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J. Biol. Chem., Vol. 279, Issue 49, 51630-51646, December 3, 2004

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Caveolin-1 Gene Disruption Promotes Mammary Tumorigenesis and Dramatically Enhances Lung Metastasis in Vivo

ROLE OF CAV-1 IN CELL INVASIVENESS AND MATRIX METALLOPROTEINASE (MMP-2/9) SECRETION^*

From the Departments of ^aMolecular Pharmacology and Medicine, ^ePathology, and ⁱCell Biology and Medicine, Albert Einstein College of Medicine and the ^bAlbert Einstein Cancer Center, Bronx, New York 10461, the ^fWhitehead Institute for Biomedical Research, Cambridge, Massachussetts 02142 the ^gDepartment of Medicine and Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada, the ^hDepartment of Pathology, Jacobi Medical Center, Bronx, New York 10461, and the ^kDepartment of Oncology, Lombardi Cancer Center, Georgetown University, Washington, D. C. 20007

Caveolin-1 (Cav-1) is the principal structural component of caveolae membrane domains in non-muscle cells, including mammary epithelia. There is now clear evidence that caveolin-1 influences the development of human cancers. For example, a dominant-negative mutation (P132L) in the Cav-1 gene has been detected in up to 16% of human breast cancer samples. However, the exact functional role of caveolin-1 remains controversial. Mechanistically, in cultured cell models, Cav-1 is known to function as a negative regulator of the Rasp42/44 MAP kinase cascade and as a transcriptional repressor of cyclin D1 gene expression, possibly explaining its in vitro transformation suppressor activity. Genetic validation of this hypothesis at the in vivo and whole organismal level has been prevented by the lack of a Cav-1 (-/-)-null mouse model. Here, we examined the role of caveolin-1 in mammary tumorigenesis and lung metastasis using a molecular genetic approach. We interbred a well characterized transgenic mouse model of breast cancer, MMTV-PyMT (mouse mammary tumor virus-polyoma middle T antigen), with Cav-1 (-/-)-null mice. Then, we followed the onset and progression of mammary tumors and lung metastases in female mice over a 14-week period. Interestingly, PyMT/Cav-1 (-/-) mice showed an accelerated onset of mammary tumors, with increased multiplicity and tumor burden (2-fold). No significant differences were detected between PyMT/Cav-1 (+/+) and PyMT/Cav-1 (+/-) mice, indicating that complete loss of caveolin-1 is required to accelerate both tumorigenesis and metastasis. Molecularly, mammary tumor samples derived from PyMT/Cav-1 (-/-) mice showed ERK-1/2 hyperactivation, cyclin D1 up-regulation, and Rb hyperphosphorylation, consistent with dys-regulated cell proliferation. PyMT/Cav-1 (-/-) mice also developed markedly advanced metastatic lung disease. Conversely, recombinant expression of Cav-1 in a highly metastatic PyMT mammary carcinoma-derived cell line, namely Met-1 cells, suppressed lung metastasis by 4.5-fold. In vitro, these Cav-1-expressing Met-1 cells (Met-1/Cav-1) demonstrated a 4.8-fold reduction in invasion through Matrigel-coated membranes. Interestingly, delivery of a cell permeable peptide encoding the caveolin-1 scaffolding domain (residues 82-101) into Met-1 cells was sufficient to inhibit invasion. Coincident with this decreased invasive index, Met-1/Cav-1 cells exhibited marked reductions in MMP-9 and MMP-2 secretion and associated gelatinolytic activity, as well as diminished ERK-1/2 signaling in response to growth factor stimulation. These results demonstrate, for the first time, that caveolin-1 is a potent suppressor of mammary tumor growth and metastasis using novel in vivo animal model approaches.

Received for publication, August 11, 2004

^* This work was supported in part by grants from the National Institutes of Health (NIH), the Susan G. Komen Breast Cancer Foundation, as well as Hirschl/Weil-Caulier Career Scientist Award (all to M. P. L.). Work conducted at the Lombardi Cancer Center was supported by Comprehensive Cancer Center Core National Institute of Health Grant P30 CA51008-13. The costs of publication of this article were defrayed 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.

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

^d Supported by an NIH Graduate Training Program Grant (T32-DK07513).

^j Supported by Grant R01-DK55758 from the NIH and the Komen Breast Cancer Foundation.

^l Supported by Grants R01CA70896, R01CA75503, R01CA86072 from the NIH.

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

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