|ROUBERT, AGATHA - University Of Massachusetts|
|GREGORY, KELLY - Baystate Medical Center|
|LI, YUYANG - Shandong University|
|PFALZER, ANNA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|LI, JINCHAO - University Of Massachusetts|
|SCHNEIDER, SALLIE - Baystate Medical Center|
|WOOD, RICHARD - University Of Massachusetts|
|LIU, ZHENHUA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
Submitted to: Oncotarget
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/10/2017
Publication Date: 3/28/2017
Citation: Roubert, A., Gregory, K., Li, Y., Pfalzer, A.C., Li, J., Schneider, S.S., Wood, R.J., Liu, Z. 2017. The influence of tumor necrosis factor-a on the tumorigenic Wnt-signaling pathway in human mammary tissue from obese women. Oncotarget. 8(22):36127-36136. https://doi.org/10.18632/oncotarget.16632.
Interpretive Summary: Obesity increases the risk of post-menopausal breast cancer, but the causative pathway by which obesity increases risk remains unclear. Prior work has shown that the state of obesity produces elevated concentrations of inflammatory molecules called cytokines in the blood, and cytokines can activate pro-cancerous pathways in tissues. Breast tissue was removed from women undergoing breast reduction surgery and grown in culture. The release of inflammatory cytokines was significantly greater in the obese women than in the non-obese women, and the levels of these cytokines rose progressively with increasing obesity. Evidence of activation of a pro-cancerous pathway involved in the development of breast cancer, called the Wnt pathway, increased in parallel with the elevations in cytokines. These observations support the concept that obesity also produces a state of inflammation in the human breast and it is accompanied by activation of relevant pro-cancerous pathways.
Technical 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 years or older) undergoing reduction mammoplasty. Moreover, we specifically examined the role of tumor necrosis factor-a (TNF-a), an important proinflammatory cytokine associated with obesity and a possible modulator of the Wnt pathway. The regulatory effects of TNF-a on Wnt pathway targets were measured in an ex vivo culture of breast tissue treated with anti-TNF-a antibody of TNF-a recombinant protein. We found that BMI was positively associated with the secretion of inflammatory cytokines IL-1beta, IL-6 and TNF-a, all of which were negatively correlated with the expression of SFRP1. The transcription expression of Wnt-signaling targets, AXIN2 and CYCLIN D1, were higher in mammary tissue from women with BMI greater of equal to 30 compared to those with BMI less than 30. Our ex vivo work confirmed that TNF-a is causally linked to the up regulation of active beta-CATENIN, a key component in the Wnt pathway, and several Wnt signaling target genes (ie 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.