title: Caveolin-1 upregulation contributes to c-Myc-induced high-grade prostatic intraepithelial neoplasia and prostate cancer.
abstract: Previously we reported caveolin-1 (Cav-1) overexpression in prostate cancer cells and showed that it promotes prostate cancer progression. Here, we report that Cav-1 was overexpressed in 41.7% (15 of 36) of human high-grade prostatic intraepithelial neoplasia (HGPIN) specimens obtained during radical prostatectomies. Positive correlations exist between Cav-1-positive (Cav-1(+)) HGPIN and Cav-1(+) primary prostate cancer (rho = 0.655, P < 0.0001) and between Cav-1 and c-Myc expression in HGPIN (rho = 0.41, P = 0.032). To determine whether Cav-1 cooperates with c-Myc in development of premalignant lesions and prostate cancer in vivo, we generated transgenic mice with c-Myc overexpression driven by the ARR(2)PB promoter. In this ARR(2)PB-c-myc model, Cav-1 overexpression was found in mouse PIN (mPIN) lesions and prostate cancer cells and was associated with a significantly higher ratio of proliferative to apoptotic labeling in mPIN lesions than in the Cav-1-negative epithelia adjacent to those lesions (10.02 vs. 4.34; P = 0.007). Cav-1 overexpression was also associated with increased levels of P-Akt and VEGF-A, which were previously associated with Cav-1-induced prostate cancer cell survival and positive feedback regulation of cellular Cav-1 levels, respectively. In multiple prostate cancer cell lines, Cav-1 protein (but not mRNA) was induced by c-Myc transfection, whereas VEGF siRNA transfection abrogated c-Myc-induced Cav-1 overexpression, suggesting a c-Myc-VEGF-Cav-1 signaling axis. Overall, our results suggest that Cav-1 is associated with c-Myc in the development of HGPIN and prostate cancer. Furthermore, Cav-1 overexpression in HGPIN is potentially a biomarker for early identification of patients who tend to develop Cav-1(+) primary prostate cancer.
authors.affiliation: Department of Genitourinary Medical Oncology-Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Alexei A
authors.initials: AA
authors.lastname: Goltsov
authors.forename: Chengzhen
authors.initials: C
authors.lastname: Ren
authors.forename: Shinji
authors.initials: S
authors.lastname: Kurosaka
authors.forename: Kohei
authors.initials: K
authors.lastname: Edamura
authors.forename: Richard
authors.initials: R
authors.lastname: Logothetis
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
authors.forename: Patricia
authors.initials: P
authors.lastname: Troncoso
authors.forename: Jorge
authors.initials: J
authors.lastname: Blando
authors.forename: John
authors.initials: J
authors.lastname: DiGiovanni
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Thompson
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009367:Neoplasm Staging; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D051242:Caveolin 1; D016271:Proto-Oncogene Proteins c-myc; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D051057:Proto-Oncogene Proteins c-akt