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.