title: The influence of tumor necrosis factor-α 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-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.
authors.affiliation: Nutrition and Cancer Prevention Laboratory, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA, USA.
authors.forename: Agathe
authors.initials: A
authors.lastname: Roubert
authors.affiliation: Pioneer Valley Life Sciences Institute, Baystate Medical Center, Springfield, MA, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Gregory
authors.affiliation: Department of Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China.
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Pfalzer
authors.affiliation: Nutrition and Cancer Prevention Laboratory, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA, USA.
authors.forename: Jinchao
authors.initials: J
authors.lastname: Li
authors.affiliation: Pioneer Valley Life Sciences Institute, Baystate Medical Center, Springfield, MA, USA.
authors.forename: Sallie S
authors.initials: SS
authors.lastname: Schneider
authors.affiliation: Nutrition and Cancer Prevention Laboratory, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wood
authors.affiliation: Nutrition and Cancer Prevention Laboratory, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA, USA.|Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Liu
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000150:complications / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D042361:Mammary Glands, Human / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000276:immunology*; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D019138:Antibodies, Blocking; D060466:Axin Protein; D019938:Cyclin D1; D036341:Intercellular Signaling Peptides and Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; C491761:AXIN2 protein, human; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins
keywords: Wnt pathway; breast cancer; inflammation; obesity; tumor necrosis factor-α