BRCA1 transcriptionally regulates genes associated with the basal-like phenotype in breast cancer
Julia J. Gorski,Colin R. James,Jennifer E. Quinn,Gail E. Stewart,Kieran Crosbie Staunton,Niamh E. Buckley,F. A. McDyer,Richard D. Kennedy,Richard H. Wilson,Paul B. Mullan,D. Paul Harkin +10 more
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TLDR
It is demonstrated that functional BRCA1 represses the expression of cytokeratins 5 (KRT5) and 17(KRT17) and p-Cadherin (CDH3) in HCC1937 and T47D breast tumours at both mRNA and protein level.Abstract:
Expression profiling of BRCA1-deficient tumours has identified a pattern of gene expression similar to basal-like breast tumours. In this study, we examine whether a BRCA1-dependent transcriptional mechanism may underpin the link between BRCA1 and basal-like phenotype. In methods section, the mRNA and protein were harvested from a number of BRCA1 mutant and wild-type breast cancer cell lines and from matched isogenic controls. Microarray-based expression profiling was used to identify potential BRCA1-regulated transcripts. These gene targets were then validated (by in silico analysis of tumour samples) by real-time PCR and Western blot analysis. Chromatin immunoprecipitation (ChIP) assays were used to confirm recruitment of BRCA1 to specific promoters. In results, we demonstrate that functional BRCA1 represses the expression of cytokeratins 5(KRT5) and 17(KRT17) and p-Cadherin (CDH3) in HCC1937 and T47D breast cancer cell lines at both mRNA and protein level. ChIP assays demonstrate that BRCA1 is recruited to the promoters of KRT5, KRT17 and CDH3, and re-ChIP assays confirm that BRCA1 is recruited independently to form c-Myc and Sp1 complexes on the CDH3 promoter. We show that siRNA-mediated inhibition of endogenous c-Myc (and not Sp1) results in a marked increase in CDH3 expression analogous to that observed following the inhibition of endogenous BRCA1. The data provided suggest a model whereby BRCA1 and c-Myc form a repressor complex on the promoters of specific basal genes and represent a potential mechanism to explain the observed overexpression of key basal markers in BRCA1-deficient tumours.read more
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Journal ArticleDOI
Triple-negative breast cancer.
TL;DR: Triple-negative breast cancer, so called because it lacks expression of the estrogen receptor, progesterone receptor, and HER2, is often, but not always, a basal-like breast cancer.
Journal ArticleDOI
BRCA1 Basal-like Breast Cancers Originate from Luminal Epithelial Progenitors and Not from Basal Stem Cells
Gemma Molyneux,Felipe C. Geyer,Fiona-Ann Magnay,Afshan McCarthy,Howard Kendrick,Rachael Natrajan,Alan Mackay,Anita Grigoriadis,Andrew Tutt,Alan Ashworth,Jorge S. Reis-Filho,Matthew J. Smalley +11 more
TL;DR: It is demonstrated that deleting Brca1 in mouse mammary epithelial luminal progenitors produces tumors that phenocopy human BRCA1 breast cancers and that when target cells for transformation have the potential for phenotypic plasticity, tumor phenotypes may not directly reflect histogenesis.
Journal ArticleDOI
Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists
Sunil Badve,David J. Dabbs,Stuart J. Schnitt,Frederick L. Baehner,Thomas Decker,Vincenzo Eusebi,Stephen B. Fox,Shu Ichihara,Jocelyne Jacquemier,Sunil R. Lakhani,José Palacios,Emad A. Rakha,Andrea L. Richardson,Fernando Schmitt,Puay Hoon Tan,Gary Tse,Britta Weigelt,Ian O. Ellis,Jorge S. Reis-Filho +18 more
TL;DR: The purpose of this article was to discuss the relationship between basal-like and triple-negative breast cancers, and to clarify practical implications of these diagnoses for pathologists and oncologists.
Journal ArticleDOI
Histological types of breast cancer: How special are they?
TL;DR: The associations between the molecular taxonomy of breast cancer and histological special types are reviewed, the possible origins of the heterogeneity of breast cancers are discussed, and an approach for the identification of novel therapeutic targets based on the study of histologicalspecial types of Breast cancer is proposed.
