Dataset Information

The influence of tumor necrosis factor-? on the tumorigenic Wnt-signaling pathway in human mammary tissue from obese women.

ABSTRACT: Epidemiological studies have convincingly suggested that obesity is an important risk factor for postmenopausal breast cancer, but the mechanisms responsible for this relationship are still not fully understood. We hypothesize that obesity creates a low-grade inflammatory microenvironment, which stimulates Wnt-signaling and thereby promotes the development of breast cancer. To test this hypothesis, we evaluated the correlations between expression of multiple inflammatory cytokines and Wnt pathway downstream genes in mammary tissues from women (age ? 50) undergoing reduction mammoplasty. Moreover, we specifically examined the role of tumor necrosis factor-? (TNF-?), an important proinflammatory cytokine associated with obesity and a possible modulator of the Wnt pathway. The regulatory effects of TNF-? on Wnt pathway targets were measured in an ex vivo culture of breast tissue treated with anti-TNF-? antibody or TNF-? recombinant protein. We found that BMI was positively associated with the secretion of inflammatory cytokines IL-1?, IL-6 and TNF-?, all of which were negatively correlated with the expression of SFRP1. The transcriptional expression of Wnt-signaling targets, AXIN2 and CYCLIN D1, were higher in mammary tissue from women with BMI ? 30 compared to those with BMI < 30. Our ex vivo work confirmed that TNF-? is causally linked to the up-regulation of active ?-CATENIN, a key component in the Wnt pathway, and several Wnt-signaling target genes (i.e. CYCLIN D1, AXIN2, P53 and COX-2). Collectively, these findings indicate that obesity-driven inflammation elevates Wnt-signaling in mammary tissue and thereby creates a microenvironment conducive to the development of breast cancer.

SUBMITTER: Roubert A

PROVIDER: S-EPMC5482643 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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The influence of tumor necrosis factor-α on the tumorigenic Wnt-signaling pathway in human mammary tissue from obese women.

Roubert Agathe A Gregory Kelly K Li Yuyang Y Pfalzer Anna C AC Li Jinchao J Schneider Sallie S SS Wood Richard J RJ Liu Zhenhua Z

Oncotarget 20170501 22

Epidemiological studies have convincingly suggested that obesity is an important risk factor for postmenopausal breast cancer, but the mechanisms responsible for this relationship are still not fully understood. We hypothesize that obesity creates a low-grade inflammatory microenvironment, which stimulates Wnt-signaling and thereby promotes the development of breast cancer. To test this hypothesis, we evaluated the correlations between expression of multiple inflammatory cytokines and Wnt pathwa ...[more]

PMID: 28402277

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Project description:Interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and WNT/β-catenin signaling cause dysregulation of rat primary articular chondrocytes (rArCs), resulting in cartilage extracellular matrix destruction and osteoarthritis (OA) progression. microRNA (miR) miR-122 represses these effects whereas miR-451 exacerbates IL-1β-stimulated matrix metalloproteinase-13 (MMP-13) and prostaglandin E2 (PGE2) production. The goals of this study were to evaluate crosstalk between these signaling pathways and determine if miR-122 and miR-451 exert their protective/destructive effects through these pathways in an in vitro model of OA. Primary rArCs were treated with IL-1β or TNF-α for 24 h and total DNA, MMP-13, and PGE2, as well as expression levels of miR-122 and miR-451 were measured. After 24-h transfection with miR-122, miR-451, miR-122-inhibitor, or miR-451-inhibitor, rArCs were treated with or without TNF-α for 24 h; total DNA, MMP-13, and PGE2 were measured. Similarly, cells were treated with WNT-agonist lithium chloride (LiCl), WNT-antagonist XAV-939 (XAV), or PKF-118-310 (PKF) with and without IL-1β or TNF-α stimulation. Both IL-1β and TNF-α-stimulation increased MMP-13 and PGE2 production. Transfection with miR-122 prevented TNF-α-stimulated increases in MMP-13 and PGE2 whereas transfection with miR-451 did not change these levels. No differences were found in MMP-13 or PGE2 production with miR-122 or miR-451 inhibitors. LiCl treatment decreased PGE2 production in cultures treated with TNF-α, but not MMP-13. XAV increased TNF-α-stimulated increases in PGE2 but not MMP-13. LiCl reduced IL-1β-stimulated increases in MMP-13 and PGE2. XAV and PKF increased IL-1β-stimulated increases in MMP-13 and PGE2. In this in vitro OA model, miR-122 protects against both IL-1β and TNF-α stimulated increases in MMP-13 and PGE2 production. miR-451 does not act through the TNF-α pathway. The WNT/β-catenin pathway regulates the effects of IL-1β and TNF-α stimulation. This study suggests that miR-122 can be used as a treatment or prevention for OA.

Dataset Information

The influence of tumor necrosis factor-? on the tumorigenic Wnt-signaling pathway in human mammary tissue from obese women.

Publications

The influence of tumor necrosis factor-α on the tumorigenic Wnt-signaling pathway in human mammary tissue from obese women.

Similar Datasets

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