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J. Biol. Chem., Vol. 280, Issue 26, 25134-25145, July 1, 2005

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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^*

From the ^aDepartment of Molecular Pharmacology and The Albert Einstein Cancer Center, ^eDepartment of Urology, Albert Einstein College of Medicine, Bronx, New York 10461, ^gDepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgtown University, Washington, D. C. 20007, and ^hDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115

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.

Received for publication, February 1, 2005 , and in revised form, March 22, 2005.

^* This work was supported in part by grants from the National Institutes of Health as well as a Hirschl/Weil-Caulier Career Scientist Award (to M. P. L.). The costs of publication of this article were de-frayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^b Supported by a National Institutes of Health Medical Scientist Training Program Grant (T32-GM07288).

^c Recipient of a post-doctoral fellowship from the Foundation of Health Research, Quebec, Canada.

^d Supported by a National Institutes of Health Graduate Training Program Grant (T32-DK07513).

^f Recipient of a Scientist Development grant from the American Heart Association. To whom correspondence may be addressed. Tel.: 718-430-8829; Fax: 718-430-8830; E-mail: pfrank{at}aecom.yu.edu.

ⁱ To whom correspondence may be addressed. Tel.: 718-430-8828; Fax: 718-430-8830; E-mail: lisanti{at}aecom.yu.edu.

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