title: A mouse model of heterogeneous, c-MYC-initiated prostate cancer with loss of Pten and p53.
abstract: Human tumors are heterogeneous and evolve through a dynamic process of genetic mutation and selection. During this process, the effects of a specific mutation on the incipient cancer cell may dictate the nature of subsequent mutations that can be tolerated or selected for, affecting the rate at which subsequent mutations occur. Here we have used a new mouse model of prostate cancer that recapitulates several salient features of the human disease to examine the relative rates in which the remaining wild-type alleles of Pten and p53 tumor suppressor genes are lost. In this model, focal overexpression of c-MYC in a few prostate luminal epithelial cells provokes a mild proliferative response. In the context of compound Pten/p53 heterozygosity, c-MYC-initiated cells progress to prostatic intraepithelial neoplasia (mPIN) and adenocarcinoma lesions with marked heterogeneity within the same prostate glands. Using laser capture microdissection and gene copy number analyses, we found that the frequency of Pten loss was significantly higher than that of p53 loss in mPIN but not invasive carcinoma lesions. c-MYC overexpression, unlike Pten loss, did not activate the p53 pathway in transgenic mouse prostate cells, explaining the lack of selective pressure to lose p53 in the c-MYC-overexpressing cells. This model of heterogeneous prostate cancer based on alterations in genes relevant to the human disease may be useful for understanding pathogenesis of the disease and testing new therapeutic agents.
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.forename: M
authors.initials: M
authors.lastname: Roh
authors.forename: I
authors.initials: I
authors.lastname: Doubinskaia
authors.forename: G N
authors.initials: GN
authors.lastname: Algarroba
authors.forename: I-E A
authors.initials: IE
authors.lastname: Eltoum
authors.forename: S A
authors.initials: SA
authors.lastname: Abdulkadir
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061346:Laser Capture Microdissection; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse