Homeobox transcription factor muscle segment homeobox 2 Msx2 correlates with good prognosis in breast cancer patients and induces apoptosis in vitroReportar como inadecuado




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Breast Cancer Research

, 12:R59

First Online: 03 August 2010Received: 22 March 2010Revised: 09 June 2010Accepted: 03 August 2010

Abstract

IntroductionThe homeobox-containing transcription factor muscle segment homeobox 2 Msx2 plays an important role in mammary gland development. However, the clinical implications of Msx2 expression in breast cancer are unclear. The aims of this study were to investigate the potential clinical value of Msx2 as a breast cancer biomarker and to clarify its functional role in vitro.

MethodsMsx2 gene expression was first examined in a well-validated breast cancer transcriptomic dataset of 295 patients. Msx2 protein expression was then evaluated by immunohistochemistry in a tissue microarray TMA containing 281 invasive breast tumours. Finally, to assess the functional role of Msx2 in vitro, Msx2 was ectopically expressed in a highly invasive breast tumour cell line MDA-MB-231 and an immortalised breast cell line MCF10a, and these cell lines were examined for changes in growth rate, cell death and cell signalling.

ResultsExamination of Msx2 mRNA expression in a breast cancer transcriptomic dataset demonstrated that increased levels of Msx2 were associated with good prognosis P = 0.011. Evaluation of Msx2 protein expression on a TMA revealed that Msx2 was detectable in both tumour cell nuclei and cytoplasm. Cytoplasmic Msx2 expression was associated with low grade tumours P = 0.012 and Ki67 negativity P = 0.018. Nuclear Msx2 correlated with low-grade tumours P = 0.015, estrogen receptor positivity P = 0.038, low Ki67 P = 0.005 and high cyclin D1 expression P = 0.037. Increased cytoplasmic Msx2 expression was associated with a prolonged breast cancer-specific survival P = 0.049, recurrence-free survival P = 0.029 and overall survival P = 0.019. Ectopic expression of Msx2 in breast cell lines resulted in radically decreased cell viability mediated by induction of cell death via apoptosis. Further analysis of Msx2-expressing cells revealed increased levels of p21 and phosphorylated extracellular signal-regulated kinase ERK and decreased levels of Survivin and the -split ends- SPEN protein family member RBM15.

ConclusionsWe conclude that increased Msx2 expression results in improved outcome for breast cancer patients, possibly by increasing the likelihood of tumour cell death by apoptosis.

AbbreviationsBCSSbreast cancer-specific survival

BMPbone morphogenetic protein

BSPbone sialoprotein

CPAcell pellet array

DLX5distal-less homeobox 5

EMTepithelial to mesenchymal transition

ERestrogen receptor

ERKextracellular signal-regulated kinase

EVempty vector

FFPEformalin-fixed paraffin-embedded

Her2human epidermal growth factor 2

HRhazard ratio

IHCimmunohistochemistry

Ki67proliferation-related Ki-67 antigen

Msx2muscle segment homeobox 2

MTT3-4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide

OSoverall survival

PBSphosphate-buffered saline

PIpropidium iodide

PRprogesterone receptor

RBM15RNA-binding motif protein 15

RFSrecurrence-free survival

Shhsonic hedgehog-1

SPENa derivation of -split ends- Drosophila

SPOCSPEN paralog and ortholog C-terminal

TMAtissue microarray

VEGFvascular endothelial growth factor.

Electronic supplementary materialThe online version of this article doi:10.1186-bcr2621 contains supplementary material, which is available to authorized users.

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Autor: Fiona Lanigan - Gabriela Gremel - Rowena Hughes - Donal J Brennan - Finian Martin - Karin Jirström - William M Gallagher

Fuente: https://link.springer.com/







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