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Estrogen receptor alpha (ERα, encoded by  ESR1 ) is a well-characterized transcription factor expressed in more than 75% of breast tumors and is the key biomarker to direct endocrine therapies. On the other hand, much less is known about estrogen receptor beta (ERβ, encoded by  ESR2 ) and its importance in cancer. Previous studies had some disagreement, however most reports suggested a more favorable prognosis for patients with high  ESR2  expression. To add further clarity to  ESR2  in breast cancer, we interrogated a large population-based cohort of primary breast tumors (n = 3207) from the SCAN-B study. RNA-seq shows  ESR2  is expressed at low levels overall with a slight inverse correlation to  ESR1  expression (Spearman R = −0.18, p = 2.2e−16), and highest  ESR2  expression in the basal- and normal-like PAM50 subtypes.  ESR2 -high tumors had favorable overall survival (p = 0.006), particularly in subgroups receiving endocrine therapy (p = 0.03) and in triple-negative breast cancer (p = 0.01). These results were generally robust in multivariable analyses accounting for patient age, tumor size, node status, and grade. Gene modules consistent with immune response were associated to  ESR2 -high tumors. Taken together, our results indicate that  ESR2  is generally expressed at low levels in breast cancer but associated with improved overall survival and may be related to immune response modulation.

Clinical associations of ESR2 (estrogen receptor beta) expression across thousands of primary breast tumors