Tumor cell growth inhibition by caveolin re-expression in human breast cancer cells

Lee, Sam W.; Reimer, Corinne; Oh, Phil; Campbell, Doreen B; Schnitzer, Jan E.

doi:10.1038/sj.onc.1201661

Cited by 395 publications

(330 citation statements)

References 18 publications

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“…Prior studies have suggested that oncogenic transformation results in reduced cellular levels of caveolin (Glenney and Soppet, 1992;Sager et al, 1994;Koleske et al, 1995), and that this reduction probably contributes to a loss of caveolae (Koleske et al, 1995). Lee et al (1998) found that the CAV1 levels were inversely correlated to breast cancer progression in vitro and the overexpression of CAV1 resulted in substantial growth inhibition of breast tumour cells, which normally had no endogenous caveolin expression. Our study confirmed that mRNA level of CAV1 and CAV2 were significantly downregulated in human breast cancer tissues compared to corresponding normal tissues (Po0.001), and that CAV1 and CAV2 mRNA levels were significantly correlated with each other in breast cancer cell lines and tissues.…”

Section: Discussionmentioning

confidence: 95%

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: 95%

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

et al. 2004

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“…Loss or reduction of caveolae and of cav-1 expression was ®rst described in NIH3T3 cells transformed by activated oncogenes (Koleske et al, 1995) and more recently, in cell lines derived from breast and lung cancer (Lee et al, 1998;Racine et al, 1999). Based on several observations, it has been suggested that regulation of cav-1 gene expression might be a critical point in maintaining the transformed phenotype and that cav-1 itself might be considered a tumor suppressor gene (Engelman et al, 1998b;Lee et al, 1998).…”

Section: Regulation Of Afr Expression In Cav-1-transfected Igrov1 Cellsmentioning

confidence: 99%

“…Based on several observations, it has been suggested that regulation of cav-1 gene expression might be a critical point in maintaining the transformed phenotype and that cav-1 itself might be considered a tumor suppressor gene (Engelman et al, 1998b;Lee et al, 1998).…”

Section: Regulation Of Afr Expression In Cav-1-transfected Igrov1 Cellsmentioning

confidence: 99%

Downmodulation of caveolin-1 expression in human ovarian carcinoma is directly related to α-folate receptor overexpression

et al. 2000

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Caveolin (cav-1) and the GPI-anchored a-folate receptor (aFR) are membrane proteins both found associated to caveolar structures. Several studies in tumor cells independently reported cav-1 downregulation and aFR overexpression. Here we analysed the expression of the two molecules in normal and tumor ovarian samples derived from fresh specimens and from cultured cell lines. Whereas normal ovary surface epithelial cells displayed only cav-1 expression, ovarian tumor surgical samples and cell lines (COR, IGROV1, OVCAR3 and OVCA432) displayed high aFR and low-level or no cav-1 expression, except those cell lines (SKOV3 and SW626) with the lower aFR expression. SKOV3, but not two aFR-negative non-ovarian cell lines, exhibited downregulation of cav-1 expression following stable aFR cDNA transfection. Conversely, cav-1 transfection in IGROV1 cells led to downregulated aFR expression, together with formation of caveolar structures and reduction of growth capability. Moreover, cav-1 expression was induced in IGROV1 cells by transfection with intracellular anti-aFR antibodies to downmodulate aFR expression. In cav-1 transfected cells, transcriptional activity of the aFR-speci®c promoter P1 was reduced by 70% and an additional speci®c DNA-protein complex was identi®ed by gel-shift assay, indicating that cav-1 expression in¯uences aFR gene transcription. Together these results support the notion that aFR and cav-1 protein expression is reciprocally regulated in ovary cancer cells.

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“…Furthermore, several independent studies have demonstrated a reciprocal interaction between the expression of caveolin-1 and activated components of the ERK1/2 MAP kinase signalling pathway [17][18][19][20]. While, caveolin-1 mRNA and protein has been shown to be present in normal human mammary epithelial cells it has also been reported to be greatly reduced or absent in an extensive range of transformed cells derived from human breast cancers [21][22][23][24]. Caveolin-1 has been proposed as the elusive tumour suppressor protein residing at chromosomal loci 7q31.1, a fragile site frequently deleted in a wide spectrum of human cancers [25].…”

Section: Introductionmentioning

confidence: 99%

Growth of hormone-dependent MCF-7 breast cancer cells is promoted by constitutive caveolin-1 whose expression is lost in an EGF-R-mediated manner during development of tamoxifen resistance

Thomas

Hutcheson

Campbell

et al. 2009

Breast Cancer Res Treat

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Growth of hormone-dependent MCF-7 breast cancer cells is promoted by constitutive caveolin-1 whose expression is lost in an EGF-R-mediated manner during development of tamoxifen resistance. Breast Cancer Research and Treatment, Springer Verlag, 2009, 119 (3) Abstract Caveolin-1 displays both tumour-suppressor and tumour-promoter properties in breast cancer. Using characterised preclinical cell models for the transition of oestrogen-sensitive (WT-MCF-7 cells) to a tamoxifenresistant (TAM-R cells) phenotype we examined the role caveolin-1 in the development of hormone-resistant breast cancer. The WT-MCF-7 cells showed abundant expression of caveolin-1 which potentiated oestrogen-receptor (ERa) signalling and promoted cell growth despite caveolin-1 mediating inhibition of ERK signalling. In TAM-R cells caveolin-1 expression was negligible, repressed by EGF-R/ERK signalling. Pharmacological inhibition of EGFR/ERK in TAM-R cells restored caveolin-1 and also resulted in the emergence of pools of phosphorylated caveolin-1. WT-MCF-7 cells exposed to tamoxifen for upto 12 weeks displayed increased caveolin-1 (peaking by week 2) followed (after week 8) by a marked decrease as the cells progress to develop a stable tamoxifen-resistant phenotype. The targeted down-regulation (siRNA) of caveolin-1 in WT-MCF-7 cells reduced growth but did not affect their sensitivity to tamoxifen, suggesting loss of caveolin-1 alone is not sufficient to confer tamoxifen-resistance. Hyperactivation of EGFR/ERK is a feature of tamoxifen-resistant breast cancer cells, a principal driver of cell growth. Recombinant expression of caveolin-1 in TAM-R cells did not affect EGFR/ERK activity, potentially due to mislocalisation of caveolin-1 through hyperactivation of the mTOR pathway or altered caveolin-1 phosphorylation. This work defines a novel role for caveolin-1 with implications for the clinical course of breast cancer and identifies caveolin-1 as a potential drug target for the treatment of early oestrogen-dependent breast cancers. Further, the loss of caveolin-1 may have benefit as a molecular signature for tamoxifen resistance.

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Tumor cell growth inhibition by caveolin re-expression in human breast cancer cells

Cited by 395 publications

References 18 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

Downmodulation of caveolin-1 expression in human ovarian carcinoma is directly related to α-folate receptor overexpression

Growth of hormone-dependent MCF-7 breast cancer cells is promoted by constitutive caveolin-1 whose expression is lost in an EGF-R-mediated manner during development of tamoxifen resistance

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