Abstract
To delineate the role of matrix metalloproteinase 7 (MMP7) in mammary tumorigenesis, MMP7 was expressed in the normal murine mammary gland cell line, c57MG. MMP7 markedly enhanced the growth rate of the c57MG cells in three-dimensional culture and promoted tumor formation in vivo. Subsequent investigation showed that MMP7 (a) up-regulated ErbB4 receptor levels, (b) solubilized the ErbB4 receptor cognate ligand heparin-bound epidermal growth factor, and (c) mediated the proteolytic processing of ErbB4 to yield a soluble intracellular domain (ICD) that localized to the cytoplasm and the nucleus. Furthermore, overexpression of the ErbB4 ICD in the c57MG cell line recapitulated the proliferative effects of MMP7 in vitro and in vivo. These data indicate a novel mechanism for mammary epithelial cell transformation by MMP7.
Highlights
Matrix metalloproteinases (MMP) have been implicated in the invasion and metastasis of breast cancer due to their ability to degrade the extracellular matrix [1]
Analysis of the cell growth under monolayer conditions showed that matrix metalloproteinase 7 (MMP7) expression resulted in a slight but significant 0.24-fold shorter doubling time (Dt) compared with the vector controls
We present a mechanism through which MMP7 can mediate these effects (Fig. 6)
Summary
Matrix metalloproteinases (MMP) have been implicated in the invasion and metastasis of breast cancer due to their ability to degrade the extracellular matrix [1]. In recent years, it has become apparent that the MMPs are exquisite regulators of cell:cell communication by virtue of their ability to process many nonmatrix molecules, such as cytokines and growth factors [1]. The MMPs can affect tumor progression on multiple levels, including tumor growth, apoptosis, angiogenesis, and immunoevasion. Immunohistochemical studies have shown that MMP7 is highly expressed during the early stages of human breast cancer [2, 3]. Transgenic mice that express MMP7 in the mammary epithelium have been shown to develop areas of hyperplasia in the mammary gland by as yet unidentified mechanisms [4]
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