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Vol. 14, Issue 3, 1027-1042, March 2003
§
§ and¶
*Department of Molecular Pharmacology, Albert Einstein
College of Medicine, Bronx, New York 10461;
Caveolin-1 is the principal structural component of caveolae
microdomains, which represent a subcompartment of the plasma membrane. Several independent lines of evidence support the
notion that caveolin-1 functions as a suppressor of cell
transformation. For example, the human CAV-1 gene maps to a suspected
tumor suppressor locus (D7S522/7q31.1) that is frequently deleted in a
number of carcinomas, including breast cancers. In addition, up to 16%
of human breast cancers harbor a dominant-negative mutation, P132L, in
the CAV-1 gene. Despite these genetic associations, the tumor suppressor role of caveolin-1 still remains controversial. To directly
assess the in vivo transformation suppressor activity of the caveolin-1
gene, we interbred Cav-1 (Division of Hormone-dependent Tumor Biology, The
Albert Einstein Cancer Center, Bronx, New York 10461;
Department of Biology, Institute for Molecular
Biology and Biotechnology, McMaster University, Hamilton, Ontario, L8S
4L8 Canada and The Samuel Lunenfeld Research Institute, Mt. Sinai
Hospital, Toronto, Ontario, M5G 1X5 Canada;
§Departments of Developmental and Molecular
Biology and Medicine, Albert Einstein College of Medicine, Bronx, New
York 10461; and Department of Pathology, Jacobi
Medical Center, Bronx, New York 10461
/) null mice with tumor-prone transgenic
mice (MMTV-PyMT) that normally develop multifocal dysplastic lesions
throughout the entire mammary tree. Herein, we show that loss of
caveolin-1 gene expression dramatically accelerates the development of
these multifocal dysplastic mammary lesions. At 3 wk of age, loss of
caveolin-1 resulted in an approximately twofold increase in the number
of lesions (foci per gland; 3.3 ± 1.0 vs. 7.0 ± 1.2) and an
approximately five- to sixfold increase in the total area occupied by
these lesions. Similar results were obtained at 4 wk of age. However,
complete loss of caveolin-1 was required to accelerate the appearance
of these dysplastic mammary lesions, because Cav-1 (+/) heterozygous
mice did not show any increases in foci development. We also show that
loss of caveolin-1 increases the extent and the histological grade of
these mammary lesions and facilitates the development of papillary projections in the mammary ducts. Finally, we demonstrate that cyclin
D1 expression levels are dramatically elevated in Cav-1 (/) null
mammary lesions, consistent with the accelerated appearance and growth
of these dysplastic foci. This is the first in vivo demonstration that
caveolin-1 can function as a transformation suppressor gene.
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