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PMID: 23939832 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

MiR-26b is down-regulated in carcinoma-associated fibroblasts from ER-positive breast cancers leading to enhanced cell migration and invasion.

The Journal of pathology ·Vol. 231 ·No. 3 ·2013-11-00 ·Pages 388-99

Verghese ET, Drury R, Green CA, Holliday DL, Lu X, Nash C, Speirs V, Thorne JL, Thygesen HH, Zougman A, Hull MA, Hanby AM, Hughes TA

Abstract

Carcinoma-associated fibroblasts (CAFs) influence the behaviour of cancer cells but the roles of microRNAs in this interaction are unknown. We report microRNAs that are differentially expressed between breast normal fibroblasts and CAFs of oestrogen receptor-positive cancers, and explore the influences of one of these, miR-26b, on breast cancer biology. We identified differentially expressed microRNAs by expression profiling of clinical samples and a tissue culture model: miR-26b was the most highly deregulated microRNA. Using qPCR, miR-26b was confirmed as down-regulated in fibroblasts from 15 of 18 further breast cancers. Next, we examined whether manipulation of miR-26b expression changed breast fibroblast behaviour. Reduced miR-26b expression caused fibroblast migration and invasion to increase by up to three-fold in scratch-closure and trans-well assays. Furthermore, in co-culture with MCF7 breast cancer epithelial cells, fibroblasts with reduced miR-26b expression enhanced both MCF7 migration in trans-well assays and MCF7 invasion from three-dimensional spheroids by up to five-fold. Mass spectrometry was used to identify expression changes associated with the reduction of miR-26b expression in fibroblasts. Pathway analyses of differentially expressed proteins revealed that glycolysis/TCA cycle and cytoskeletal regulation by Rho GTPases are downstream of miR-26b. In addition, three novel miR-26b targets were identified (TNKS1BP1, CPSF7, COL12A1) and the expression of each in cancer stroma was shown to be significantly associated with breast cancer recurrence. MiR-26b in breast CAFs is a potent regulator of cancer behaviour in oestrogen receptor-positive cancers, and we have identified key genes and molecular pathways that act downstream of miR-26b in CAFs.

Keywords
fibroblast microRNA microRNA-26b stroma tumour microenvironment
MeSH Terms
Breast Neoplasms/genetics,metabolism,pathology Cell Movement Coculture Techniques Down-Regulation Female Fibroblasts/metabolism,pathology Gene Expression Profiling/methods Gene Expression Regulation, Neoplastic Humans MCF-7 Cells MicroRNAs/metabolism Neoplasm Invasiveness Oligonucleotide Array Sequence Analysis Paracrine Communication Polymerase Chain Reaction Receptors, Estrogen/metabolism Signal Transduction Time Factors Transfection Tumor Microenvironment
Chemicals
MIRN26A microRNA, human MicroRNAs Receptors, Estrogen
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Verghese Eldo T
Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK; Department of Histopathology, St James's University Hospital, Leeds, UK.
Drury Ruth
Green Caroline A
Holliday Deborah L
Lu Xiaomei
Nash Claire
Speirs Valerie
Thorne James L
Thygesen Helene H
Zougman Alexandre
Hull Mark A
Hanby Andrew M
Hughes Thomas A
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Article Info
Journal
The Journal of pathology
Abbr.
J Pathol
ISSN
1096-9896
DOI
10.1002/path.4248
Published
2013-11-00
Pages
388-99
Language
English
Region
England
NLM ID
0204634
PMCID
PMC4030585
Subset
IM
Grants
Medical Research Council · G0902032 · United Kingdom
Cancer Research UK · C37059/A11941 · United Kingdom
External Links
PubMed source DOI: 10.1002/path.4248 PMC Full Text View journal details
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