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Estrogen-related Receptor and Estrogen-related Receptor Associate with Unfavorable and Favorable Biomarkers, Respectively, in Human Breast Cancer¹

McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53706 [E. A. A., J. E. M.], and Breast Center, Baylor College of Medicine, Houston, Texas 77030 [G. M. C.]

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 ER, ERß, epidermal growth factor receptor, ErbB2, ErbB3, ErbB4, ERR, ERRß, and ERR were determined in unselected primary breast tumors (n = 38) and normal mammary epithelial cells enriched from reduction mammoplasties (n = 9). ERR showed potential as a biomarker of unfavorable clinical outcome and, possibly, hormonal insensitivity. ERR mRNA was expressed at levels greater than or similar to ER mRNA in 24% of unselected breast tumors, and generally at higher levels than ER in the progesterone receptor (PgR)-negative tumor subgroup (1-way ANOVA with repeated measures, P = 0.030). Increased ERR 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). ERR levels also correlated with expression of ErbB2 (Spearman’s rho, P = 0.005), an indicator of aggressive tumor behavior. Thus, ERR was the most abundant nuclear receptor in a subset of tumors that tended to lack functional ER and expressed ErbB2 at high levels. Consequently, ERR may potentiate constitutive transcription of estrogen response element-containing genes independently of ER and antiestrogens in ErbB2-positive tumors. ERRß’s potential as a biomarker remains unclear; it showed a direct relationship with ERß (Spearman’s rho, P = 0.0002) and an inverse correlation with S-phase fraction (Spearman’s rho, P = 0.026). Unlike ERR, ERR showed potential as a biomarker of favorable clinical course and, possibly, hormonal sensitivity. ERR was overexpressed in 75% of the tumors, resulting in the median ERR level being elevated in breast tumors compared with normal mammary epithelial cells (Kruskal-Wallis ANOVA, P = 0.001). ERR overexpression associated with hormonally responsive ER- and PgR-positive status (Fisher’s exact, P = 0.054 and P = 0.045, respectively). Additionally, ERR 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, ERR and ERR status may be predictive of sensitivity to hormonal blockade therapy, and ERR status may also be predictive of ErbB2-based therapy such as Herceptin. Moreover, ERR and ERR are candidate targets for therapeutic development.

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