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

Abstract

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.

• Authors: Julie Decock, Wouter Hendrickx, Sally Thirkettle, Ana Gutiérrez-Fernández, Stephen D Robinson, Dylan R Edwards
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 17 Pg. 38 (Mar 14 2015) ISSN: 1465-542X [Electronic] England
• PMID: 25848906 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Viral, Tumor
• Inflammation Mediators
• Matrix Metalloproteinase 8

Topics

• Animals
• Antigens, Viral, Tumor (genetics)
• Cell Transformation, Neoplastic
• Disease Progression
• Female
• Inflammation Mediators (metabolism)
• Lung Neoplasms (secondary)
• Mammary Neoplasms, Experimental (etiology, pathology)
• Mammary Tumor Virus, Mouse (genetics)
• Matrix Metalloproteinase 8 (genetics, metabolism)
• Mice
• Mice, Knockout
• Multigene Family
• Neoplasm Metastasis
• Neovascularization, Pathologic (genetics)
• Neutrophil Infiltration
• Retroviridae Infections (complications)
• Tumor Virus Infections (complications)