Journal Article

Pleiotropic functions of the tumor- and metastasis-suppressing matrix metalloproteinase-8 in mammary cancer in MMTV-PyMT transgenic mice

Hendrickx, Wouter, Thirkettle, Sally, Robinson, Stephen D, Edwards, Dylan R, Decock, Julie, Gutiérrez-Fernández, Ana

2015

Overview

Introduction Matrix metalloproteinase-8 (MMP-8; neutrophil collagenase) is an important regulator of innate immunity that has oncosuppressive actions in numerous tumor types. Methods We have intercrossed Mmp8 -null mice with the Polyoma virus middle T oncogene-driven (MMTV-PyMT) mouse model of mammary cancer to explore the effects of loss of MMP-8 on the incidence and progression of mammary carcinomas. Results In this aggressive mouse model of breast cancer, loss of MMP-8 accelerated tumor onset even further, such that 90% of MMTV-PyMT ; Mmp8 -null female mice were tumor-bearing at the time of weaning. Throughout the 14 weeks of the model, tumor burden increased in homozygous Mmp8 -null mice compared to Mmp8 -wild-type and -heterozygote animals. Likewise, lung metastasis dramatically increased in the MMTV-PyMT ; Mmp8 -null mice. Immunohistochemistry revealed that tumors in wild-type, Mmp8 -heterozygotes and -null animals had similar vascular density at 8 weeks, but at 10 weeks Mmp8 -wild-type tumors had a lower vascularity than their heterozygote and null counterparts. No differences in macrophage infiltration were apparent throughout primary tumor development, though at 10 weeks a drop in neutrophil infiltrates was observed in Mmp8 -wild-type tumors. Using quantitative real-time RT-PCR, we tracked the expression of the entire Mmp and Timp gene families, observing a significant decrease in Mmp3 expression in Mmp8 -null tumors compared to wild-type and heterozygotes throughout the time course of the model, which was confirmed at the protein level. Conclusions These findings provide novel insight into the suppressive action of MMP-8 on mammary tumorigenesis and metastasis, and indicate that the loss of MMP-8 likely has pleiotropic effects on innate immunity and angiogenesis that are reflected in changes in the protease web.

• Publisher: BioMed Central,BioMed Central Ltd
• Subject: Analysis / Animals / Antigens, Viral, Tumor - genetics / Biomedical and Life Sciences / Biomedicine / Breast cancer / Cancer Research / Cell Transformation, Neoplastic / Disease Progression / Female / Genetic engineering / Inflammation Mediators - metabolism / Lung Neoplasms - secondary / Mammary Neoplasms, Experimental - etiology / Mammary Neoplasms, Experimental - pathology / Mammary Tumor Virus, Mouse - genetics / Matrix Metalloproteinase 8 - genetics / Matrix Metalloproteinase 8 - metabolism / Metastasis / Mice / Mice, Knockout / Multigene Family / Neoplasm Metastasis / Neovascularization, Pathologic - genetics / Neutrophil Infiltration / Oncology / Proteases / Research Article / Retroviridae Infections - complications / Surgical Oncology / Tumor Virus Infections - complications