomal serine protease that cleaves peptide substrates when the penultimate amino acid is proline. A role for PRCP in TNBC or other cancers, and its potential as a therapy target has not yet been tested. In the current study, we found high tumor expression of PRCP associates with worse outcome and earlier recurrence in TNBC patients. Knockdown of PRCP or treatment with a small molecule PRCP inhibitor blocked proliferation and survival in TNBC cell lines and inhibited growth of TNBC tumors in mice. Mechanistically, we found PRCP maintains signaling from multiple receptor tyrosine kinases (RTKs), potentially by promoting crosstalk between RTKs and G-protein coupled receptors (GPCRs). Lastly, we found that the PRCP inhibitor caused synergistic killing of TNBC cells when combined with the EGFR and ErbB2 inhibitor lapatinib. Our results suggest that PRCP is potential prognostic marker for TNBC patient outcome and a novel therapeutic target for TNBC treatment.

Highlights

Triple negative (TNBC) breast cancer accounts for 10–20% of all breast cancer cases.TNBC patients have poor prognosis due to the aggressive nature of the tumors, the lack of therapeutic targets, and the high rate of tumor recurrence [1,2]
Ligand binding to receptor tyrosine kinases (RTKs) triggers receptor autophosphorylation and activation of pathways, such as AKT-mTORC1, MAPK-ERK, and others that promote cancer proliferation, survival, and metastasis (ErbB3 lacks kinase activity and mediates signaling through dimerization with EGFR) The importance of RTK signaling in TNBC was illustrated in a recent study examining PTPN12, a tumor suppressor and phosphatase enzyme that is frequently deleted in TNBC [13]
The findings suggest that PRCP is required for AKT activation in response to multiple findings suggest that PRCP is required for AKT activation in response to multiple RTKs

Summary

Introduction

Triple negative (TNBC) breast cancer accounts for 10–20% of all breast cancer cases.TNBC patients have poor prognosis due to the aggressive nature of the tumors, the lack of therapeutic targets, and the high rate of tumor recurrence (metastasis) [1,2]. Multiple receptor tyrosine kinase (RTK) pathways contribute to TNBC growth and progression. These includes the IGF-1R, PDGFR, EGFR, ErbB3 (HER3), FGFR, and c-MET signaling pathways, among others [6,7,8,9,10,11,12]. Ligand binding to RTKs triggers receptor autophosphorylation and activation of pathways, such as AKT-mTORC1, MAPK-ERK, and others that promote cancer proliferation, survival, and metastasis (ErbB3 lacks kinase activity and mediates signaling through dimerization with EGFR) The importance of RTK signaling in TNBC was illustrated in a recent study examining PTPN12, a tumor suppressor and phosphatase enzyme that is frequently deleted in TNBC [13].

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