Estrogen-related Receptor α and Estrogen-related Receptor γ Associate with Unfavorable and Favorable Biomarkers, Respectively, in Human Breast Cancer

The importance of estrogen-related receptors (ERRs) in human breast cancer was assessed by comparing their mRNA profiles with established clinicopathological indicators and mRNA profiles of estrogen receptors (ERs) and ErbB family members. Using real-time quantitative PCR assays, mRNA levels of ERα, ERβ, epidermal growth factor receptor, ErbB2, ErbB3, ErbB4, ERRα, ERRβ, and ERRγ were determined in unselected primary breast tumors ( n = 38) and normal mammary epithelial cells enriched from reduction mammoplasties ( n = 9). ERRα showed potential as a biomarker of unfavorable clinical outcome and, possibly, hormonal insensitivity. ERRα mRNA was expressed at levels greater than or similar to ERα mRNA in 24% of unselected breast tumors, and generally at higher levels than ERα in the progesterone receptor (PgR)-negative tumor subgroup (1-way ANOVA with repeated measures, P = 0.030). Increased ERRα levels associated with ER-negative (Fisher’s exact, P = 0.003) and PgR-negative tumor status (Fisher’s exact, P = 0.006; Kruskal-Wallis ANOVA, P = 0.021). ERRα levels also correlated with expression of ErbB2 (Spearman’s rho, P = 0.005), an indicator of aggressive tumor behavior. Thus, ERRα was the most abundant nuclear receptor in a subset of tumors that tended to lack functional ERα and expressed ErbB2 at high levels. Consequently, ERRα may potentiate constitutive transcription of estrogen response element-containing genes independently of ERα and antiestrogens in ErbB2-positive tumors. ERRβ’s potential as a biomarker remains unclear; it showed a direct relationship with ERβ (Spearman’s rho, P = 0.0002) and an inverse correlation with S-phase fraction (Spearman’s rho, P = 0.026). Unlike ERRα, ERRγ showed potential as a biomarker of favorable clinical course and, possibly, hormonal sensitivity. ERRγ was overexpressed in 75% of the tumors, resulting in the median ERRγ level being elevated in breast tumors compared with normal mammary epithelial cells (Kruskal-Wallis ANOVA, P = 0.001). ERRγ overexpression associated with hormonally responsive ER- and PgR-positive status (Fisher’s exact, P = 0.054 and P = 0.045, respectively). Additionally, ERRγ expression correlated with levels of ErbB4 (Spearman’s rho, P = 0.052), a likely indicator of preferred clinical course, and associated with diploid-typed tumors (Fisher’s exact, P = 0.042). Hence, ERRα and ERRγ status may be predictive of sensitivity to hormonal blockade therapy, and ERRα status may also be predictive of ErbB2-based therapy such as Herceptin. Moreover, ERRα and ERRγ are candidate targets for therapeutic development.