MET and MYC cooperate in mammary tumorigenesis.
In human breast cancer, overexpression of the protooncogene MET is strongly associated with poor prognosis and high risk of metastasis. It stands out as a reliable prognostic indicator of survival and defines a set of tumors exclusive of those that express HER2 or hormone receptors. Studies have shown that overexpression of mutant forms of MET cause cancer in mice. However, MET mutations have not been found in human breast cancer, and the consequences of overexpression of normal MET are unknown. To investigate the role of MET and other putative oncogenes in breast cancer, we developed an experimental system that involves retroviral delivery of genes into primary mammary epithelial cells, followed by transplantation of the transduced cells into mammary fat pads. Using this approach, we found that overexpression of wild-type MET leads to the development of nonprogressive neoplasms. The lesions progressed to mammary adenocarcinoma when a second protooncogene, MYC, was overexpressed, indicating that MET and MYC cooperate in mammary tumorigenesis. Both the nonprogressive neoplasms and adenocarcinomas display characteristics consistent with transformation and expansion of mammary progenitor cells. The approach described here should provide a useful model with which to efficiently test effects of various genes on tumor development in the breast.
Welm
Alana L
AL
G. W. Hooper Research Foundation and Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA. awelm@itsa.ucsf.edu
Kim
Suwon
S
Welm
Bryan E
BE
Bishop
J Michael
JM
D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism / Q000637:transplantation; D005260:Female; D015870:Gene Expression; D016259:Genes, myc; D005822:Genetic Vectors; D006801:Humans; D007633:Keratins / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D011519:Proto-Oncogenes; D012190:Retroviridae / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D014161:Transduction, Genetic
D007633:Keratins; D019859:Proto-Oncogene Proteins c-met
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