Building Prognostic Models for Breast Cancer Patients Using Clinical Variables and Gene Expression Signatures
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE15393 | GEO | 2010/10/25
SECONDARY ACCESSION(S): PRJNA117131
REPOSITORIES: GEO
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Project description:Our findings indicate that the integration of expression signatures and clinicopathological factors can better determine the individual risk of recurrence for newly diagnosed patients with lymph-node negative ER-positive breast cancer. Models incorporating other variables yet to be discovered will be needed to obtain robust prognostic models for ER-negative and HER2-positive breast cancer patients. A large data set was created by combining five different publicly available microarray datasets of node-negative breast cancer patients treated with local therapy only. The microarray gene expression data was combined using the batch effect adjustment by the Distance Weighted Discrimination method.
2010-10-25 | E-GEOD-15393 | biostudies-arrayexpress
Project description:Micro RNA (miRNA) profiling of breast cancer subtype was demonstrated using RT-PCR. We present herein two cases with miRNA profiling in estrogen receptor (ER)-positive and -negative breast cancer. The level of miR-181a expression in ER-positive cancer was higher than in ER-negative cancer, while expression of miR-27a, -107 and -195 was lower in ER-positive when compared with ER-negative cancer.
2018-10-13 | GSE121172 | GEO
Project description:Background: The androgen receptor (AR) is a tumor suppressor in estrogen receptor (ER) positive breast cancer, a role sustained in some ER negative breast cancers. Key factors dictating AR genomic activity in a breast context are largely unknown. Herein, we employed an unbiased chromatin immunoprecipitation-based proteomic technique to identify endogenous AR interacting co-regulatory proteins in ER positive and negative models of breast cancer to gain new insight into mechanisms of AR signaling in this disease. Results: The DNA-binding factor GATA3 is identified and validated as a novel AR interacting protein in breast cancer cells irrespective of ER status. AR activation by the natural ligand 5α-dihydrotestosterone (DHT) increases nuclear AR-GATA3 interactions, resulting in AR-dependent enrichment of GATA3 chromatin binding at a sub-set of genomic loci. Silencing GATA3 reduces but does not prevent AR DNA binding and transactivation of genes associated with AR/GATA3 co-occupied loci, indicating a co-regulatory role for GATA3 in AR signaling. DHT-induced AR/GATA3 binding coincides with upregulation of luminal differentiation genes, including EHF and KDM4B, established master regulators of a breast epithelial cell lineage. These findings are validated in a patient-derived xenograft model of breast cancer. Interaction between AR and GATA3 is also associated with AR-mediated growth inhibition in ER positive and ER negative breast cancer.
2024-01-30 | PXD047997 | Pride
Project description:Genomic complexity in breast tumors has been associated with aggressive disease and less favorable outcome. Recently, we developed an algorithm to calculate complexity scores per chromosome arm in order to sub-classify breast tumors with respect to progression paths and prognosis. We have further developed this method to calculate probe-focused complexity scores per sample, enabling identification of regions with recurrent complexities and grouping of tumors according to genome-wide complexity patterns. Probe-focused complexity scores were calculated based on data derived from aCGH analyses of 394 invasive ductal breast carcinomas. These continuous complexity scores (CCI) were used to identify regions with recurrent high level complexity, and the regional complexity scores were correlated to clinicopathological variables and survival data. A total of 25 recurrent regions with high level complexity were identified. Regional complexities on chromosome arms 8p, 11q and 17q were each associated with clinical parameters associated with aggressive disease. Complexity patterns were different between tumors of different gene expression subtypes. Multivariate Cox analysis revealed that regional complexity on 17q21.32-q21.33 was significantly associated with shorter survival, independent of established clinical variables.
