Open Access Highly Accessed Research article

Tumor-specific HMG-CoA reductase expression in primary premenopausal breast cancer predicts response to tamoxifen

Donal J Brennan1, Henriette Laursen1, Darran P O'Connor1, Signe Borgquist2, Mathias Uhlen3, William M Gallagher1, Fredrik Pontén4, Robert C Millikan5, Lisa Rydén6 and Karin Jirström7*

Author Affiliations

1 UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland

2 Department of Oncology, Clinical Sciences, Lund University, Skåne University Hospital, 221 85 Lund, Sweden

3 Department of Biotechnology, AlbaNova University Center, Royal Institute of Technology, 106 91 Stockholm, Sweden

4 Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden

5 Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

6 Department of Surgery, Clinical Sciences, Lund University, Skåne University Hospital, 221 85 Lund, Sweden

7 Department of Pathology, Clinical Sciences, Lund University, Skåne University Hospital, 221 85 Lund, Sweden

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Breast Cancer Research 2011, 13:R12  doi:10.1186/bcr2820

Published: 31 January 2011

Abstract

Introduction

We previously reported an association between tumor-specific 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) expression and a good prognosis in breast cancer. Here, the predictive value of HMG-CoAR expression in relation to tamoxifen response was examined.

Methods

HMG-CoAR protein and RNA expression was analyzed in a cell line model of tamoxifen resistance using western blotting and PCR. HMG-CoAR mRNA expression was examined in 155 tamoxifen-treated breast tumors obtained from a previously published gene expression study (Cohort I). HMG-CoAR protein expression was examined in 422 stage II premenopausal breast cancer patients, who had previously participated in a randomized control trial comparing 2 years of tamoxifen with no systemic adjuvant treatment (Cohort II). Kaplan-Meier analysis and Cox proportional hazards modeling were used to estimate the risk of recurrence-free survival (RFS) and the effect of HMG-CoAR expression on tamoxifen response.

Results

HMG-CoAR protein and RNA expression were decreased in tamoxifen-resistant MCF7-LCC9 cells compared with their tamoxifen-sensitive parental cell line. HMG-CoAR mRNA expression was decreased in tumors that recurred following tamoxifen treatment (P < 0.001) and was an independent predictor of RFS in Cohort I (hazard ratio = 0.63, P = 0.009). In Cohort II, adjuvant tamoxifen increased RFS in HMG-CoAR-positive tumors (P = 0.008). Multivariate Cox regression analysis demonstrated that HMG-CoAR was an independent predictor of improved RFS in Cohort II (hazard ratio = 0.67, P = 0.010), and subset analysis revealed that this was maintained in estrogen receptor (ER)-positive patients (hazard ratio = 0.65, P = 0.029). Multivariate interaction analysis demonstrated a difference in tamoxifen efficacy relative to HMG-CoAR expression (P = 0.05). Analysis of tamoxifen response revealed that patients with ER-positive/HMG-CoAR tumors had a significant response to tamoxifen (P = 0.010) as well as patients with ER-positive or HMG-CoAR-positive tumors (P = 0.035). Stratification according to ER and HMG-CoAR status demonstrated that ER-positive/HMG-CoAR-positive tumors had an improved RFS compared with ER-positive/HMG-CoAR-negative tumors in the treatment arm (P = 0.033); this effect was lost in the control arm (P = 0.138), however, suggesting that HMG-CoAR predicts tamoxifen response.

Conclusions

HMG-CoAR expression is a predictor of response to tamoxifen in both ER-positive and ER-negative disease. Premenopausal patients with tumors that express ER or HMG-CoAR respond to adjuvant tamoxifen.