Matrix metalloproteinase 7 mediates mammary epithelial cell tumorigenesis through the ErbB4 receptor.
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.
Lynch
Conor C
CC
Department of Cancer Biology, Vanderbilt University, 23rd and Pierce Avenue, Nashville, TN 37232, USA.
Vargo-Gogola
Tracy
T
Martin
Michelle D
MD
Fingleton
Barbara
B
Crawford
Howard C
HC
Matrisian
Lynn M
LM
D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells; D066246:ErbB Receptors / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D008321:Mammary Glands, Animal / Q000378:metabolism*; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D066247:Receptor, ErbB-4
D018960:Hyaluronan Receptors; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D020783:Matrix Metalloproteinase 7