Integrated genomic analysis of triple-negative breast cancers reveals novel microRNAs associated with clinical and molecular phenotypes and sheds light on the pathways they control.
BACKGROUND
This study focuses on the analysis of miRNAs expression data in a cohort of 181 well characterised breast cancer samples composed primarily of triple-negative (ER/PR/HER2-negative) tumours with associated genome-wide DNA and mRNA data, extensive patient follow-up and pathological information.


RESULTS
We identified 7 miRNAs associated with prognosis in the triple-negative tumours and an additional 7 when the analysis was extended to the set of all ER-negative cases. miRNAs linked to an unfavourable prognosis were associated with a broad spectrum of motility mechanisms involved in the invasion of stromal tissues, such as cell-adhesion, growth factor-mediated signalling pathways, interaction with the extracellular matrix and cytoskeleton remodelling. When we compared different intrinsic molecular subtypes we found 46 miRNAs that were specifically expressed in one or more intrinsic subtypes. Integrated genomic analyses indicated these miRNAs to be influenced by DNA genomic aberrations and to have an overall influence on the expression levels of their predicted targets. Among others, our analyses highlighted the role of miR-17-92 and miR-106b-25, two polycistronic miRNA clusters with known oncogenic functions. We showed that their basal-like subtype specific up-regulation is influenced by increased DNA copy number and contributes to the transcriptional phenotype as well as the activation of oncogenic pathways in basal-like tumours.


CONCLUSIONS
This study analyses previously unreported miRNA, mRNA and DNA data and integrates these with pathological and clinical information, from a well-annotated cohort of breast cancers enriched for triple-negative subtypes. It provides a conceptual framework, as well as integrative methods and system-level results and contributes to elucidate the role of miRNAs as biomarkers and modulators of oncogenic processes in these types of tumours.
Breakthrough Breast Cancer Research Unit, Division of Cancer Studies, School of Medicine, King's College London, Guy's Hospital, London, UK. emanuele.de_rinaldis@kcl.ac.uk.
Emanuele
E
de Rinaldis
Patrycja
P
Gazinska
Anca
A
Mera
Zora
Z
Modrusan
Grazyna M
GM
Fedorowicz
Brian
B
Burford
Cheryl
C
Gillett
Pierfrancesco
P
Marra
Anita
A
Grigoriadis
David
D
Dornan
Lars
L
Holmberg
Sarah
S
Pinder
Andrew
A
Tutt
D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D005260:Female; D005500:Follow-Up Studies; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D034622:RNA Interference; D015398:Signal Transduction; D014158:Transcription, Genetic; D059467:Transcriptome; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology
D035683:MicroRNAs