The influence of tumor necrosis factor-α on the tumorigenic Wnt-signaling pathway in human mammary tissue from obese women
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Agathe Roubert1, Kelly Gregory2, Yuyang Li3, Anna C. Pfalzer4, Jinchao Li1, Sallie S. Schneider2, Richard J. Wood1, Zhenhua Liu1,4
1Nutrition and Cancer Prevention Laboratory, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA, USA
2Pioneer Valley Life Sciences Institute, Baystate Medical Center, Springfield, MA, USA
3Department of Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
4Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA
Zhenhua Liu, email: firstname.lastname@example.org
Keywords: obesity, inflammation, tumor necrosis factor-α, Wnt pathway, breast cancer
Received: November 11, 2016 Accepted: March 10, 2017 Published: March 28, 2017
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-α (TNF-α), an important proinflammatory cytokine associated with obesity and a possible modulator of the Wnt pathway. The regulatory effects of TNF-α on Wnt pathway targets were measured in an ex vivo culture of breast tissue treated with anti-TNF-α antibody or TNF-α recombinant protein. We found that BMI was positively associated with the secretion of inflammatory cytokines IL-1β, IL-6 and TNF-α, 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-α is causally linked to the up-regulation of active β-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.
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