Abstract
Two rapidly evolving fields are converging to impact breast cancer: one has identified novel substrates of metalloproteinases that alter immune cell function, and the other has revealed a role for inflammation in human cancers. Evidence now shows that the mechanisms underlying these two fields interact in the context of breast cancer, providing new opportunities to understand this disease and uncover novel therapeutic strategies. The metalloproteinase class of enzymes is well studied in mammary gland development and physiology, but mostly in the context of extracellular matrix modification. Aberrant metalloproteinase expression has also been implicated in breast cancer progression, where these genes act as tumor modifiers. Here, we review how the metalloproteinase axis impacts mammary physiology and tumorigenesis and is associated with inflammatory cell influx in human breast cancer, and evaluate its potential as a regulator of inflammation in the mammary gland.
Highlights
Breast cancer continues to be one of the leading causes of cancer-related mortality in women in the western world
MMP3 overexpression driven by the whey acidic protein promoter or MMP7 overexpression under the mouse mammary tumor virus (MMTV) promoter both lead to mammary tumor formation at low frequency [32,33], while MMP7 deficiency results in 60% reduction of early mammary lesions in a chemical carcinogenesis model [34]
A few studies using mice point to a protective role of immune cells in tumorigenesis: concurrent lack of the immune mediators granulocyte macrophage Colony stimulating factor (CSF) (GM-CSF)1 and interferon-γ lead to spontaneous tumor formation in mice, including mammary adenocarcinoma [49]; and the loss of neutrophil collagenase, MMP8, leads to increased susceptibility to skin cancer due to ineffectual neutrophil infiltration, indicating the importance of a timely inflammatory response in protecting against skin carcinogenesis [50]
Summary
Breast cancer continues to be one of the leading causes of cancer-related mortality in women in the western world. While genetic deletion of MMP3 in the gland does not affect epithelial apoptosis, immature adipocytes have increased differentiation, displaying accelerated adipogenesis; an effect phenocopied by TIMP1 overexpression [25] These studies highlight the importance of tissue interactions during involution, with the mammary stroma actively contributing towards epithelial cell death. A few studies using mice point to a protective role of immune cells in tumorigenesis: concurrent lack of the immune mediators granulocyte macrophage CSF (GM-CSF) and interferon-γ lead to spontaneous tumor formation in mice, including mammary adenocarcinoma [49]; and the loss of neutrophil collagenase, MMP8, leads to increased susceptibility to skin cancer due to ineffectual neutrophil infiltration, indicating the importance of a timely inflammatory response in protecting against skin carcinogenesis [50]. While this one study shows intriguing trends, further clinical studies that document lymphocyte involvement are needed to reveal the association between global gene expression patterns, inflammation, and breast cancer
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