Loss of Caveolin-1 Gene Expression Accelerates the Development of Dysplastic Mammary Lesions in Tumor-Prone Transgenic Mice

Williams, Terence M.; Cheung, Michelle W.-C.; Park, David; Razani, Babak; Cohen, Arnold W.; Muller, William J.; Vizio, Dolores Di; Chopra, Neeru; Pestell, Richard G.; Lisanti, Michael P.

doi:10.1091/mbc.e02-08-0503

Cited by 136 publications

(113 citation statements)

References 55 publications

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“…CAV1-null mice show a striking increase in the frequency and size of multifocal dysplastic lesions in mammary grands, with the nuclei and the nuclei of mammary grand cells showing anaplastic characteristics with increased mitotic figures (Williams et al, 2003). This suggests that CAV1-mediated interactions between myoepithelial cells and the rest of mammary gland may play an important role in oncogenesis.…”

Section: Discussionmentioning

confidence: 97%

Clinical significance of Caveolin-1, Caveolin-2 and HER2/neu mRNA expression in human breast cancer

et al. 2004

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Caveolin-1 and -2 (CAV1, CAV2) are closely linked genes localised to the fragile region of 7q31 (FRA7G), and loss of heterozygosity involving this region has been reported in breast cancer. Several studies have suggested that CAV1 is a negative regulator of HER2/ neu signal transduction in vitro. However, the clinical significance of CAV1 in breast cancer has not yet been clarified. We examined quantitatively the mRNA levels of CAV1, CAV2 and HER2/neu in 162 cases of breast cancer using real-time PCR. Caveolin-1 and -2 protein expression was also examined by Western blotting and immunohistochemistry. We then evaluated for correlations between CAV1, CAV2 and HER2/neu gene expression and clinicopathologic factors in the 162 breast cancer cases. Results showed higher HER2/neu mRMA levels and lower CAV1 and CAV2 mRMA levels in breast cancer tissues than in corresponding normal tissues (Po0.001). Caveolin-1 and -2 protein expression levels were also suppressed in cancer tissues compared to normal tissues by Western blotting. Immunohistochemistry revealed that CAV1 and CAV2 proteins were abundantly expressed in mammary gland myoepithelial cells, but only weakly in ductalepithelial cells. Reduced CAV1 mRNA level was significantly associated with increasing tumour size (P ¼ 0.041), and negative oestrogen receptor status (P ¼ 0.021). There was also a significant association between low CAV2 mRNA level and negative progesterone receptor status (P ¼ 0.013), and between high HER2/neu mRNA level and negative hormonal receptor status (ER, P ¼ 0.029, PgR, P ¼ 0.019). While there was no relationship between HER2/neu and CAV1 mRNA levels, a significant association between CAV1 and CAV2 mRNA levels was observed (Po0.001). Our results indicated that CAV1 suppression correlated closely with that of CAV2 in breast cancer, that CAV1 level was inversely correlated with tumour size, and that CAV1 and CAV2 levels were correlated with hormonal receptor status. Therefore, CAV1 and CAV2 play an important role in tumour progression in breast cancer patients.

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Section: Discussionmentioning

confidence: 97%

Clinical significance of Caveolin-1, Caveolin-2 and HER2/neu mRNA expression in human breast cancer

et al. 2004

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“…Secondly, genetic disruption of both Cav-1 alleles results in premature development of the lobulo-alveolar compartment during pregnancy (57). Finally, complete absence of Cav-1 accelerates the appearance of oncogene-induced dysplasias (pre-malignant lesions) in the mammary epithelium (28). Although these results are suggestive, it remains unknown whether loss of caveolin-1 has any consequences for the development of advanced and aggressive mammary tumors and resulting metastatic disease.…”

Section: Discussionmentioning

confidence: 99%

“…Animal protocols used for this study were approved by the AECOM Institute for Animal Studies. Cav-1-null mice and MMTV-PyMT transgenic mice (strain 634) were generated as previously described (8,28). All the mice used in this study were in the FVB/N background.…”

