Breast Cancer Research and Treatment

, Volume 115, Issue 1, pp 57–67 | Cite as

Dual targeting of Src and ER prevents acquired antihormone resistance in breast cancer cells

  • S. Hiscox
  • N. J. Jordan
  • C. Smith
  • M. James
  • L. Morgan
  • K. M. Taylor
  • T. P. Green
  • R. I. Nicholson
Preclinical Study

Abstract

Acquired resistance to endocrine therapies presents a major obstacle to the successful treatment of breast cancer patients. Previously, we have shown that acquisition of resistance to tamoxifen in breast cancer cells is accompanied by an elevation in Src kinase activity which promotes an aggressive, invasive phenotype in vitro. Here, we have explored the potential therapeutic effects of combining Src inhibition with anti-oestrogen treatment on the development of endocrine insensitivity in breast cancer cells. Treatment of MCF7 and T47D cells with tamoxifen alone resulted in an initial growth inhibitory phase followed by the eventual development of tamoxifen resistance together with an elevation of Src kinase activity, which was central to their increased invasive capacity. Chronic exposure of both cell types to the Src inhibitor, AZD0530, as a monotherapy resulted in outgrowth of AZD0530-resistant cells, in which Src kinase activity remained suppressed as did their in vitro invasive nature. Treatment of both MCF7 and T47D cells with AZD0530 in combination with tamoxifen resulted in a reduction of Src activity together with inhibition of focal adhesion kinase phosphorylation and a complete abrogation of their in vitro invasive behaviour. Furthermore, combination therapy significantly suppressed expression of cyclinD1 and c-myc and prevented cell proliferation and the subsequent emergence of a resistant phenotype, with total cell loss occurring by 12 weeks. These data demonstrate that pharmacological targeting of Src kinase, in conjunction with antihormone therapies, effectively prevents antihormone resistance in breast cancer cells in vitro and suggests a potential novel therapeutic benefit of Src kinase inhibitors clinically.

Keywords

Src ER Tamoxifen-resistance Breast cancer 

Notes

Acknowledgments

The authors wish to thank Carol Dutkowski, Denise Barrow, Lindy Goddard, Huw Mottram and Lucy Green for their expert contributions to this work.

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Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • S. Hiscox
    • 1
  • N. J. Jordan
    • 1
  • C. Smith
    • 1
  • M. James
    • 1
  • L. Morgan
    • 1
  • K. M. Taylor
    • 1
  • T. P. Green
    • 2
  • R. I. Nicholson
    • 1
  1. 1.Tenovus Centre for Cancer ResearchWelsh School of PharmacyCardiffUK
  2. 2.AstraZenecaMacclesfieldUK

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