Review What clinicians need to know about antioestrogen resistance in breast cancer therapy Amalia Milano, Lissandra Dal Lago, Christos Sotiriou, Martine Piccart, Fatima Cardoso* Medical Oncology and Translational Research Unit, Jules Bordet Institute, Rue He ´ger-Bordet, 1, B-1000 Brussels, Belgium ARTICLE INFO Article history: Received 24 February 2006 Received in revised form 24 May 2006 Accepted 23 June 2006 Available online 11 September 2006 Keywords: Breast cancer Tamoxifen-resistance Predictive marker AIB1 HER-2 Oestrogen receptor Progesterone receptor Cox-2 Cyclin E UPA/PAI-1 ABSTRACT Tamoxifen is the drug most used for early breast cancer treatment in oestrogen receptor (ER) positive patients. Unfortunately, despite high ER tumour levels in a tumour, resistance to endocrine therapy, either de novo or acquired after prolonged treatment, can occur. In this review, we will try to summarise the postulated mechanisms of hormonal-resistance, namely, the role of co-regulators and the crosstalk between the HER-2, IGF-IR, Cox-2 and ER pathways. Other predictive markers of tamoxifen-resistance/response, such as cyclin E and UPA/PAI-1, are also discussed. Ó 2006 Elsevier Ltd. All rights reserved. 1. Introduction Tamoxifen has been the drug most widely used for breast cancer treatment. Administered after loco-regional and adju- vant chemotherapy treatment of early breast cancer, it signif- icantly reduces the risk of relapse and death in women with hormone-receptor positive disease. Specifically, 5 years of tamoxifen reduces the annual risk of recurrence and death by 47% and 26%, respectively. 1 In addition, tamoxifen has been shown to reduce the risk of contralateral breast cancer by almost 50%. 2 Tamoxifen is beneficial irrespective of age, nodal and menopausal status. The magnitude of the effect of adjuvant tamoxifen is directly correlated to duration of treatment and to oestrogen receptor (ER) status in the primary tumour, with no effect on ER-negative cancers. 1 Unfortu- nately, many patients experience resistance to endocrine therapy either de novo (at the beginning of the treatment) or acquired (after prolonged use), despite detectable levels of ER in their tumours. Several mechanisms could contribute to the development of this resistant phenotype. These include the following: loss of ER in the tumour; selection of ER muta- tions; alteration in the intracellular pharmacology and/or 0959-8049/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2006.06.022 * Corresponding author: Tel.: +32 2 541 30 82; fax: +32 2 538 08 58. E-mail address: fatima.cardoso@bordet.be (F. Cardoso). EUROPEAN JOURNAL OF CANCER 42 (2006) 2692 – 2705 available at www.sciencedirect.com journal homepage: www.ejconline.com