Section: Materials and Expressionmentioning

confidence: 99%

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

Williams

Medina

Badano

et al. 2004

Journal of Biological Chemistry

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273

214

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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 (ϳ2-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 Caveolin-1 (Cav-1) 1 was first discovered as a tyrosine-phosphorylated target in Rous sarcoma virus (RSV)-transformed avian fibroblasts, suggesting a possible role for this protein in cellular transformation (1). Subsequent studies identified caveolin-1 as a component of plasma membrane caveolae, small 50 -100-nm omega-shaped invaginations involved in vesicular trafficking and cholesterol homeostasis (2, 3). Analysis of its protein expression pattern revealed that Cav-1 is found in a diverse range of cell types, including adipocytes, fibroblasts, endothelial cells, smooth muscle cells, and mammary epithelial cells (4 -7). It is now clear that the majority of caveolae require caveolin-1 for proper formation, indicating that Cav-1 is a requisite caveolar structural protein. For example, Cav-1

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“…On the other hand, the expression levels of both ER␣ and caveolin-1 were reduced, as expected in more advanced tumor lesions ( Figure 5A). 21,29 Cytokeratin protein levels were not affected by the treatment ( Figure 5D). Moreover, normalization with cytokeratin indicated that caveolin-1 and ER␣ protein levels were reduced 1.5-and 1.3-fold, respectively, in tumors obtained from animals fed a Western diet.…”

Section: Dietary Cholesterol Is Associated With a Protein Expression mentioning

confidence: 95%

“…21 Whole mounts were digitally photographed with a ruler, and total area measurements for the dysplastic lesions were quantified using Image J software. 22 …”

Section: Whole-mount Analysis Of Mammary Glandsmentioning

confidence: 99%

Role of Cholesterol in the Development and Progression of Breast Cancer

Llaverı́as

Danilo

Mercier

et al. 2011

The American Journal of Pathology

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270

237

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Breast cancer is the most commonly occurring cancer in women in Western societies. 1 It is estimated that 207,090 new cases will be diagnosed and that in the United States, 39,840 women will die of the disease in 2010 (American Cancer Society, Cancer Facts & Figures 2010, http://www. cancer.org/Research/cancer-facts-and-figures-2010, last accessed November 15, 2010. Interestingly, the incidence is about 5 times higher in Western countries than in developing countries. 2 Moreover, relocation and migrational studies have demonstrated that migration from a region with low incidence to a region with high incidence increases breast cancer incidence in the immigrant population. 3 These observations suggest a strong environmental influence on breast cancer development.Diet and obesity are now considered important risk factors for cancer development. 4,5 However, despite major modifications of its metabolism during obesity development and its function in tissue pathogenesis, little is known about the metabolism and role of plasma cholesterol in cancer development. Epidemiological studies have demonstrated that patients with cancer have abnormal levels of high-density lipoprotein (HDL)-cholesterol and low-density lipoprotein (LDL)-cholesterol, 6,7 which are the major lipoprotein carriers of cholesterol in human plasma. In addition, numerous studies have established that transformed cells and tumors exhibit abnormal regulation of several genes that are under the control of cholesterol. The products of these genes include the LDL receptor (LDL-R), hydroxy-methyl-glutaryl coenzyme A reductase (HMG-CoA Reductase), and their regulators, the sterol regulatory element binding proteins. 8 -13 As a consequence, these genes are dysregulated at the transcriptional level during tumorigenesis. These data suggest that transformed cells may require or utilize more cholesterol than normal cells, and this may be associated with their increased rate of proliferation. More recent studies have implicated HDL during tumor formation in breast cancer. 14 -16 However, their precise function remains controversial. The present study was performed to test the hypothesis that dietary cholesterol and plasma cholesterol levels have an important role in the regulation of breast cancer onset and progression.

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Loss of Caveolin-1 Gene Expression Accelerates the Development of Dysplastic Mammary Lesions in Tumor-Prone Transgenic Mice

Cited by 136 publications

References 55 publications

Clinical significance of Caveolin-1, Caveolin-2 and HER2/neu mRNA expression in human breast cancer

Clinical significance of Caveolin-1, Caveolin-2 and HER2/neu mRNA expression in human breast cancer

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

Role of Cholesterol in the Development and Progression of Breast Cancer

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