Matrix Metalloproteinase-Induced Epithelial-Mesenchymal Transition in Breast Cancer

Abstract

Matrix metalloproteinases (MMPs) degrade and modify the extracellular matrix (ECM) as well as cell-ECM and cell-cell contacts, facilitating detachment of epithelial cells from the surrounding tissue. MMPs play key functions in embryonic development and mammary gland branching morphogenesis, but they are also upregulated in breast cancer, where they stimulate tumorigenesis, cancer cell invasion and metastasis. MMPs have been investigated as potential targets for cancer therapy, but clinical trials using broad-spectrum MMP inhibitors yielded disappointing results, due in part to lack of specificity toward individual MMPs and specific stages of tumor development. Epithelial-mesenchymal transition (EMT) is a developmental process in which epithelial cells take on the characteristics of invasive mesenchymal cells, and activation of EMT has been implicated in tumor progression. Recent findings have implicated MMPs as promoters and mediators of developmental and pathogenic EMT processes in the breast. In this review, we will summarize recent studies showing how MMPs activate EMT in mammary gland development and in breast cancer, and how MMPs mediate breast cancer cell motility, invasion, and EMT-driven breast cancer progression. We also suggest approaches to inhibit these MMP-mediated malignant processes for therapeutic benefit.

Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

“…Consistent with this idea, gain in hSETD1A gene copy number is detected in approximately 45% of breast tumors (39). Finally, increased MMP activity is commonly observed in breast cancer cells and promotes a variety of cellular activities including proliferation, migration, and invasion (33,(40)(41)(42)(43). Taken together, these facts prompted us to investigate a possible link between hSETD1A, H3K4me3, MMP expression, and metastatic breast cancer phenotype.…”

“…MMPs are widely known as critically important in promoting cancer cell migration and invasion by degrading extracellular matrix proteins (33,(40)(41)(42)(43). As previous work from our group indicated that hSETD1A was required for MMP7 expression in colorectal tumor lines (26), we examined a number of MMP genes that could be potentially affected by hSETD1A knockdown in breast cancer cells.…”

“…MMPs are enzymes which catalyze degradation of extracellular matrix components and are secreted by cells within the tumor microenvironment and/or by the tumor cells themselves. This activity promotes cancer cell invasion, migration, and proliferation, and associates with poorer survival in breast cancer (33,(40)(41)(42)(43).…”

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

“…Another group of molecules with the ability to induce EMT in physiological and pathological conditions are the metalloproteinases (MMP) (reviewed in [51]). The role of MMPs as EMT inducers has been described in kidney, lung, ovary, oral, and mammary epithelium [52][53][54][55][56][57].…”

PRSS3/mesotrypsin in prostate cancer progression: implications for translational medicine

“…8,9 Identifying proteases that drive tumor progression and metastasis, and defining their specific mechanisms of action, can potentially reveal novel druggable targets and underexplored avenues for slowing or halting the spread of metastatic disease. 10 Moreover, as extracellular molecules with binding sites for highly specific substrate ligands, secreted proteases are more amenable to pharmacological inhibition that are many oncogenic signaling pathways within the cell.…”