Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of human breast carcinoma tissues representing 930 patients with 17.4 years mean follow-up, basal cytokeratin expression was associated with decreased disease-specific survival

ABSTRACT: Expression profiling studies have classified breast carcinomas into luminal, normal breast-like, HER2 expressing and basal-like groups, with the latter two associated with poor outcomes. This study's objectives were to define an immunohistochemical profile that identifies basal-like tumors, to identify the presence of potential drug targets, and to determine the prognostic significance of the basal-like immunophenotype in a large series with long-term follow-up. On a panel of 21 breast tumors with basal-like expression profiles, we determined that this subtype was immunohistochemically negative for estrogen receptor and HER2, but positive for basal cytokeratins, HER1 and/or c-KIT. Using breast carcinoma tissue microarrays representing 930 patients with 17.4 years mean follow-up, basal cytokeratin expression was associated with decreased disease-specific survival. HER1 expression was observed in 54% of cases positive for basal cytokeratins (vs. 11% of negative cases) and was associated with poor survival independent of nodal status and size. c-KIT expression was more common in basal-like tumors than in other breast cancers, but did not influence prognosis. A panel of four antibodies (ER, HER1, HER2, and cytokeratin 5/6) can accurately identify basal-like tumors and suggests candidate drugs for therapies targeting HER1 or c-KIT.

ORGANISM(S): Homo sapiens

SUBMITTER: Janos Demeter

PROVIDER: E-SMDB-2863 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma.

Nielsen Torsten O TO Hsu Forrest D FD Jensen Kristin K Cheang Maggie M Karaca Gamze G Hu Zhiyuan Z Hernandez-Boussard Tina T Livasy Chad C Cowan Dave D Dressler Lynn L Akslen Lars A LA Ragaz Joseph J Gown Allen M AM Gilks C Blake CB van de Rijn Matt M Perou Charles M CM

Clinical cancer research : an official journal of the American Association for Cancer Research 20040801 16

<h4>Purpose</h4>Expression profiling studies classified breast carcinomas into estrogen receptor (ER)+/luminal, normal breast-like, HER2 overexpressing, and basal-like groups, with the latter two associated with poor outcomes. Currently, there exist clinical assays that identify ER+/luminal and HER2-overexpressing tumors, and we sought to develop a clinical assay for breast basal-like tumors.<h4>Experimental design</h4>To identify an immunohistochemical profile for breast basal-like tumors, we c ...[more]

PMID: 15328174

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Project description:Abstract BACKGROUND: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated. METHODS: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor therapy was investigated in breast cancer cell lines and mouse xenograft models, respectively. RESULTS: Sixty-four % of cases had an oncogenic alteration to PIK3CA, PTEN, or INPP4B; when including upstream kinases HER2 and EGFR, 75 % of cases had one or more aberration including 97 % of estrogen receptor (ER)-negative tumors. PTEN-loss was significantly associated to stathmin and EGFR overexpression, positivity for the BLBC markers cytokeratin 5/14, and the BLBC molecular subtype by gene expression profiling, informing a potential therapeutic combination targeting these pathways in BLBC. Combination treatment of BLBC cell lines with the EGFR-inhibitor gefitinib plus the PI3K pathway inhibitor LY294002 was synergistic, and correspondingly, in an in vivo BLBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy and caused tumor regression. CONCLUSIONS: Our study emphasizes the importance of PI3K/PTEN pathway activity in ER-negative and basal-like breast cancer and supports the future clinical evaluation of combining EGFR and PI3K pathway inhibitors for the treatment of BLBC. Gene expression profiles were generated for 95 breast tumors using Agilent Human 44K v5 microarrays following the manufacturer protocol. Stratagene Universal Human Reference RNA was used as the common control sample.