2014-05-21 | GSE32291 | GEO
Project description:Expression of HOX transcript antisense intergenic RNA (HOTAIR)—a long intergenic non-coding RNA (lincRNA)—has been examined in a variety of human cancers, and overexpression of HOTAIR is correlated with poor survival among breast, colon, and liver cancer patients. In this retrospective study, we examine HOTAIR expression in 164 primary breast tumors, from patients who do not receive adjuvant treatment, in a design that is paired with respect to the traditional prognostic markers. We show that HOTAIR expression differs between patients with or without a metastatic endpoint, respectively. Survival analysis shows that high HOTAIR expression in primary tumors is significantly associated with worse prognosis independent of prognostic markers. This association is even stronger when looking only at estrogen receptor (ER)-positive tumor samples. In ER-negative tumor samples, it is not possible to detect a prognostic value of HOTAIR expression. These results are successfully validated in an independent dataset with similar associations. Furthermore, we find that high HOTAIR expression is associated with strong positive expression of multiple neighboring HOXC genes of the HOXC locus on chromosome 12q13.13 and have both negative and positive correlation with other genes located on different chromosomes. Independent datasets verify these significant correlations and thus indicate that HOTAIR might regulate additional genes than those previously reported. In conclusion, our findings suggest that HOTAIR expression may serve as an independent biomarker for the prediction of the risk of metastasis in ER-positive breast cancer patients. 164 breast cancer samples
2013-11-29 | E-GEOD-48408 | biostudies-arrayexpress
Project description:To better understand the biology of hormone receptor-positive and negative breast cancer and to identify methylated gene markers of disease progression, we performed a genome-wide methylation array analysis on 103 primary invasive breast cancers and 21 normal breast samples using the Illumina Infinium HumanMethylation27 array that queried 27,578 CpG loci. Estrogen and/or progesterone receptor-positive tumors displayed more hypermethylated loci than ER-negative tumors. However, the hypermethylated loci in ER-negative tumors were clustered closer to the transcriptional start site compared to ER-positive tumors. An ER-classifier set of CpG loci was identified, which independently partitioned primary tumors into ER-subtypes. Forty (32 novel, 8 previously known) CpG loci showed differential methylation specific to either ER-positive or ER-negative tumors. Each of the 40 ER-subtype-specific loci was validated in silico using an independent, publicly available methylome dataset from The Cancer Genome Atlas (TCGA). In addition, we identified 100 methylated CpG loci that were significantly associated with disease progression; the majority of these loci were informative particularly in ER-negative breast cancer. Overall, the set was highly enriched in homeobox containing genes. This pilot study demonstrates the robustness of the breast cancer methylome and illustrates its potential to stratify and reveal biological differences between ER-subtypes of breast cancer. Further, it defines candidate ER-specific markers and identifies potential markers predictive of outcome within ER subgroups.
2011-09-09 | GSE31979 | GEO
Project description:Purpose: As estrogen receptor (ER)-positive breast cancer in BRCA1 mutation carriers arises at an older age with less aggressive tumor characteristics than ER negative BRCA1 mutated breast cancer, it has been suggested that these tumors are ?sporadic? and not BRCA1-driven. With the introduction of targeted treatments specific for tumors with a non-functioning BRCA1 or BRCA2 gene, the question whether the BRCA genes are impaired in the tumor, is highly relevant. Therefore, we performed genomic profiling of BRCA1-mutated ER+ tumors. Experimental design: Genomic profiling, BRCA1 promoter methylation assessment, and loss of heterozygosity analysis were done on 16 BRCA1-mutated ER+ tumors. Results were compared with 57 BRCA1-mutated ER- tumors, 36 BRCA2-mutated ER+ associated tumors, and 182 sporadic ER+ tumors [GSE9021, GSE9114, GSE16511, GSE50407]. Results: The genomic profile of BRCA1-mutated ER+ tumors was different from BRCA1-mutated ER- breast tumors, but highly similar to BRCA2-mutated ER+ tumors. In 83% of the BRCA1-mutated ER+ tumors, loss of the wildtype BRCA1 allele was observed. In addition, clinico-pathological variables in BRCA1-mutated ER+ cancer were also more similar to BRCA2-mutated ER+ and sporadic ER+ breast cancer than to BRCA1 mutated ER- cancers. Conclusions: As BRCA1-mutated ER+ tumors show a BRCAness copy number profile and LOH, it is likely that the loss of a functional BRCA1 protein plays a role in tumorigenesis in BRCA1-mutated ER+ tumors. Therefore, we hypothesize that these tumors are sensitive to drugs targeting the BRCA1 gene defect, providing new targeted treatment modalities for advanced BRCA-deficient, ER-positive breast cancer.
