Unopposed c-MYC expression in benign prostatic epithelium causes a cancer phenotype.
BACKGROUND
We have sought to develop a new in vivo model of prostate carcinogenesis using human prostatic epithelial cell cultures. Human prostate cancers frequently display DNA amplification in the 8q24 amplicon, which leads to an increase in the copy number of the c-MYC gene, a finding that suggests a role for c-MYC in human prostate carcinogenesis. In addition overexpression of c-MYC in transgenic mouse models results in prostatic carcinogenesis.


METHODS
We took advantage of the ability of retroviruses to integrate foreign DNA into human prostatic epithelium (huPrE) to generate cell lines that overexpress the c-MYC protooncogene. These cells were recombined with inductive rat urogenital sinus mesenchyme and grafted beneath the renal capsule of immunocompromised rodent hosts.


RESULTS
The resultant tissue displayed a phenotype consistent with a poorly differentiated human prostatic adenocarcinoma. The tumors were rapidly growing with a high proliferative index. The neoplastic cells in the tumor expressed both androgen receptors (AR) and prostate-specific antigen (PSA), both characteristic markers of human prostate cancers. Microarray analysis of human prostatic epithelial cells overexpression c-MYC identified a large number of differentially expressed genes some of which have been suggested to characterize a subset of human cancers that have myc overexpression. Specific examples were confirmed by Western blot analysis and include upregulation of c-Myb and decreased expression of PTEN. Control grafts using either uninfected huPrE or using huPrE cells infected using an empty vector expressing a green fluorescent protein tag gave rise to well differentiated benign prostatic glandular ducts.


CONCLUSIONS
By using a retroviral infection strategy followed by tissue recombination we have created a model of human prostate cancer that demonstrates that the c-MYC gene is sufficient to induce carcinogenesis.
Williams
Karin
K
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37212-2765, USA. karin.williams@vanderbilt.edu
Fernandez
Suzanne
S
Stien
Xavier
X
Ishii
Kenichiro
K
Love
Harold D
HD
Lau
Yun-Fai Chris
YF
Roberts
Richard L
RL
Hayward
Simon W
SW
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D014408:Biomarkers, Tumor; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004848:Epithelium / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011467:Prostate / Q000166:cytology* / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics
D014408:Biomarkers, Tumor; D016271:Proto-Oncogene Proteins c-myc; D049452:Green Fluorescent Proteins