3 years ago

Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer

Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer
Maryam Raeeszadeh-Sarmazdeh, Derek C. Radisky, Evette S. Radisky
Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that cleave nearly all components of the extracellular matrix as well as many other soluble and cell-associated proteins. MMPs have been implicated in normal physiological processes, including development, and in the acquisition and progression of the malignant phenotype. Disappointing results from a series of clinical trials testing small molecule, broad spectrum MMP inhibitors as cancer therapeutics led to a re-evaluation of how MMPs function in the tumor microenvironment, and ongoing research continues to reveal that these proteins play complex roles in cancer development and progression. It is now clear that effective targeting of MMPs for therapeutic benefit will require selective inhibition of specific MMPs. Here, we provide an overview of the MMP family and its biological regulators, the tissue inhibitors of metalloproteinases (TIMPs). We then summarize recent research from model systems that elucidate how specific MMPs drive the malignant phenotype of breast cancer cells, including acquisition of cancer stem cell features and induction of the epithelial–mesenchymal transition, and we also outline clinical studies that implicate specific MMPs in breast cancer outcomes. We conclude by discussing ongoing strategies for development of inhibitors with therapeutic potential that are capable of selectively targeting the MMPs most responsible for tumor promotion, with special consideration of the potential of biologics including antibodies and engineered proteins based on the TIMP scaffold. J. Cell. Biochem. 118: 3531–3548, 2017. © 2017 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc. Matrix metalloproteinases (MMPs) have been implicated in the acquisition and progression of the malignant phenotype, yet early clinical trials of MMP inhibitors as cancer therapeutics led to disappointing results. It is now clear that effective targeting of MMPs for therapeutic benefit will require selective inhibition of specific MMPs. Here, we provide an overview of the role of MMPs in breast cancer malignancy and outline clinical studies that implicate specific MMPs in breast cancer outcomes. We then discuss current strategies for development of selective MMP inhibitors with therapeutic potential, with special consideration of biologics including antibodies and engineered proteins based on the TIMP scaffold.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/jcb.26185

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