NKX3.1 Expression in Male Breast Carcinoma: The Phantom Menace

Background. Male breast carcinoma is a rare, hormonally driven neoplasm constituting 0.1% of all malignancies. Molecular studies have identified 1000 genes differentially expressed between male breast carcinoma and female breast cancer with an up-regulation of androgen receptor (AR) related genes and X chromosome gain in male breast cancer. NKX3.1, an androgen-regulated homeobox gene, also has a stem cell signature. In prostate carcinoma, NKX3.1 expression correlates with AR. Although male breast cancer has greater AR expression, the expression profile of NKX3.1, as well as its correlation with AR, remains to be elucidated. Methods. This was a retrospective study conducted in a North Indian tertiary-care oncology institute. A clinicopathological review of registered male breast carcinoma patients from January 2020 to December 2024 was conducted. AR and NKX3.1 immunohistochemistry were attempted. Results. There were 57 patients of male breast cancer constituting 1.2% (57/4600) of all the breast carcinoma patients. The median age of diagnosis was 61 years. AR expression was observed in 83% of tumors (n = 44/53). NKX3.1 expression was observed in 23% of tumors (n = 12/53), which were predominantly grade 3 (n = 10/12, 83%), luminal B tumors. All NKX3.1 positive tumors expressed AR suggesting biological association. AR-expressing tumors had a longer duration of symptoms (P = .044) and had a significant association with the molecular subtype. Conclusion. NKX3.1 expression in male breast cancer is intriguing and needs to be explored in terms of tumor stemness. To the best of our knowledge, this is the first study evaluating AR and NKX3.1 expression in a single cohort of male breast carcinoma.