The orphan nuclear estrogen-related receptors (ERR) have homology to steroid hormone receptors. Unlike classical steroid hormone receptors, ERRs do not have known ligands but are transcriptionally activated upon binding to nuclear receptor coregulators such as PGC1α, PGC1β, and PPRC1. ERRs regulate energy metabolism and are accordingly expressed in tissues that require high energy production. ERRs recognize their own ERRE (estrogen-related receptor response element) gene promoters, but can also activate transcription via ERE (estrogen receptor response element) promoters, representing the ability of ERRs to cross participate in ERα regulatory pathways in the absence of estrogen. Of the three family members (α,β,γ), ERRα is the most highly expressed in breast tissue. ERRα expression was found to be increased in ERα negative breast cancers and associated with poor prognoses. ERRα and its coactivators can increase the expression of a critical mediator of breast tumor angiogenesis and metastasis, VEGFA. We have previously shown that VEGFA is regulated by insulin and IGF receptor activation and hypothesized that ERRα may be a mediator of this finding. We therefore explored whether ERRα and its coactivators are necessary for IGF-I/insulin dependent regulation of VEGFA and cell migration. ERRα was expressed in breast cancer cell lines, but no correlation was observed with breast cancer subtypes. Reducing endogenous ERRα levels by shRNA reduced IGF-I dependent migration in MDA-MB-231 cells. These results were confirmed using an ERRα specific inverse agonist (XCT-790), which also inhibited MDA-MB-231 cell migration. Modulating ERRα mRNA levels via shRNA resulted in decreased VEGFA mRNA levels in MCF7L cells and increased VEGFA mRNA levels in MDA-MB-231 cells, while the inverse agonist XCT-790 caused an increase in VEGFA mRNA levels in both cell lines. Reducing ERRa levels did not affect the expression of the IGF1R, InsR, IRS-1, IRS-2, PI-3K-Akt-mTOR dependent signaling pathway. Neither ERRα protein nor mRNA levels were modulated by IGF-I or insulin. We conclude that ERRα is important for mediating IGF-I dependent migration, but have shown that ERRα is not directly regulated by the IGF signaling. We will next explore the role of ERRα's coregulators (PGC1α, PGC1β, and PPRC1) in the regulation of VEGFA by the IGF/insulin pathway given their central role in regulating ERRα's function.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-09.