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Tumor-specific HMG-...
Tumor-specific HMG-CoA reductase expression in primary premenopausal breast cancer predicts response to tamoxifen
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Brennan, Donal J. (author)
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Laursen, Henriette (author)
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O'Connor, Darran P. (author)
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- Borgquist, Signe (author)
- Lund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Uhlén, Mathias (author)
- KTH,Proteomik
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Gallagher, William M. (author)
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- Pontén, Fredrik (author)
- Uppsala universitet,Molekylär och morfologisk patologi
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Millikan, Robert C. (author)
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- Rydén, Lisa (author)
- Lund University,Lunds universitet,Kirurgi, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Surgery (Lund),Section V,Department of Clinical Sciences, Lund,Faculty of Medicine,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund
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- Jirström, Karin (author)
- Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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(creator_code:org_t)
- 2011-01-31
- 2011
- English.
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In: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 13:1, s. R12-
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- TEKNIK OCH TEKNOLOGIER -- Industriell bioteknik (hsv//swe)
- ENGINEERING AND TECHNOLOGY -- Industrial Biotechnology (hsv//eng)
Keyword
- STATIN USE
- FOLLOW-UP
- RISK
- RECURRENCE
- METAANALYSIS
- SURVIVAL
- CELLS
- COMBINATION
- MEVALONATE
- RESISTANCE
- Oncology
- Onkologi
- Bioengineering
- Bioteknik
- MEDICINE
Publication and Content Type
- ref (subject category)
- art (subject category)
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Brennan, Donal J ...
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Laursen, Henriet ...
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O'Connor, Darran ...
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Borgquist, Signe
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Uhlén, Mathias
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Gallagher, Willi ...
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show more...
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Pontén, Fredrik
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Millikan, Robert ...
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Rydén, Lisa
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Jirström, Karin
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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- ENGINEERING AND TECHNOLOGY
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Breast Cancer Re ...
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Royal Institute of Technology
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Lund University
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Uppsala University