Weigelt B, Hu Z, He X, Livasy C, Carey LA, Ewend MG et al.. Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancer. Cancer Res 65: 9155-9158

Department of Medicine, University of North Carolina at Chapel Hill, North Carolina, United States
Cancer Research (Impact Factor: 9.33). 11/2005; 65(20):9155-8. DOI: 10.1158/0008-5472.CAN-05-2553
Source: PubMed


Microarray analysis has been shown to improve risk stratification of breast cancer. Breast tumors analyzed by hierarchical clustering of expression patterns of "intrinsic" genes have been reported to subdivide into at least four molecular subtypes that are associated with distinct patient outcomes. Using a supervised method, a 70-gene expression profile has been identified that predicts the later appearance or absence of clinical metastasis in young breast cancer patients. Here, we show that distant metastases display both the same molecular breast cancer subtype as well as the 70-gene prognosis signature as their primary tumors. Our results suggest that the capacity to metastasize is an inherent feature of most breast cancers. Furthermore, our data imply that poor prognosis breast carcinomas classified either by the intrinsic gene set or the 70 prognosis genes represent distinct disease entities that seem sustained throughout the metastatic process.

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Available from: Matthew G Ewend, Nov 23, 2014
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    • "The latter result, limited to c-erbB-2 overexpressing phenotypes in primary tumours and local regional lymph node metastases, is in agreement with the cited study of feline tumours (Brunetti et al., 2013). Phenotypic concordance of the primary tumour and its related lymph node and distant metastases could be explained by an intrinsic and early metastatic capability of the dominant phenotype in the primary tumours, which is maintained in their distant metastases (Weigelt et al., 2005). Two cases in the present study had discordant results . "
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    ABSTRACT: Distant metastases represent a major step in the progression and fatal outcome of canine and feline mammary carcinomas. Recent studies have characterized the molecular phenotypes of mammary tumours and provided information on molecules that may allow targeted therapy in sites from which the tumours may not readily be surgically resected. Molecular phenotypes were determined immunohistochemically in three feline and two canine cases of mammary neoplasia, each presenting with multiple distant metastases. These tumours and their metastases often overexpressed the c-erbB-2 phenotype. A basal-like phenotype was found in the distant metastases from two cases. These findings suggest that canine and feline mammary tumours with distant metastases may be amenable to novel targeted therapies.
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    • ". Basal - like breast cancers express the aberrant DNA hypermethylation - associated gene expression signature . Gene expression data from 946 primary human breast cancers from publically available databases including ( A ) UNC Breast Cancer Microarray Database ( N = 272 cancers ) ( Hu et al . , 2006 ; Oh et al . , 2006 ; Perreard et al . , 2006 ; Weigelt et al . , 2005"
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    ABSTRACT: A subset of human breast cancer cell lines exhibit aberrant DNA hypermethylation that is characterized by hyperactivity of the DNA methyltransferase enzymes, overexpression of DNMT3b, and concurrent methylation-dependent silencing of numerous epigenetic biomarker genes. The objectives of this study were to determine if this aberrant DNA hypermethylation (i) is found in primary breast cancers, (ii) is associated with specific breast cancer molecular subtypes, and (iii) influences patient outcomes. Analysis of epigenetic biomarker genes (CDH1, CEACAM6, CST6, ESR1, GNA11, MUC1, MYB, SCNN1A, and TFF3) identified a gene expression signature characterized by reduced expression levels or loss of expression among a cohort of primary breast cancers. The breast cancers that express this gene expression signature are enriched for triple-negative subtypes - basal-like and claudin-low breast cancers. Methylation analysis of primary breast cancers showed extensive promoter hypermethylation of epigenetic biomarker genes among triple-negative breast cancers, compared to other breast cancer subclasses where promoter hypermethylation events were less frequent. Furthermore, triple-negative breast cancers either did not express or expressed significantly reduced levels of protein corresponding to methylation-sensitive biomarker gene products. Together, these findings suggest strongly that loss of epigenetic biomarker gene expression is frequently associated with gene promoter hypermethylation events. We propose that aberrant DNA hypermethylation is a common characteristic of triple-negative breast cancers and may represent a fundamental biological property of basal-like and claudin-low breast cancers. Kaplan-Meier analysis of relapse-free survival revealed a survival disadvantage for patients with breast cancers that exhibit aberrant DNA hypermethylation. Identification of this distinguishing trait among triple-negative breast cancers forms the basis for development of new rational therapies that target the epigenome in patients with basal-like and claudin-low breast cancers.
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    • "High expression of FBL mRNA was significantly associated with a poor relapse-free survival rate and poor breast cancer-specific survival rate (Figures 7F and 7G). We also performed retrospective statistical analyses of published gene expression array data (Gyö rffy et al., 2010; Sabatier et al., 2011; Weigelt et al., 2005). This investigation confirmed that the high levels of FBL mRNA are associated with poor breast cancer-specific survival and relapse-free survival rates (Figures S7B–S7F). "
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    ABSTRACT: Ribosomes are specialized entities that participate in regulation of gene expression through their rRNAs carrying ribozyme activity. Ribosome biogenesis is overactivated in p53-inactivated cancer cells, although involvement of p53 on ribosome quality is unknown. Here, we show that p53 represses expression of the rRNA methyl-transferase fibrillarin (FBL) by binding directly to FBL. High levels of FBL are accompanied by modifications of the rRNA methylation pattern, impairment of translational fidelity, and an increase of internal ribosome entry site (IRES)-dependent translation initiation of key cancer genes. FBL overexpression contributes to tumorigenesis and is associated with poor survival in patients with breast cancer. Thus, p53 acts as a safeguard of protein synthesis by regulating FBL and the subsequent quality and intrinsic activity of ribosomes.
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