Induction of mammary gland hyperplasia and carcinomas in transgenic mice expressing human cyclin E.
Deregulated expression of several cell cycle regulatory genes has been demonstrated to be associated with cancer. In particular, a strong correlation has been established between inappropriate cyclin E expression and human breast cancer. To determine the ability of cyclin E to play a causative role in mammary tumorigenesis, regulatory sequences from the ovine beta-lactoglobulin gene were utilized to specifically target expression of human cyclin E to the mammary glands of pregnant and lactating mice. Lactating mammary glands of transgenic mice expressing cyclin E contained areas of hyperplasia, primarily papillary projections of hyperplastic cells, which were rarely observed in lactating glands of control mice. Over 10% of female cyclin E transgenic mice have developed mammary carcinomas, with latencies ranging from 8 to 13 months. Tumor analysis revealed the presence of transgene-specific cyclin E RNA and protein, as well as cyclin E- and cdk2-associated kinase activity, suggesting that cyclin E is likely a contributing component of tumorigenic progression in this model system.
Bortner
D M
DM
Department of Cellular Sciences, Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA. bortner-dm@glaxo.com
Rosenberg
M P
MP
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics*; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D005260:Female; D015870:Gene Expression; D006801:Humans; D006965:Hyperplasia / Q000235:genetics*; D007774:Lactation; D007782:Lactoglobulins / Q000235:genetics; D008223:Lymphoma / Q000201:enzymology; D008321:Mammary Glands, Animal / Q000737:chemistry / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012756:Sheep
D016213:Cyclins; D007782:Lactoglobulins; D011494:Protein Kinases; C102333:histone H1 kinase; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases