title: Matrix metalloproteinase 9 promoter activity is induced coincident with invasion during tumor progression.
abstract: Matrix metalloproteinase 9 (MMP-9, also known as gelatinase B or 92-kd Type IV collagenase) is overexpressed in many human and murine cancers. We induced carcinomas in mice carrying a transgene that links the MMP-9 promoter to the reporter ss-galactosidase so that activation of the MMP-9 promoter would be indicated by ss-galactosidase. Mammary carcinomas were induced by mating the MMP-9 promoter reporter transgenic mice with mice carrying a transgene for murine mammary tumor virus promoter linked to polyoma middle T antigen, a transgene that leads to rapid development of mammary tumors in female mice. None of the hyperplastic mammary glands and none of the carcinomas in situ expressed ss-galactosidase. However, all invasive tumors had evidence of ss-galactosidase expression. In addition to the breast carcinomas, a malignant teratoma in a female and a papillary adenocarcinoma in the pelvic region of a male arose and were also ss-galactosidase positive. We also induced skin tumors in the mice with the MMP-9 reporter transgene with 7, 12-dimethylbenz[a]anthracene (DMBA) treatment followed by phorbol 12 myristate 13-acetate (TPA). None of the papillomas or in situ carcinomas showed any ss-galactosidase expression, but expression was seen in invasive carcinoma. Although normal skin epithelial cells did not express ss-galactosidase, we did find staining in a few cells at the duct of the sebaceous gland at the base of the hair follicles. The MMP-9 reporter transgene did not lead to expression in the alveolar macrophages, confirming that additional upstream sequences are required for expression in macrophages. These experiments have revealed that MMP-9 promoter activity is induced coincident with invasion during tumor progression. Furthermore, this indicates that the more proximal upstream elements of the promoter are sufficient for MMP-9 transcription during tumor progression.
authors: Departments of Pathology and Laboratory Medicine and Otorhinolaryngology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: M E
authors: ME
authors: Kupferman
authors: M E
authors: ME
authors: Fini
authors: W J
authors: WJ
authors: Muller
authors: R
authors: R
authors: Weber
authors: Y
authors: Y
authors: Cheng
authors: R J
authors: RJ
authors: Muschel
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D017930:Genes, Reporter / Q000502:physiology; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009361:Neoplasm Invasiveness; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000502:physiology*; D011817:Rabbits; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019076:Transgenes / Q000502:physiology; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D000952:Antigens, Polyomavirus Transforming; D001616:beta-Galactosidase; D020780:Matrix Metalloproteinase 9