Matrix metalloproteinase-induced epithelial-mesenchymal transition in breast cancer.
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.
Radisky
Evette S
ES
Mayo Clinic Cancer Center, Griffin Building, 4500 San Pablo Road, Jacksonville, FL 32224, USA. radisky.evette@mayo.edu
Radisky
Derek C
DC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D054337:Cell Dedifferentiation; D054338:Cell Transdifferentiation; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism; D042361:Mammary Glands, Human / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009362:Neoplasm Metastasis; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D020782:Matrix Metalloproteinases