Estrogen Receptor Expression in Human Tumors: A Tissue Microarray Study Evaluating More Than 18,000 Tumors from 149 Different Entities

Estrogen receptor (ER) is a ligand-activated transcription factor with a critical role in development and function of multiple organ systems and a well-established drug target for breast cancer. To comprehensively evaluate ER expression in normal and tumor tissues, a tissue microarray containing 18,560 samples from 149 different tumor types and subtypes and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry (IHC). ER positivity was found in 55 different tumor types including 26 entities with at least one strongly positive tumor. ER positivity strongly predominated in breast neoplasms (81.1%) and in other gynecological tumors (39.4%) while only 0.8% of non-gynecological and non-mammary tumors showed ER positivity. Among these, ER staining - often at lower intensity - especially occurred in neuroendocrine neoplasms (up to 9.1%), salivary gland tumors (up to 8.3%), and in squamous cell carcinomas of different sites of origin (up to 6.7%). In invasive breast carcinoma (NST), reduced ER immunostaining was linked to high pT (p < 0.0001), high grade (p < 0.0001), distant metastasis (p = 0.0012), HER2 positivity (p < 0.0001), PR negativity (p < 0.0001) and shorter overall survival (p = 0.0576). In serous high-grade ovarian cancer, reduced ER staining was linked to nodal metastasis (p = 0.0012). ER staining was unrelated to histopathological features in 145 analyzable endometroid endometrial carcinomas. Within non-mammary, non-gynecological, non-prostate, and non-testicular tumors, ER positivity was more common in tumors from female (1.4% of 2528) than from male patients (0.6% of 3228; p = 0.0003). In summary, our data provide a ranking list of tumor entities according to their prevalence of ER positivity and shows that ER can be strongly expressed in a small number of non-breast and non-gynecological tumors which could potentially represent a diagnostic pitfall in a cancer of unknown primary but also represents a therapeutic opportunity.