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

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  • Brennan, Donal J
    • Other Affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
  • Laursen, Henriette
    • Other Affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
  • O'Connor, Darran P
    • Other Affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
  • Borgquist, Signe
    • Other Affiliation: Department of Oncology, Clinical Sciences, Lund University, Skåne University Hospital, 221 85 Lund, Sweden
  • Uhlen, Mathias
    • Other Affiliation: Department of Biotechnology, AlbaNova University Center, Royal Institute of Technology, 106 91 Stockholm, Sweden
  • Gallagher, William M
    • Other Affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
  • Pontén, Fredrik
    • Other Affiliation: Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden
  • Millikan, Robert C.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Rydén, Lisa
    • Other Affiliation: Department of Surgery, Clinical Sciences, Lund University, Skåne University Hospital, 221 85 Lund, Sweden
  • Jirström, Karin
    • Other Affiliation: Department of Pathology, Clinical Sciences, Lund University, Skåne University Hospital, 221 85 Lund, Sweden
Abstract
  • 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.
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  • Article
Rights statement
  • In Copyright
Rights holder
  • Donal J Brennan et al.; licensee BioMed Central Ltd.
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Journal title
  • Breast Cancer Research
Journal volume
  • 13
Journal issue
  • 1
Page start
  • R12
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1465-5411
Bibliographic citation
  • Breast Cancer Research. 2011 Jan 31;13(1):R12
Publisher
  • BioMed Central Ltd
Access right
  • Open Access
Date uploaded
  • January 20, 2017

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