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.
journal_name
Breast Cancer Resjournal_title
Breast cancer research : BCRauthors
Brennan DJ,Laursen H,O'Connor DP,Borgquist S,Uhlen M,Gallagher WM,Pontén F,Millikan RC,Rydén L,Jirström Kdoi
10.1186/bcr2820subject
Has Abstractpub_date
2011-01-31 00:00:00pages
R12issue
1eissn
1465-5411issn
1465-542Xpii
bcr2820journal_volume
13pub_type
杂志文章abstract:BACKGROUND:MicroRNAs (miRNAs) regulate gene expression and influence cancer. Primary transcripts of miRNAs (pri-miRNAs) are poorly annotated and little is known about the role of germline variation in miRNA genes and breast cancer (BC). We sought to identify germline miRNA variants associated with BC risk and tumor sub...
journal_title:Breast cancer research : BCR
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journal_title:Breast cancer research : BCR
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pub_type: 杂志文章,多中心研究
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abstract:INTRODUCTION:Gene expression analysis is used to subtype breast cancers such that the most aggressive tumors are identified, but translating this into clinical practice can be cumbersome. Our goal is to develop a universal biomarker that distinguishes patients at high risk across all breast cancer subtypes. We previous...
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pub_type: 杂志文章
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章,随机对照试验
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr956
更新日期:2005-01-01 00:00:00
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章
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更新日期:2013-04-23 00:00:00
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr539
更新日期:2002-01-01 00:00:00
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pub_type: 杂志文章,评审
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更新日期:2009-01-01 00:00:00
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pub_type: 杂志文章
doi:10.1186/s13058-014-0405-y
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr2139
更新日期:2008-01-01 00:00:00
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doi:10.1186/s13058-019-1111-6
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pub_type: 杂志文章
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更新日期:2012-06-07 00:00:00
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章
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更新日期:2010-01-01 00:00:00
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pub_type: 杂志文章
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更新日期:2004-01-01 00:00:00
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pub_type: 杂志文章
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更新日期:2009-01-01 00:00:00
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pub_type: 杂志文章
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更新日期:2020-05-19 00:00:00
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章
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更新日期:2009-01-01 00:00:00
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pub_type: 杂志文章
doi:10.1186/s13058-014-0437-3
更新日期:2014-09-09 00:00:00
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journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-014-0431-9
更新日期:2014-09-17 00:00:00
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更新日期:2014-05-07 00:00:00
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journal_title:Breast cancer research : BCR
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更新日期:2019-07-29 00:00:00