The MSP-RON axis stimulates cancer cell growth in models of triple negative breast cancer.

Rhona Millar,Karen Blyth,Anna Kilbey,Tesa M Severson,Sarah‐Jane Remak,David M Bryant,Sandeep Dhayade,Emma Sandilands,Seth B Coffelt,Kyla Foster

doi:10.1002/1878-0261.12734

Abstract

Triple‐negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis and high rates of relapse. The lack of actionable targets for TNBC has contributed to the high mortality rates of this disease, and new candidate molecules for potential manipulation are urgently required. Here, we show that macrophage‐stimulating protein (MSP) and its tyrosine kinase receptor, Recepteur d’origine nantais (RON), are potent drivers of cancer cell growth and tumor progression in a mouse model of TNBC driven by the loss of Trp53 and Brca1. After comparison of two genetically engineered mouse models of TNBC, we found that mammary tumors from K14‐Cre;Brca1 F/F ;Trp53 F/F (KB1P) mice exhibit high endogenous levels of MSP and RON expression. We show that MSP stimulates serine/threonine kinase 1 and extracellular regulated MAPK activation as well as cancer cell growth in cell lines derived from the two mouse models, while genetic and pharmacological inhibition of RON prevents these effects. Similarly, KB1P tumor progression in mice was robustly attenuated by treatment with a RON inhibitor with accompanied reduction in the proliferation marker, Ki‐67. Analysis of human gene expression data confirmed that the genes encoding MSP and RON are robustly expressed in human TNBC as well as other subsets of breast cancer. Our findings uncover a mouse model where MSP expression and RON expression are naturally increased, and they provide evidence that this receptor and its ligand are viable candidate molecules for targeted treatment of breast cancer.

Highlights

Triple-negative breast cancer (TNBC) represents a subgroup of about 15–20% of breast tumors that lacks expression of three main biomarkers: estrogen receptor (ER), progesterone receptor, and epidermal growth factor receptor 2 (HER2) amplification (Bianchini et al, 2016)
We found that the expression of the Mst1 gene—which encodes the Recepteur d’origine nantais (RON) receptor ligand, macrophage-stimulating protein (MSP)—is increased in KB1P tumors when compared with KP tumors
Mst1 levels were increased in KB1P tumors when compared to normal mammary gland tissue (MG) and KP tumors, while Mst1r levels were lower in both KP and KB1P tumors when compared to mammary glands (MG) (Fig. 1A)

Summary

Introduction

Triple-negative breast cancer (TNBC) represents a subgroup of about 15–20% of breast tumors that lacks expression of three main biomarkers: estrogen receptor (ER), progesterone receptor, and epidermal growth factor receptor 2 (HER2) amplification (Bianchini et al, 2016). AKT, serine/threonine kinase 1; BRCA1, breast cancer 1; ER, estrogen receptor; ERK1/2, extracellular regulated MAPK; FPKM, fragments per kilobase of transcript per million mapped reads; HER2, human epidermal growth factor receptor 2; KB1P, K14-Cre;Brca1F/F;Trp53F/F; KP, K14-Cre;Trp53F/F; MAPK, mitogen-activated protein kinase; MMTV-PyMT, murine mammary tumor virus–polyoma middle T antigen; MSP, macrophage-stimulating protein; MST1, macrophage stimulating 1; MST1R, macrophage stimulating 1 receptor; RON, Recepteur d’origine nantais; TNBC, triple-negative breast cancer. TNBC is highly heterogeneous, but unlike ER-positive and HER2-amplified breast cancers, the discovery of uniform actionable molecular targets has eluded researchers (Bianchini et al, 2016). The absence of approved targeted therapies for TNBC leaves chemotherapy as the only therapeutic option

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