Predicting the clinical status of human breast cancer by using gene expression profiles

West, Mike; Blanchette, Carrie; Dressman, Holly K.; Huang, Erich; Ishida, Susumu; Spang, Rainer; Zuzan, Harry; Olson, John A.; Marks, Jeffrey R.; Nevins, Joseph R.

doi:10.1073/pnas.201162998

Cited by 1,171 publications

(816 citation statements)

References 30 publications

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“…Microarray analysis of breast tumor samples suggested that FOXA1 is expressed only in ER þ breast tumors and is reduced significantly in ERÀ breast tumors (West et al, 2001;van't Veer et al, 2002). We determined that FOXA1 expression did indeed correlate with ER positivity in breast cancer cell lines.…”

Section: Discussionmentioning

confidence: 78%

“…Variable expression of FOXA1 was found in these breast cancer cell lines. Since a previous study had suggested that FOXA1 expression correlated with ER positivity in breast cancer, we identified the ER status of the cell lines examined here (West et al, 2001). Of these eight, four are ER þ (BT474, MCF7, T-47D, ZR-75-1) and four are ERÀ (BT20, MDA-MB-231, MDA-MD-468, SKBr3).…”

Section: Brca1-responsive Element In P27 Kip1 Promotermentioning

confidence: 99%

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BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27Kip1

et al. 2005

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We have previously shown that the breast cancer susceptibility gene, BRCA1, can transcriptionally activate the p27 Kip1 promoter. The BRCA1-responsive element was defined as a 35 bp region from position À545 to À511. We next determined that within this region is also a potential binding site for the transcription factor Forkhead box (FOX)A1. RNA and protein analysis as well as immunohistochemistry showed that expression of FOXA1 correlated with the expression of the estrogen receptor in a panel of breast cancer cell lines and tissues. In transient transfection reporter assays, FOXA1 could activate the p27 Kip1 promoter. Cotransfection of BRCA1 and FOXA1 resulted in a synergistic activation of the p27 Kip1 promoter. Mutation of the FOXA1 DNA-binding site in the p27 Kip1 promoter-luciferase construct significantly diminished the activity of FOXA1 alone or in combination with BRCA1. Cotransfection of FOXA1 and BRCA1 resulted in a greater amount of each protein compared to transfection of each expression vector alone. The half-life of FOXA1 was increased when coexpressed with BRCA1. Electrophoretic mobility shift assay analysis demonstrated that FOXA1 could bind to a wild-type oligonucleotide containing the FOXA1 binding site in the p27 Kip1 promoter, but this binding was lost upon mutation of this FOXA1 binding site. The protein-DNA binding complex could be supershifted with an antibody directed against FOXA1. The activity of the p27 Kip1 promoter as well as FOXA1 expression was reduced in cells treated with BRCA1 siRNA, thus silencing the expression of BRCA1 protein. In summary, we identified a FOXA1 binding site within the BRCA1-responsive element of the p27 Kip1 promoter and showed that FOXA1 activated the promoter alone and in conjunction with BRCA1. Furthermore, we identified high expression of FOXA1 in breast cancer cell lines and tissues, discovered a role for BRCA1 in the regulation of p27 Kip1 transcription and a possible interaction with BRCA1.

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Section: Discussionmentioning

confidence: 78%

Section: Brca1-responsive Element In P27 Kip1 Promotermentioning

confidence: 99%

BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27Kip1

et al. 2005

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“…The association of tumoral MAP-Tau gene transcription with premenopausal patient status, a marker of more aggressive tumor biology, may be a random one in a relatively small sample or may suggest that a subgroup of premenopausal women harbour breast carcinomas of more benign biology. Alternatively, this could be a result of high plasma estrogen levels in premenopausal patients, with increased expression of MAPTau in ER positive tumors of comparatively benign nature, compared to the more aggressive ER negative, potentially BRCA1 or BRCA2-positive, premenopausal breast cancer [30,31]. Interestingly, MAP-Tau is the target of multiple signalling pathways and thereby may represent an important checkpoint for microtubule and cellular functions beyond its interplay with hormonal activities.…”

Section: Discussionmentioning

confidence: 99%

Gene expression of estrogen receptor, progesterone receptor and microtubule-associated protein Tau in high-risk early breast cancer: a quest for molecular predictors of treatment benefit in the context of a Hellenic Cooperative Oncology Group trial

