Breast Cancer Research and Treatment

, Volume 119, Issue 3, pp 575–591 | Cite as

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

  • Nicholas B. P. Thomas
  • Iain R. Hutcheson
  • Lee Campbell
  • Julia Gee
  • Kathryn M. Taylor
  • Robert I. Nicholson
  • Mark Gumbleton
Preclinical Study


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.


Caveolin Tamoxifen Breast cancer Resistance Hormone-dependent EGFR ERK1/2 Phosphorylated-caveolin mTOR Oestrogen receptor ERα 



The authors would like to thank Carol Dutkowski and Denise Barrow for their excellent technical assistance. To Dr. Andrew Hollins for construction of the recombinant caveolin-1 construct and Dr. Arwyn T. Jones for advice on subcellular fractionation. This research was generously supported by the Tenovus organisation and a Welsh School of Pharmacy studentship to NBPT. ‘Iressa’ and ‘Faslodex’ are trademarks of the AstraZeneca group of companies.


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Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Nicholas B. P. Thomas
    • 1
    • 2
  • Iain R. Hutcheson
    • 2
  • Lee Campbell
    • 1
  • Julia Gee
    • 2
  • Kathryn M. Taylor
    • 2
  • Robert I. Nicholson
    • 2
  • Mark Gumbleton
    • 1
  1. 1.Experimental Therapeutics, Welsh School of PharmacyCardiff UniversityCardiffUK
  2. 2.Tenovus Centre for Cancer ResearchCardiff UniversityCardiffUK

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