Comparative Digital Estrogen Receptor Alpha (ERα) Expression Analysis in Benign and Malignant Prostate Tissue of Men...

The dog is the only large mammal, other than humans, that commonly develops spontaneous prostate cancer (PCa) and is, therefore, considered a valuable model for comparative studies. Estrogens are critical for normal prostate development and contribute to prostatic carcinogenesis in men. The number of transgender women undergoing male to female transition involving exogenous estrogen treatment and surgical or chemical castration has increased markedly in recent years. Few studies have evaluated estrogen receptor α (ERα) expression in benign and malignant canine prostatic tissue, and comparative data between dogs and men are currently lacking. This study analyzed and compared the spatial distribution and level of ERα expression in the benign and malignant prostatic tissue of men and dogs using immunohistochemistry (IHC) and assessed the suitability of dogs as a model to further understand the role of ERα in human PCa.

Formalin-fixed paraffin-embedded (FFPE) human (n = 146) and canine (n = 61) prostatic tissue specimens were analyzed immunohistochemically for ERα expression using a monoclonal anti-human ERα antibody, previously validated for cross-reactivity with canine tissue. Nuclear staining was digitally quantified with Visiopharm software. Tissue segmentation allowed separate analyses of ERα expression patterns in both epithelial and stromal compartments.

ERα expression was present in the stroma of both non-malignant and neoplastic prostatic tissue in men and dogs. Both non-malignant and malignant human glandular epithelium was consistently negative for ERα. In contrast, benign glandular epithelium in sexually intact dogs expressed ERα, showing weak but consistent immunolabeling. Malignant transformation in canine glands was associated with a reduction of ERα expression compared with benign tissue. Similarly, non-secretory glands in premature and atrophic (both castration-induced and age-related) canine prostates exhibited very low levels of ERα expression. Higher stromal ERα expression was observed in premature canine prostatic tissue when compared with mature, confirming the relevance of ERα in prostate development.

Malignant glandular epithelium lacked ERα expression in both dogs and men, with a notable shift from epithelial to stromal ERα expression in dogs during neoplastic transformation. Unlike in men, benign canine glands show diffuse ERα expression, whereas premature and atrophic glands display very low ERα levels. The observed differences in ERα expression across prostate tissue types in the dog -premature, normal, atrophic, and tumor-warrant further investigation to provide a clearer understanding of the role of ERα in PCa progression, particularly in castration-resistant cases. Such insights gained from the canine disease model may also help guide screening and management strategies for the growing population of young transgender women undergoing estrogen therapy and orchiectomy.