Pentheroudakis

Kalogeras

Wirtz

et al. 2008

Breast Cancer Res Treat

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Background Estrogen receptor (ER) and progesterone receptor (PgR) protein expression carry weak prognostic and moderate predictive utility for the outcome of early breast cancer patients on adjuvant chemohormonotherapy. We sought to study the predictive significance and correlations of transcriptional profiling of the ER, PgR and microtubule-associated protein Tau (MAPTau) genes in early breast cancer. Materials and methods Messenger RNA (mRNA) was extracted from 279 formalinfixed paraffin-embedded breast carcinomas (T1-3N0-1M0) of patients enrolled in the Hellenic Cooperative Oncology Group (HeCOG) trial HE 10/97, evaluating epirubicin-alkylator based adjuvant chemotherapy with or without paclitaxel (E-T-CMF versus E-CMF). Kinetic reverse transcription polymerase chain reaction (kRT-PCR) was applied for assessment of the expression of estrogen receptor, progesterone receptor and MAP-Tau genes in 274 evaluable patients. Cohort-based cut-offs were defined at the 25th percentile mRNA value for ER and PgR and the median for MAP-Tau. Results Two hundred and ten patients (77%) were ER and/or PgR-positive by immunohistochemistry (IHC). Positive ER and MAP-Tau mRNA status was significantly associated with administration of hormonal therapy and low grade, while MAP-Tau mRNA status correlated with premenopausal patient status. MAP-Tau strongly correlated with ER and PgR mRNA status (Spearmann r = 0.52 and 0.64, P\0.001). The observed chance corrected agreement between determination of hormonal receptor status by kRT-PCR and IHC was moderate (Kappa = 0.41) for ER and fair (Kappa = 0.33) for PgR. At a median follow-up of 8 years, univariate analysis adjusted for treatment showed positive ER mRNA status to be of borderline significance for reduced risk of relapse (HR = 0.65, 95% CI 0.41-1.01, P = 0.055) and death (HR = 0.62, 95% CI 0.36-1.05, P = 0.077), while positive MAP-Tau mRNA status was significantly associated with reduced risk of relapse (HR = 0.50, 95% CI 0.32-0.78, P = 0.002) and death (HR = 0.49, 95% CI 0.29-0.83, P = 0.008). In multivariate analysis, only axillary nodal metastases (HR = 2.33, 95% CI 1.05-5.16, P = 0.04) and MAP-Tau mRNA status (HR = 0.46, 95% CI 0.25-0.85, P = 0.01) independently predicted patient outcome. However, MAP-Tau mRNA levels did not predict enhanced benefit from inclusion of paclitaxel in the adjuvant chemotherapy regimen (test for interaction P = 0.99). No correlation was evident between increasing ER and PgR mRNA transcription and increasing benefit from endocrine therapy in 203 ER and/or PgR IHC-positive patients receiving adjuvant hormone therapy (Wald P = 0.54 for ER, 0.51 for PR). Conclusions ER gene transcription carries weak predictive significance for benefit from endocrine therapy or for outcome, with no apparent dose-response association. The predictive significance is possibly exerted via MAP-Tau gene expression, an ER-inducible tubulin modulator with strong predictive significance for patient outcome. However, MAP-Tau mRNA did not predict benefit from the addition...

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“…breast cancer do not respond to tamoxifen. These unsolved issues led to a significant number of studies investigating ER status and prognosis in breast cancer [8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Meta-analysis of gene expression profiles related to relapse-free survival in 1,079 breast cancer patients

Győrffy

Schäfer

2008

Breast Cancer Res Treat

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The transcriptome of breast cancers have been extensively screened with microarrays and large sets of genes associated with clinical features have been established. The aim of this study was to validate original gene sets on a large cohort of raw breast cancer microarray data with known clinical follow-up. We recovered 20 publications and matched them to Affymetrix HGU133A annotations. Raw Affymetrix HGU133A microarray data were extracted from GEO and MAS5 normalized. For classifying patients using the selected gene sets, we applied prediction analysis of microarrays and constructed KaplanMeier plots. A new classification including all patients was generated using supervised principal components analysis. Seven studies including 1,470 patients were downloaded from GEO. Notably, we uncovered 641 microarrays representing 251 individual tumor specimens among them, which were repeatedly described under independent GEO identifiers. We excluded all redundant data and used the remaining 1,079 samples. Eight of the 20 gene sets were able to predict response at a significance of P \ 0.05. The discrimination of good and poor prognosis groups exclusively relying on gene expression data resulted in high significance (P = 1.8E-12). A model including genes fitted by both gene expression and clinical covariates (lymph node status and grade) contains 44 genes and can predict response at P = 9.5E-7. The outcome provides a ranking of the gene lists regarding applicability on an independent dataset. We established a consensus predictor combining the available clinical and gene expression data. The database comprising expression profiles of 1,079 breast cancers can be used to classify individual patients.

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Predicting the clinical status of human breast cancer by using gene expression profiles

Cited by 1,171 publications

References 30 publications

BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27Kip1

BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27Kip1

Gene expression of estrogen receptor, progesterone receptor and microtubule-associated protein Tau in high-risk early breast cancer: a quest for molecular predictors of treatment benefit in the context of a Hellenic Cooperative Oncology Group trial

Meta-analysis of gene expression profiles related to relapse-free survival in 1,079 breast cancer patients

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