TY - JOUR
T1 - Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer
AU - Radisky, Evette S.
AU - Raeeszadeh-Sarmazdeh, Maryam
AU - Radisky, Derek C.
N1 - Funding Information:
This work was supported by NCI grants (R01CA154387 and R21CA205471 to ESR) and (R01CA187692 to DCR), the Bankhead-Coley Foundation (5BC02 to DCR), and the Mayo Clinic SPORE in Breast Cancer grant P50CA116201 (PI James Ingle).
Publisher Copyright:
© 2017 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc.
PY - 2017/11
Y1 - 2017/11
N2 - 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.
AB - 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.
KW - BREAST CANCER
KW - CANCER BIOMARKERS
KW - EPITHELIAL MESENCHYMAL TRANSITION
KW - MATRIX METALLOPROTEINASES
KW - MMP INHIBITORS
KW - TISSUE INHIBITORS OF METALLOPROTEINASES
KW - TUMOR MICROENVIRONMENT
KW - TUMOR PROGRESSION
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U2 - 10.1002/jcb.26185
DO - 10.1002/jcb.26185
M3 - Article
C2 - 28585723
AN - SCOPUS:85024369497
SN - 0730-2312
VL - 118
SP - 3531
EP - 3548
JO - Journal of supramolecular structure and cellular biochemistry
JF - Journal of supramolecular structure and cellular biochemistry
IS - 11
ER -