The 76-gene signature defines high-risk patients that benefit from adjuvant tamoxifen therapy

Zhang, Yi; Sieuwerts, Anieta M.; McGreevy, Michelle; Casey, Graham; Čufer, Tanja; Paradiso, Angelo; Harbeck, Nadia; Span, Paul N.; Hicks, David G.; Crowe, Joseph P.; Tubbs, Raymond R.; Budd, G. Thomas; Lyons, Joanne; Sweep, Fred C.G.J.; Schmitt, Manfred; Schittulli, F.; Golouh, Rastko; Talantov, Dmitri; Wang, Yixin; Foekens, John A.

doi:10.1007/s10549-008-0183-2

Cited by 137 publications

(100 citation statements)

References 24 publications

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“…We included 238 of our own samples (datasets Frankfurt, Frankfurt-2, and Frankfurt-3) which have been described previously (Ahr et al 2002 [9], [10], Rody et al 2008 [11], Ruckhäberle et al 2008 [12], and Rody et al 2007 [13], respectively) as well as 2792 samples from 22 different publicly available datasets (Table 1): Rotterdam [14][15][16], Mainz [17], Trans-BIG [18], Oxford-Untreated [19], London [20], London-2 [21], Oxford-Tamoxifen, Veridex-Tam [22], Stockholm [23], Uppsala [24,25], San Francisco [26], New York [27], MDA133 [28], EORTC [29], Edinburgh [30], ExpO [31], Signapore [32], Genentech [33], Boston [34], Berlin [35], Paris [36], and Tampa [37]. For comparability, only the ProbeSets from the Affymetrix HG-U133A microarray were used from seven datasets where HG-U133?…”

Section: Methodsmentioning

confidence: 99%

Data driven derivation of cutoffs from a pool of 3,030 Affymetrix arrays to stratify distinct clinical types of breast cancer

Karn

Metzler

Ruckhäberle

et al. 2009

Breast Cancer Res Treat

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Section: Methodsmentioning

confidence: 99%

Data driven derivation of cutoffs from a pool of 3,030 Affymetrix arrays to stratify distinct clinical types of breast cancer

Karn

Metzler

Ruckhäberle

et al. 2009

Breast Cancer Res Treat

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“…1C, Supplementary Table S1B; refs. [30][31][32][33][34]. Kaplan-Meier survival plots (KMplots) of tamoxifen-treated ER-positive patients indicate that increased RRM2 expression is strongly correlated with reduced RFS and OS ( Fig.…”

Section: Rrm2 Expression Inversely Correlates With Er Expression In Bmentioning

confidence: 99%

Targeting Ribonucleotide Reductase M2 and NF-κB Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer

Shah

Wilson

Malla

et al. 2015

Molecular Cancer Therapeutics

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Tamoxifen is widely used as an adjuvant therapy for patients with estrogen receptor (ERa)-positive tumors. However, the clinical benefit is often limited because of the emergence of drug resistance. In this study, overexpression of ribonucleotide reductase M2 (RRM2) in MCF-7 breast cancer cells resulted in a reduction in the effectiveness of tamoxifen, through downregulation of ERa66 and upregulation of the 36-kDa variant of ER (ERa36). We identified that NF-kB, HIF1a, and MAPK/JNK are the major pathways that are affected by RRM2 overexpression and result in increased NF-kB activity and increased protein levels of EGFR, HER2, IKKs, Bcl-2, RelB, and p50. RRM2-overexpressing cells also exhibited higher migratory and invasive properties. Through time-lapse microscopy and protein profiling studies of tamoxifen-treated MCF-7 and T-47D cells, we have identified that RRM2, along with other key proteins, is altered during the emergence of acquired tamoxifen resistance. Inhibition of RRM2 using siRRM2 or the ribonucleotide reductase (RR) inhibitor didox not only eradicated and effectively prevented the emergence of tamoxifen-resistant populations but also led to the reversal of many of the proteins altered during the process of acquired tamoxifen resistance. Because didox also appears to be a potent inhibitor of NF-kB activation, combining didox with tamoxifen treatment cooperatively reverses ER-a alterations and inhibits NF-kB activation. Finally, inhibition of RRM2 by didox reversed tamoxifenresistant in vivo tumor growth and decreased in vitro migratory and invasive properties, revealing a beneficial effect of combination therapy that includes RRM2 inhibition to delay or abrogate tamoxifen resistance.

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“…The gene expression signature predicts that 70-80% of these patients are unlikely to develop metastasis, so these patients are currently overtreated. Several other gene expression profiles predict recurrence and overall survival and/or tamoxifen resistance (Ma et al 2004, Paik et al 2004, Jansen et al 2005, Wang et al 2005, Frasor et al 2006, Oh et al 2006, Gräf et al 2007, Chanrion et al 2008, Kok et al 2009, Lippman et al 2008, Zhang et al 2009). …”

Section: Era Target Genes and Breast Cancermentioning

confidence: 99%

Genomic actions of estrogen receptor α: what are the targets and how are they regulated?

Welboren

Sweep²,

Span³

et al. 2009

Endocrine-Related Cancer

144

113

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The estrogen receptor a (ERa) is a ligand-dependent transcription factor that regulates a large number of genes in many different target tissues and is important in the development and progression of breast cancer. ERa-mediated transcription is a complex process regulated at many different levels. The interplay between ligand, receptor, DNA sequence, cofactors, chromatin context, and post-translational modifications culminates in transcriptional regulation by ERa. Recent technological advances have allowed the identification of ERa target genes on a genomewide scale. In this review, we provide an overview of the progress made in our understanding of the different levels of regulation mediated by ERa. We discuss the recent advances in the identification of the ERa-binding sites and target gene network and their clinical applications.

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The 76-gene signature defines high-risk patients that benefit from adjuvant tamoxifen therapy

Cited by 137 publications

References 24 publications

Data driven derivation of cutoffs from a pool of 3,030 Affymetrix arrays to stratify distinct clinical types of breast cancer

Data driven derivation of cutoffs from a pool of 3,030 Affymetrix arrays to stratify distinct clinical types of breast cancer

Targeting Ribonucleotide Reductase M2 and NF-κB Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer

Genomic actions of estrogen receptor α: what are the targets and how are they regulated?

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