Journal ArticleDOI
Triple-negative breast cancer: Present challenges and new perspectives
Franca Podo,Lutgarde M. C. Buydens,Hadassa Degani,Riet Hilhorst,Edda Klipp,Ingrid S. Gribbestad,Sabine Van Huffel,Hanneke W. M. van Laarhoven,Jan Luts,Daniel Monleon,Geert Postma,Nicole Schneiderhan-Marra,Filippo Santoro,Hans J. P. Wouters,Hege G. Russnes,Therese Sørlie,Therese Sørlie,Elda Tagliabue,Anne Lise Børresen-Dale +18 more
TL;DR: An overview is here presented on TNBC profiling in terms of expression signatures, within the functional genomic breast tumor classification, and ongoing efforts toward identification of new therapy targets and bioimaging markers.
References
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Journal ArticleDOI
Molecular portraits of human breast tumours
Charles M. Perou,Therese Sørlie,Michael B. Eisen,Matt van de Rijn,Stefanie S. Jeffrey,Christian A. Rees,Jonathan R. Pollack,Douglas T. Ross,Hilde Johnsen,Lars A. Akslen,Øystein Fluge,Alexander Pergamenschikov,Cheryl A. Williams,Shirley Zhu,Per Eystein Lønning,Anne Lise Børresen-Dale,Patrick O. Brown,David Botstein +17 more
TL;DR: Variation in gene expression patterns in a set of 65 surgical specimens of human breast tumours from 42 different individuals were characterized using complementary DNA microarrays representing 8,102 human genes, providing a distinctive molecular portrait of each tumour.
Journal ArticleDOI
Repeated observation of breast tumor subtypes in independent gene expression data sets
Therese Sørlie,Robert Tibshirani,Joel S. Parker,Trevor Hastie,James Stephen Marron,Andrew B. Nobel,Shibing Deng,Hilde Johnsen,Robert Pesich,Stephanie Geisler,Janos Demeter,Charles M. Perou,Per Eystein Lønning,Patrick O. Brown,Anne Lise Børresen-Dale,David Botstein +15 more
TL;DR: The results strongly support the idea that many of these breast tumor subtypes represent biologically distinct disease entities.
Journal ArticleDOI
A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes
Richard M. Neve,Richard M. Neve,Koei Chin,Jane Fridlyand,Jennifer Yeh,Frederick L. Baehner,Tea Fevr,Laura Clark,Nora Bayani,Jean-Philippe Coppe,Frances Tong,Terence P. Speed,Paul T. Spellman,Sandy DeVries,Anna Lapuk,Nicholas J. Wang,Wen-Lin Kuo,Jackie L. Stilwell,Daniel Pinkel,Donna G. Albertson,F. M. Waldman,Frank McCormick,Robert B. Dickson,Michael D. Johnson,Marc E. Lippman,Stephen P. Ethier,Adi F. Gazdar,Joe W. Gray,Joe W. Gray +28 more
TL;DR: It is shown, using Trastuzumab (Herceptin) monotherapy as an example, that the system can be used to identify molecular features that predict or indicate response to targeted therapies or other physiological perturbations.
Journal ArticleDOI
Re: Germline BRCA1 Mutations and a Basal Epithelial Phenotype in Breast Cancer
William D. Foulkes,Ingunn M. Stefansson,Pierre O. Chappuis,Louis R. Bégin,John R. Goffin,Nora Wong,Michel Trudel,Lars A. Akslen +7 more
TL;DR: Germline BRCA1 mutations appear to be associated with a distinctive breast cancer phenotype, and the expression of cytokeratin 5/6 was statistically significantly associated with BRCa1-related breast cancers.
Journal ArticleDOI
RESPONSE: Re: Germline BRCA1 Mutations and a Basal Epithelial Phenotype in Breast Cancer
TL;DR: Germline BRCA1 mutations appear to be associated with a distinctive breast cancer phenotype, and the expression of cytokeratin 5/6 was statistically significantly associated with BRCa1-related breast cancers.
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