Matrilysin (matrix metalloproteinase-7) selects for apoptosis-resistant mammary cells in vivo.
Overexpression of the matrix metalloproteinase matrilysin (matrix metalloproteinase-7) in the mouse mammary gland promotes mammary hyperplasia and accelerates the onset of oncogene-induced mammary tumors. In cell culture models, acute exposure of cells coexpressing Fas and Fas ligand (FasL) to matrilysin induces apoptosis, whereas chronic exposure to matrilysin selects for apoptosis-resistant cells. We now demonstrate that matrilysin promotes resistance to apoptosis in vivo. Matrilysin expression increased apoptosis in the involuting mammary gland of mice that had undergone a single pregnancy and lactation cycle. Premature basement membrane disruption was detected in matrilysin-expressing mice, which could account for the increase in apoptosis. However, multiparous mice, in which the involuting mammary epithelial cells have been repeatedly exposed to matrilysin, show a significant decrease in apoptosis. Mammary tissue from multiparous matrilysin-expressing mice showed decreased FasL expression, suggesting that loss of FasL is at least one mechanism of matrilysin-induced resistance to apoptosis. We propose that matrilysin promotes mammary tumor formation by enhancing the selection of cells that are resistant to apoptosis.
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D005260:Female; D006965:Hyperplasia / Q000201:enzymology / Q000473:pathology; D007774:Lactation; D008321:Mammary Glands, Animal / Q000201:enzymology* / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000201:enzymology / Q000235:genetics; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy
D020783:Matrix Metalloproteinase 7