Anti Proliferative Activity of Caveolin1

Heterologous expression of caveolin-1 in T47-D human mammary cancer cells results in a 50% decrease in growth rate and a three- to 10-fold reduction in anchorage-independent growth [68]. Inhibition of in-vitro anchorage-independent growth, a parameter that is highly correlated with in-vivo tumorigenesis [69], was similarly seen in MCF-7 human breast adenocarcinoma cells [11] and SCLC cells [62]. Caveolin-1 may therefore block a matrix-independent, intrinsic growth signal (e. g., a signal that emanates from an activated oncogene). Indeed, transient transfection with caveolin-1 reduces growth rates in human mammary tumor cells [11,68] and human ovarian carcinoma cells [70]. Accordingly, a mutant caveolin-1 (P132L), identified in about 16% of primary human breast cancer specimens [71], induces morphological transformation in NIH-3T3 cells and supports anchorage-independent growth of mutant-transfected cells [71]. P132L appears to act by causing missorting of normal caveolin-1, leading to its retention at a perinuclear compartment that is probably the Golgi apparatus [72]. It should be noted that the occurrence of the P132L mutation in mammary tumors awaits confirmation in non-Japanese breast cancer patients [73,74]. Further support for its growth-inhibitory action was obtained by analysis of heterozygous and homozygous caveolin-1 knockout mice. Retroviral inactivation of one of the caveolin-1 alleles results in loss of ca. 50% of caveolin-1 expression and enables anchorage-independent growth [75]. Likewise, genetic knockout of caveolin-1 results in hyperplasia of pulmonary endothelial cells and mammary gland epithelial cells [39,40]. Although spontaneous development of mammary or other tumors was not evident in cav-eolin-1-null mice [72], caveolin-1 gene knockout results in increased sensitivity to carcinogenic and oncogenic stimuli [41,42]. Mammary gland tumor-prone MMTV-PyMT mice exhibit accelerated formation of larger and higher-grade dysplastic foci [42]. Long-term mammary tumorigenesis in these mice was doubled and lung metastases were significantly increased [76]. Genetic disruption of caveolin-1 was shown also to cooperate with loss of the tumor suppressor INK4a. This study showed that double knockout of caveolin-1 and INK4a stimulates proliferation of mouse embryo fibroblasts, greatly increases transformation by an activated oncogene (e.g., H-Ras-G12V; v-Src) and results in dramatic stimulation of tumor growth in vivo [77]. Taken together with the heterologous expression data, these results implicate caveolin-1 as an important anti-proliferative protein.

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