Project description:INTRODUCTION: Basal-phenotype or basal-like breast cancers are characterized by basal epithelium cytokeratin (CK5/14/17) expression, negative estrogen receptor (ER) status and distinct gene expression signature. We studied the clinical and biological features of the basal-phenotype tumors determined by immunohistochemistry (IHC) and cDNA microarrays especially within the ER-negative subgroup. METHODS: IHC was used to evaluate the CK5/14 status of 445 stage II breast cancers. The gene expression signature of the CK5/14 immunopositive tumors was investigated within a subset (100) of the breast tumors (including 50 ER-negative tumors) with a cDNA microarray. Survival for basal-phenotype tumors as determined by CK5/14 IHC and gene expression signature was assessed. RESULTS: From the 375 analyzable tumor specimens, 48 (13%) were immunohistochemically positive for CK5/14. We found adverse distant disease-free survival for the CK5/14-positive tumors during the first years (3 years hazard ratio (HR) 2.23, 95% confidence interval (CI) 1.17 to 4.24, p = 0.01; 5 years HR 1.80, 95% CI 1.02 to 3.15, p = 0.04) but the significance was lost at the end of the follow-up period (10 years HR 1.43, 95% CI 0.84 to 2.43, p = 0.19). Gene expression profiles of immunohistochemically determined CK5/14-positive tumors within the ER-negative tumor group implicated 1,713 differently expressed genes (p < 0.05). Hierarchical clustering analysis with the top 500 of these genes formed one basal-like and a non-basal-like cluster also within the ER-negative tumor entity. A highly concordant classification could be constructed with a published gene set (Sorlie's intrinsic gene set, concordance 90%). Both gene sets identified a basal-like cluster that included most of the CK5/14-positive tumors, but also immunohistochemically CK5/14-negative tumors. Within the ER-negative tumor entity there was no survival difference between the non-basal and basal-like tumors as identified by immunohistochemical or gene-expression-based classification. CONCLUSION: Basal cytokeratin-positive tumors have a biologically distinct gene expression signature from other ER-negative tumors. Even if basal cytokeratin expression predicts early relapse among non-selected tumors, the clinical outcome of basal tumors is similar to non-basal ER-negative tumors. Immunohistochemically basal cytokeratin-positive tumors almost always belong to the basal-like gene expression profile, but this cluster also includes few basal cytokeratin-negative tumors. Keywords: Disease state analysis

Project description:Purpose HER2 gene amplification or protein overexpression (HER2+) defines a clinically challenging subgroup of breast cancer with variable prognosis and response to therapy. We aimed to investigate the heterogeneous biological appearance and clinical behavior of HER2+ tumors using molecular profiling. Materials and Methods Hierarchical clustering of gene expression data from 58 HER2-amplified tumors of various stage, histological grade and estrogen receptor (ER) status was used to construct a HER2-derived prognostic predictor that was further evaluated in several large independent breast cancer data sets. Results Unsupervised analysis identified three subtypes of HER2+ tumors with mixed stage, histological grade and ER-status. One subtype had a significantly worse clinical outcome. A prognostic predictor was created based on differentially expressed genes between the subtype with worse outcome and the other subtypes. The predictor was able to define patient groups with better and worse outcome in HER2+ breast cancer across multiple independent breast cancer data sets and identify a sizable HER2+ group with long disease-free survival and low mortality. Significant correlation to prognosis was also observed in basal-like, ER−, lymph node positive or high-grade tumors, irrespective of HER2-status. The predictor included genes associated to immune response, tumor invasion and metastasis. Conclusion The HER2-derived prognostic predictor provides further insight into the heterogeneous biology of HER2+ tumors and may become useful for improved selection of patients that need additional treatment with new drugs targeting the HER2 pathway. Array comparative genomic hybridization (aCGH) identified 58 breast tumors with amplification of HER2 from a larger cohort of approx 500 tumors breast. Global gene expression profiles were obtained using 70-mer oligonucleotide microarrays. Unsupervised hierarchical clustering of the 58 tumors, using Pearson correlation and complete linkage, identified three main clusters. One cluster showed significantly poorer clinical outcome. Significance of microarray (SAM) analysis was performed to identify 158 genes separating the poor outcome cluster compared to the other two clusters. Gene expression centroids, based on the 158 genes, were created for each cluster for validation in independent breast cancer data sets.

Dataset Information

Transcription profiling of human breast carcinoma tissues representing 930 patients with 17.4 years mean follow-up, basal cytokeratin expression was associated with decreased disease-specific survival

Publications

Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma.

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