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

• Published in: Breast cancer research and treatment 2010-02, Vol.119 (3), p.575-591
• Main Authors: Thomas, Nicholas B. P, Hutcheson, Iain R, Campbell, Lee, Gee, Julia, Taylor, Kathryn M, Nicholson, Robert I, Gumbleton, Mark
• Format: Article
• Language: English
• Subjects: Analysis; Automobile driving; Biological and medical sciences; Blotting, Western; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer cells; Cancer research; Cancer therapies; Caveolin 1 - biosynthesis; Caveolin 1 - genetics; Cell Line, Tumor; Drug resistance; Drug Resistance, Neoplasm - genetics; Endocrine therapy; Epidermal growth factor; Estrogen; Estrogens; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Gene Expression; Growth; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Motor vehicle driving; Oncology; Preclinical Study; Proteins; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Selective Estrogen Receptor Modulators - pharmacology; Signal Transduction - drug effects; Signal Transduction - physiology; Tamoxifen; Tamoxifen - pharmacology; Transfection; Tumors
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-009-0355-8

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 tamoxifen-resistant (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 (ERα) 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.