Drugs

, Volume 61, Issue 12, pp 1721–1733 | Cite as

Tamoxifen Resistance in Breast Cancer

Elucidating Mechanisms
  • Lambert C. J. Dorssers
  • Silvia van der Flier
  • Arend Brinkman
  • Ton van Agthoven
  • Jos Veldscholte
  • Els M. J. J. Berns
  • Jan G. M. Klijn
  • Louk V. A. M. Beex
  • John A. Foekens
Review Article

Abstract

Tamoxifen has been used for the systemic treatment of patients with breast cancer for nearly three decades. Treatment success is primarily dependent on the presence of the estrogen receptor (ER) in the breast carcinoma. While about half of patients with advanced ER-positive disease immediately fail to respond to tamoxifen, in the responding patients the disease ultimately progresses to a resistant phenotype.

The possible causes for intrinsic and acquired resistance have been attributed to the pharmacology of tamoxifen, alterations in the structure and function of the ER, the interactions with the tumour environment and genetic alterations in the tumour cells. So far no prominent mechanism leading to resistance has been identified.

The recent results of a functional screen for breast cancer antiestrogen resistance (BCAR) genes responsible for development of tamoxifen resistance in human breast cancer cells are reviewed. Individual BCAR genes can transform estrogen-dependent breast cancer cells into estrogen-independent and tamoxifen-resistant cells in vitro. Furthermore, high levels of BCAR1/p130Cas protein in ER-positive primary breast tumours are associated with intrinsic resistance to tamoxifen treatment. These results indicate a prominent role for alternative growth control pathways independent of ER signalling in intrinsic tamoxifen resistance of ER-positive breast carcinomas.

Deciphering the differentiation characteristics of normal and malignant breast epithelial cells with respect to proliferation control and regulation of cell death (apoptosis) is essential for understanding therapy response and development of resistance of breast carcinoma.

Keywords

Breast Cancer Epidermal Growth Factor Receptor Tamoxifen Fulvestrant Breast Epithelial Cell 

Notes

Acknowledgements

This research was supported by the Dutch Cancer Society/KWF and the Netherlands Organisation for Scientific Research (NWO). The contribution of the members of our research groups is gratefully acknowledged. We appreciate the critical comments and suggestions on the manuscript of Mrs Marion Meijer-Van Gelder MD and of the reviewers of the manuscript.

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Copyright information

© Adis International Limited 2001

Authors and Affiliations

  • Lambert C. J. Dorssers
    • 1
  • Silvia van der Flier
    • 1
  • Arend Brinkman
    • 1
  • Ton van Agthoven
    • 1
  • Jos Veldscholte
    • 1
  • Els M. J. J. Berns
    • 2
  • Jan G. M. Klijn
    • 2
  • Louk V. A. M. Beex
    • 3
  • John A. Foekens
    • 2
  1. 1.Department of Pathology, Division of Molecular Biology, Josephine Nefkens Institute, Room Be432University Hospital RotterdamRotterdamThe Netherlands
  2. 2.Department of Medical Oncology, Division of Endocrine Oncology, Josephine Nefkens InstituteUniversity Hospital RotterdamRotterdamThe Netherlands
  3. 3.Medical OncologyUniversity Hospital NijmegenNijmegenThe Netherlands

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