title: Caveolin-1 promotes tumor progression in an autochthonous mouse model of prostate cancer: genetic ablation of Cav-1 delays advanced prostate tumor development in tramp mice.
abstract: Caveolin-1 (Cav-1) is the primary structural component of caveolae and is implicated in the processes of vesicular transport, cholesterol balance, transformation, and tumorigenesis. Despite an abundance of data suggesting that Cav-1 has transformation suppressor properties both in vitro and in vivo, Cav-1 is expressed at increased levels in human prostate cancer. To investigate the role of Cav-1 in prostate cancer onset and progression, we interbred Cav-1(-/-) null mice with a TRAMP (transgenic adenocarcinoma of mouse prostate) model that spontaneously develops advanced prostate cancer and metastatic disease. We found that, although the loss of Cav-1 did not affect the appearance of minimally invasive prostate cancer, its absence significantly impeded progression to highly invasive and metastatic disease. Inactivation of one (+/-) or both (-/-) alleles of Cav-1 resulted in significant reductions in prostate tumor burden, as well as decreases in regional lymph node metastases. Moreover, further examination revealed decreased metastasis to distant organs, such as the lungs, in TRAMP/Cav-1(-/-) mice. Utilizing prostate carcinoma cell lines (C1, C2, and C3) derived from TRAMP tumors, we also showed a positive correlation between Cav-1 expression and the ability of these cells to form tumors in vivo. Furthermore, down-regulation of Cav-1 expression in these cells, using a small interfering RNA approach, significantly reduced their tumorigenic and metastatic potential. Mechanistically, we showed that loss or down-regulation of Cav-1 expression results in increased apoptosis, with increased prostate apoptosis response factor-4 and PTEN levels in Cav-1(-/-) null prostate tumors. Our current findings provide the first in vivo molecular genetic evidence that Cav-1 does indeed function as a tumor promoter during prostate carcinogenesis, rather than as a tumor suppressor.
authors.affiliation: Department of Molecular Pharmacology and The Albert Einstein Cancer Center, Department of Urology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Terence M
authors.initials: TM
authors.lastname: Williams
authors.forename: Ghada S
authors.initials: GS
authors.lastname: Hassan
authors.forename: Jiangwei
authors.initials: J
authors.lastname: Li
authors.forename: Alex W
authors.initials: AW
authors.lastname: Cohen
authors.forename: Freddy
authors.initials: F
authors.lastname: Medina
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Frank
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Dolores
authors.initials: D
authors.lastname: Di Vizio
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000737:chemistry; D017209:Apoptosis; D051242:Caveolin 1; D022461:Caveolins / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000952:Antigens, Polyomavirus Transforming; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering