Trefoil factor 3 promotes metastatic seeding and predicts poor survival outcome of patients with mammary carcinomaReportar como inadecuado




Trefoil factor 3 promotes metastatic seeding and predicts poor survival outcome of patients with mammary carcinoma - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Breast Cancer Research

, 16:429

First Online: 30 September 2014Received: 18 October 2013Accepted: 15 August 2014DOI: 10.1186-s13058-014-0429-3

Cite this article as: Pandey, V., Wu, ZS., Zhang, M. et al. Breast Cancer Res 2014 16: 429. doi:10.1186-s13058-014-0429-3

Abstract

IntroductionRecurrence or early metastasis remains the predominant cause of mortality in patients with estrogen receptor positive ER+ mammary carcinoma MC. However, the molecular mechanisms underlying the initial progression of ER+ MC to metastasis remains poorly understood. Trefoil factor 3 TFF3 is an estrogen-responsive oncogene in MC. Herein, we provide evidence for a functional role of TFF3 in metastatic progression of ER+ MC.

MethodsThe association of TFF3 expression with clinicopathological parameters and survival outcome in a cohort of MC patients was assessed by immunohistochemistry. The expression of TFF3 in MCF7 and T47D cells was modulated by forced expression or siRNA-mediated depletion of TFF3. mRNA and protein levels were determined using qPCR and western blot. The functional effect of modulation of TFF3 expression in MC cells was determined in vitro and in vivo. Mechanistic analyses were performed using reporter constructs, modulation of signal transducer and activator of transcription 3 STAT3 expression, and pharmacological inhibitors against c-SRC and STAT3 activity.

ResultsTFF3 protein expression was positively associated with larger tumour size, lymph node metastasis, higher stage, and poor survival outcome. Forced expression of TFF3 in ER+ MC cells stimulated colony scattering, cell adhesion to a Collagen I-coated matrix, colony formation on a Collagen I- or Matrigel-coated matrix, endothelial cell adhesion, and transmigration through an endothelial cell barrier. In vivo, forced expression of TFF3 in MCF7 cells stimulated the formation of metastatic nodules in animal lungs. TFF3 regulation of the mRNA levels of epithelial, mesenchymal, and metastatic-related genes in ER+ MC cells were consistent with the altered cell behaviour. Forced expression of TFF3 in ER+ MC cells stimulated phosphorylation of c-SRC that subsequently increased STAT3 activity, which lead to the downregulation of E-cadherin. siRNA-mediated depletion of TFF3 reduced the invasiveness of ER+ MC cells.

ConclusionsTFF3 expression predicts metastasis and poor survival outcome of patients with MC and functionally stimulates cellular invasion and metastasis of ER+ MC cells. Adjuvant functional inhibition of TFF3 may therefore be considered to ameliorate outcome of ER+ MC patients.

AbbreviationsBMDbenign mammary disease

CAconstitutively active

CDH1E-cadherin

CDH2N-cadherin

CSCcancer stem-like cells

c-SRCv-src avian sarcoma Schmidt-Ruppin A-2 viral oncogene homologue

CTNNGγ-catenin

DMSOdimethyl sulfoxide

DNdominant negative

EMTepithelial-mesenchymal transition

ERestrogen receptor

ERBB2v-erb-b2 erythroblastic leukemia viral oncogene homologue 2

f-actinfilamentous actin

FBSfetal bovine serum

HandEhaematoxylin and eosin

HER2human epidermal growth factor receptor type 2

hHPRThuman hypoxanthine-guanine phosphoribosyltransferase

HMEC-1human microvascular endothelial cells

IFimmunofluorescence

IgGimmunoglobulin G

IHCimmunohistochemistry

ITGA6integrin-α6

MCmammary carcinoma

mgapdhmouse glyceraldehyde 3-phosphate dehydrogenase

OCLNoccludin

OSoverall survival

PBSphosphate-buffered saline

PRprogesterone receptor

qPCRquantitative PCR

RFSrelapse-free survival

siRNAsmall interfering RNA

STAT3signal transducer and activator of transcription 3

TFF3trefoil factor 3

TMAtissue microarray

VIMvimentin

Electronic supplementary materialThe online version of this article doi:10.1186-s13058-014-0429-3 contains supplementary material, which is available to authorized users.

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Autor: Vijay Pandey - Zheng-Sheng Wu - Min Zhang - Rui Li - Jian Zhang - Tao Zhu - Peter E Lobie

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



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