Transforming growth factor beta receptor type III is a tumor promoter in mesenchymal-stem like triple negative breast cancerReport as inadecuate




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Breast Cancer Research

, 16:R69

First Online: 01 July 2014Received: 22 January 2014Accepted: 19 June 2014DOI: 10.1186-bcr3684

Cite this article as: Jovanović, B., Beeler, J.S., Pickup, M.W. et al. Breast Cancer Res 2014 16: R69. doi:10.1186-bcr3684

Abstract

IntroductionThere is a major need to better understand the molecular basis of triple negative breast cancer TNBC in order to develop effective therapeutic strategies. Using gene expression data from 587 TNBC patients we previously identified six subtypes of the disease, among which a mesenchymal-stem like MSL subtype. The MSL subtype has significantly higher expression of the transforming growth factor beta TGF-β pathway-associated genes relative to other subtypes, including the TGF-β receptor type III TβRIII. We hypothesize that TβRIII is tumor promoter in mesenchymal-stem like TNBC cells.

MethodsRepresentative MSL cell lines SUM159, MDA-MB-231 and MDA-MB-157 were used to study the roles of TβRIII in the MSL subtype. We stably expressed short hairpin RNAs specific to TβRIII TβRIII-KD. These cells were then used for xenograft tumor studies in vivo; and migration, invasion, proliferation and three dimensional culture studies in vitro. Furthermore, we utilized human gene expression datasets to examine TβRIII expression patterns across all TNBC subtypes.

ResultsTβRIII was the most differentially expressed TGF-β signaling gene in the MSL subtype. Silencing TβRIII expression in MSL cell lines significantly decreased cell motility and invasion. In addition, when TβRIII-KD cells were grown in a three dimensional 3D culture system or nude mice, there was a loss of invasive protrusions and a significant decrease in xenograft tumor growth, respectively. In pursuit of the mechanistic underpinnings for the observed TβRIII-dependent phenotypes, we discovered that integrin-α2 was expressed at higher level in MSL cells after TβRIII-KD. Stable knockdown of integrin-α2 in TβRIII-KD MSL cells rescued the ability of the MSL cells to migrate and invade at the same level as MSL control cells.

ConclusionsWe have found that TβRIII is required for migration and invasion in vitro and xenograft growth in vivo. We also show that TβRIII-KD elevates expression of integrin-α2, which is required for the reduced migration and invasion, as determined by siRNA knockdown studies of both TβRIII and integrin-α2. Overall, our results indicate a potential mechanism in which TβRIII modulates integrin-α2 expression to effect MSL cell migration, invasion, and tumorigenicity.

AbbreviationsBL1basal-like 1

BL2basal-like 2

BMPbone morphogenetic protein

DAPI4′, 6-diamidino-2-phenylindole

DMEMDulbecco’s modified Eagle’s serum

ECMextracellular matrix

ERestrogen receptor

GEgene expression

HER2human epidermal growth factor receptor 2

IHCimmunohistochemistry

ITGA2integrin alpha 2

LARluminal androgen receptor

Mmesenchymal

MAtSmagnetic attachable stencils

MSLmesenchymal stem-like

PBSphosphate-buffered saline

PRprogesterone receptor

qPCRquantitative polymerase chain reaction

shRNAshort hairpin RNA

TCGAThe Cancer Genome Atlas

TGFBR3type III transforming growth factor-beta receptor

TGF-βtransforming growth factor-beta

TGFβ1transforming growth factor-beta ligand 1

TGFβ2transforming growth factor-beta ligand 2

TNBCtriple negative breast cancer

TβRItype I transforming growth factor-beta receptor

TβRIItype II transforming growth factor-beta receptor

TβRIIItype III transforming growth factor-beta receptor

TβRIII-KDtype III transforming growth factor-beta receptor knockdown.

Electronic supplementary materialThe online version of this article doi:10.1186-bcr3684 contains supplementary material, which is available to authorized users.

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Author: Bojana Jovanović - J Scott Beeler - Michael W Pickup - Anna Chytil - Agnieszka E Gorska - William J Ashby - Brian D L

Source: https://link.springer.com/



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