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

Abstract

IntroductionMatrix metalloproteinase-8 (MMP-8; neutrophil collagenase) is an important regulator of innate immunity that has oncosuppressive actions in numerous tumor types.MethodsWe 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.ResultsIn 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.ConclusionsThese 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.

Persistent Oral Human Papillomavirus (HPV) Infection is Associated with Low Salivary Levels of Matrix Metalloproteinase 8 (MMP-8)

“…The salivary MMP-8 levels were highest in non-smoking women without oral HPV infection. This result is in line with the earlier observations indicating the protective role of MMP-8 [22][23][24][25][26][27][28][29]. Based on this study, however, it cannot be concluded whether a low salivary MMP-8 concentration indicates a condition with an increased risk for chronic HPV infection or if the infection itself lowers MMP-8 expression.…”

“…Furthermore, HPV16 E7 increases the activity of MMP-9 in vitro [21]. In contrast, MMP-8 seems to have a protective role in a variety of cancers [22][23][24][25][26] and inflammatory diseases [27][28][29]. In a population based study, MMP-8 levels were positively associated with better disease specific survival of the patients with a tongue SCC [22].…”

Loss of MMP-8 in ductal carcinoma in situ (DCIS)-associated myoepithelial cells contributes to tumour promotion through altered adhesive and proteolytic function

“…MMP-8 was identified as a tumour suppressor nearly a decade ago when the MMP-8 knock-out mouse was found to be more susceptible to skin tumuorigenesis as compared to a WT mouse [28]. There is also strong evidence for a role in tumour prevention in breast cancer, melanoma and squamous cell carcinoma [22, 26, 28, 29, 31, 32, 56–59]. Particularly in melanoma; MMP-8 is frequently mutated by loss of heterozygosity (LOH), which is a hallmark for tumour-suppressor proteins [22].…”

“…Since it was first reported that MMP-8 -/- mice exhibit increased incidence of skin tumours when challenged with chemical carcinogenesis, MMP-8 has been demonstrated to exert a clear tumour-suppressor function [22, 26, 28, 29]. There is a growing body of evidence accumulating that MMP-8 has an anticancer role in breast cancer, malignant melanoma and tongue squamous cell carcinoma, [22, 26, 28, 30–32]. Interestingly, identification of non-structural substrates of MMP-8 [28, 33–37], suggests that the biological function of MMP-8 is much more complicated than just Col-I degradation.…”

Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer

“…MMP-8 provides one of the more clear-cut examples of this phenomenon. In mouse models of breast cancer, high expression of MMP-8 suppresses metastasis, while MMP-8 silencing or knockout promotes tumor progression and metastasis [Montel et al 2004; Decock et al 2015]. Importantly, the net antitumor effect of MMP-8 is corroborated by the association of MMP-8 tumor expression with longer relapse-free survival in breast cancer patients [Gutiérrez-Fernández et al 2008], and by the association of a high expression promoter variant of the MMP-8 gene with more favorable prognosis [Decock et al 2007].…”