Correlation between MMPs and their inhibitors in breast cancer tumor tissue specimens and in cell lines with different metastatic potential

Abstract

BackgroundThe metastatic disease rather than the primary tumor itself is responsible for death in most solid tumors, including breast cancer. The role of matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs) and Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in the metastatic process has previously been established. However, in all published studies only a limited number of MMPs/MMP inhibitors was analyzed in a limited number of cell lines. Here, we propose a more comprehensive approach by analyzing the expression levels of several MMPs (MMP-2, MMP-9 and MMP-14) and MMP inhibitors (TIMP-1, TIMP-2 and RECK) in different models (five human breast cancer cell lines, 72 primary breast tumors and 30 adjacent normal tissues).MethodsWe analyzed the expression levels of MMP-2, MMP-9 and MMP-14 and their inhibitors (TIMP-1, TIMP-2 and RECK) by quantitative RT-PCR (qRT-PCR) in five human breast cancer cell lines presenting increased invasiveness and metastatic potential, 72 primary breast tumors and 30 adjacent normal tissues. Moreover, the role of cell-extracellular matrix elements interactions in the regulation of expression and activity of MMPs and their inhibitors was analyzed by culturing these cell lines on plastic or on artificial ECM (Matrigel).ResultsThe results demonstrated that MMPs mRNA expression levels displayed a positive and statistically significant correlation with the transcriptional expression levels of their inhibitors both in the cell line models and in the tumor tissue samples. Furthermore, the expression of all MMP inhibitors was modulated by cell-Matrigel contact only in highly invasive and metastatic cell lines. The enzyme/inhibitor balance at the transcriptional level significantly favors the enzyme which is more evident in tumor than in adjacent non-tumor tissue samples.ConclusionOur results suggest that the expression of MMPs and their inhibitors, at least at the transcriptional level, might be regulated by common factors and signaling pathways. Therefore, the multi-factorial analysis of these molecules could provide new and independent prognostic information contributing to the determination of more adequate therapy strategies for each patient.

Biological network-driven gene selection identifies a stromal immune module as a key determinant of triple-negative breast carcinoma prognosis

“…56,57 The expression and activity of MMPs has been linked to advanced stages of breast cancer, greater tumor invasion and the construction of metastatic formations. 58,59,60 Some studies have highlighted the importance of matrix MMP expression by stromal cells as a prognostic factor in the TNBC subtype. 61 These molecules are thus attractive targets for drug development.…”

MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis

“…In addition to its catalytic domain, MMP-14 contains a short cytoplasmic sequence that is involved in the regulation of the enzyme activity and in the activation of signal transduction processes (Gingras and Be´liveau, 2010). MMP-14 is overexpressed in many types of tumors, including breast carcinomas (Okada et al, 1995;Figueira et al, 2009), where it constitutes an independent predictor of adverse outcome (McGowan and Duffy, 2008).…”

MT1-MMP regulates VEGF-A expression through a complex with VEGFR-2 and Src

“…Increased MT1-MMP expression is more frequently associated with poor outcome in patients who are lymph node and metastases positive for disease (Figueira et al, 2009;Jiang et al, 2006;Kim et al, 2006;Ueno et al, 1997), and increased VEGF-A is also associated with poor prognosis and correlates with MT1-MMP expression (Linderholm et al, 2003;Munaut et al, 2003), suggesting the MT1-MMP-VEGF-A axis might be a key element in tumour progression. An improvement in our understanding of how the VEGF-A-VEGFR-2 axis functions in pathology is of particular importance as inhibitors of the VEGF axis have recently been shown to increase tumorigenicity at metastatic sites in murine models of cancer, which parallels observations emerging from clinical data (Ebos et al, 2009;Paez-Ribes et al, 2009).…”