The non-protein coding breast cancer susceptibility locus Mcs5a acts in a non-mammary cell-autonomous fashion through the immune system and modulates T-cell homeostasis and functionsReport as inadecuate




The non-protein coding breast cancer susceptibility locus Mcs5a acts in a non-mammary cell-autonomous fashion through the immune system and modulates T-cell homeostasis and functions - Download this document for free, or read online. Document in PDF available to download.

Breast Cancer Research

, 13:R81

First Online: 16 August 2011Received: 13 February 2011Revised: 23 May 2011Accepted: 16 August 2011

Abstract

IntroductionMechanisms underlying low-penetrance, common, non-protein coding variants in breast cancer risk loci are largely undefined. We showed previously that the non-protein coding mammary carcinoma susceptibility locus Mcs5a-MCS5A modulates breast cancer risk in rats and women. The Mcs5a allele from the Wistar-Kyoto WKy rat strain consists of two genetically interacting elements that have to be present on the same chromosome to confer mammary carcinoma resistance. We also found that the two interacting elements of the resistant allele are required for the downregulation of transcript levels of the Fbxo10 gene specifically in T-cells. Here we describe mechanisms through which Mcs5a may reduce mammary carcinoma susceptibility.

MethodsWe performed mammary carcinoma multiplicity studies with three mammary carcinoma-inducing treatments, namely 7,12-dimethylbenzaanthracene DMBA and N-nitroso-N-methylurea NMU carcinogenesis, and mammary ductal infusion of retrovirus expressing the activated HER2-neu oncogene. We used mammary gland and bone marrow transplantation assays to assess the target tissue of Mcs5a activity. We used immunophenotyping assays on well-defined congenic rat lines carrying susceptible and resistant Mcs5a alleles to identify changes in T-cell homeostasis and function associated with resistance.

ResultsWe show that Mcs5a acts beyond the initial step of mammary epithelial cell transformation, during early cancer progression. We show that Mcs5a controls susceptibility in a non-mammary cell-autonomous manner through the immune system. The resistant Mcs5a allele was found to be associated with an overabundance of gd T-cell receptor TCR+ T-cells as well as a CD62L L-selectin-high population of all T-cell classes. In contrast to in mammary carcinoma, gdTCR+ T-cells are the predominant T-cell type in the mammary gland and were found to be overabundant in the mammary epithelium of Mcs5a resistant congenic rats. Most of them simultaneously expressed the CD4, CD8, and CD161α markers. In cultured T-cells of Mcs5a resistant congenic rats we found increased mitogen-induced proliferation and production of Th1 cytokines IFNg, IL-2, and Tumor Necrosis Factor TNF, but not Th2 cytokines IL-4 and IL-6, or Th17 cytokine IL-17 when compared with susceptible control rats.

ConclusionsThese data support a hypothesis that Mcs5a displays a non-mammary cell-autonomous mechanism of action to modulate breast cancer risk through the immune system. The resistant Mcs5a allele is associated with alterations in T-cell homeostasis and functions, and overabundance of γδTCR+ T-cells in carcinogen-exposed mammary epithelium.

AbbreviationsCFSEcarboxyfluorescein succinimidyl ester

CFUcolony-forming unit

ConAconcanavalin A

DMBA7,12-dimethylbenzaanthracene

DMEM-F12Dulbecco-s modified Eagle-s medium-F12

ELISAenzyme-linked immunosorbent assay

IFNγinterferon-gamma

ILinterleukin

ISCin situ carcinoma

LNlymph node

MCBmonochlorobimane

Mcs5amammary carcinoma susceptibility locus 5a

MFImean fluorescence intensity

NMUN-nitroso-N-methylurea

Rresistant

Ssusceptible

susc.susceptible congenic control

TCRT-cell receptor

TNFtumor necrosis factor

WFWistar-Furth

WKyWistar-Kyoto.

Electronic supplementary materialThe online version of this article doi:10.1186-bcr2933 contains supplementary material, which is available to authorized users.

Bart MG Smits, Deepak Sharma, David J Samuelson contributed equally to this work.

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Author: Bart MG Smits - Deepak Sharma - David J Samuelson - Stephan Woditschka - Bob Mau - Jill D Haag - Michael N Gould

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







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