2016-10-01 | GSE77604 | GEO
Project description:Purpose: As estrogen receptor (ER)-positive breast cancer in BRCA1 mutation carriers arises at an older age with less aggressive tumor characteristics than ER negative BRCA1 mutated breast cancer, it has been suggested that these tumors are ?sporadic? and not BRCA1-driven. With the introduction of targeted treatments specific for tumors with a non-functioning BRCA1 or BRCA2 gene, the question whether the BRCA genes are impaired in the tumor, is highly relevant. Therefore, we performed genomic profiling of BRCA1-mutated ER+ tumors. Experimental design: Genomic profiling, BRCA1 promoter methylation assessment, and loss of heterozygosity analysis were done on 16 BRCA1-mutated ER+ tumors. Results were compared with 57 BRCA1-mutated ER- tumors, 36 BRCA2-mutated ER+ associated tumors, and 182 sporadic ER+ tumors [GSE9021, GSE9114, GSE16511, GSE50407] Results: The genomic profile of BRCA1-mutated ER+ tumors was different from BRCA1-mutated ER- breast tumors, but highly similar to BRCA2-mutated ER+ tumors. In 83% of the BRCA1-mutated ER+ tumors, loss of the wildtype BRCA1 allele was observed. In addition, clinico-pathological variables in BRCA1-mutated ER+ cancer were also more similar to BRCA2-mutated ER+ and sporadic ER+ breast cancer than to BRCA1 mutated ER- cancers. Conclusions: As BRCA1-mutated ER+ tumors show a BRCAness copy number profile and LOH, it is likely that the loss of a functional BRCA1 protein plays a role in tumorigenesis in BRCA1-mutated ER+ tumors. Therefore, we hypothesize that these tumors are sensitive to drugs targeting the BRCA1 gene defect, providing new targeted treatment modalities for advanced BRCA-deficient, ER-positive breast cancer.
2016-10-01 | GSE77603 | GEO
Project description:CDK4/6 inhibition is the standard of care for estrogen receptor positive (ER+) breast cancer, although cytostasis is frequently observed, and new treatment strategies that enhance efficacy are required. We performed a genome-wide CRISPR screen to identify genetic determinants of CDK4/6 inhibitors sensitivity. Multiple genes involved in oxidative stress and ferroptosis modulated palbociclib sensitivity. Depletion or inhibition of GPX4 increased sensitivity to palbociclib in ER+ breast cancer models, and sensitised triple negative breast cancer models to palbociclib, with GPX4 null xenografts being highly sensitive to palbociclib. Palbociclib induced oxidative stress and disordered lipid metabolism with lipid peroxidation, leading to a ferroptosis-sensitive state. Lipid peroxidation relied on a peroxisome AGPAT3-dependent pathway in ER+ breast cancer models, rather than the classical ACSL4 pathway. Our data demonstrate that CDK4/6 inhibition creates vulnerability to ferroptosis that could be exploited through combination with GPX4 inhibitors, enhancing sensitivity to CDK4/6 inhibition in breast cancer.
2023-06-20 | PXD043133 | Pride
Project description:Expression of HOX transcript antisense intergenic RNA (HOTAIR)—a long intergenic non-coding RNA (lincRNA)—has been examined in a variety of human cancers, and overexpression of HOTAIR is correlated with poor survival among breast, colon, and liver cancer patients. In this retrospective study, we examine HOTAIR expression in 164 primary breast tumors, from patients who do not receive adjuvant treatment, in a design that is paired with respect to the traditional prognostic markers. We show that HOTAIR expression differs between patients with or without a metastatic endpoint, respectively. Survival analysis shows that high HOTAIR expression in primary tumors is significantly associated with worse prognosis independent of prognostic markers. This association is even stronger when looking only at estrogen receptor (ER)-positive tumor samples. In ER-negative tumor samples, it is not possible to detect a prognostic value of HOTAIR expression. These results are successfully validated in an independent dataset with similar associations. Furthermore, we find that high HOTAIR expression is associated with strong positive expression of multiple neighboring HOXC genes of the HOXC locus on chromosome 12q13.13 and have both negative and positive correlation with other genes located on different chromosomes. Independent datasets verify these significant correlations and thus indicate that HOTAIR might regulate additional genes than those previously reported. In conclusion, our findings suggest that HOTAIR expression may serve as an independent biomarker for the prediction of the risk of metastasis in ER-positive breast cancer patients.
2013-11-29 | GSE48408 | GEO