title: Obesity Suppresses Estrogen Receptor Beta Expression in Breast Cancer Cells via a HER2-Mediated Pathway.
abstract: Obesity is associated with a worse breast cancer prognosis, while greater breast tumor estrogen receptor beta (ERβ) expression is correlated with improved therapy response and survival. The objective of this study was to determine the impact of obesity on breast cancer cell ERβ expression, which is currently unknown. We utilized an in vitro model of obesity in which breast cancer cells were exposed to patient serum pooled by body mass index category (obese (OB): ≥30 kg/m2; normal weight (N): 18.5-24.9 kg/m2). Four human mammary tumor cell lines representing the major breast cancer subtypes (SKBR3, MCF-7, ZR75, MDA-MB-231) and mammary tumor cells from MMTV-neu mice were used. ERβ expression, assessed by qPCR and western blotting, was suppressed in the two HER2-overexpressing cell lines (SKBR3, MMTV-neu) following OB versus N sera exposure, but did not vary in the other cell lines. Expression of Bcl-2 and cyclin D1, two genes negatively regulated by ERβ, was elevated in SKBR3 cells following exposure to OB versus N sera, but this difference was eliminated when the ERβ gene was silenced with siRNA. Herceptin, a HER2 antagonist, and siRNA to HER2 were used to evaluate the role of HER2 in sera-induced ERβ modulation. SKBR3 cell treatment with OB sera plus Herceptin increased ERβ expression three-fold. Similar results were obtained when HER2 expression was silenced with siRNA. OB sera also promoted greater SKBR3 cell viability and growth, but this variance was not present when ERβ was silenced or the cells were modified to overexpress ERβ. Based on this data, we conclude that obesity-associated systemic factors suppress ERβ expression in breast cancer cells via a HER2-mediated pathway, leading to greater cell viability and growth. Elucidation of the mechanism(s) mediating this effect could provide important insights into how ERβ expression is regulated as well as how obesity promotes a more aggressive disease.
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Laura W
authors.initials: LW
authors.lastname: Bowers
authors.affiliation: Department of Nutritional Sciences, University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Megan
authors.initials: M
authors.lastname: Wiese
authors.affiliation: Division of Hematology and Medical Oncology, University of Texas Health Science Center, San Antonio, Texas, United States of America.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brenner
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Rossi
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, Texas, United States of America.
authors.forename: Rajeshwar R
authors.initials: RR
authors.lastname: Tekmal
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hursting
authors.affiliation: Department of Nutritional Sciences, University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Linda A
authors.initials: LA
authors.lastname: deGraffenried
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D019938:Cyclin D1 / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D009765:Obesity / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D019938:Cyclin D1; D047629:Estrogen Receptor beta; D019253:Proto-Oncogene Proteins c-bcl-2; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human