Exogenous testosterone exacerbates pre-neoplastic lesions in the prostate of NKX3.1-deficient mice

Abstract

Background NKX3.1 is a prostate-specific tumor suppressor that is frequently downregulated during the early stages of prostate cancer. Although NKX3.1 knockout (KO) mice develop spontaneous epithelial abnormalities, these lesions rarely progress beyond early neoplastic changes without additional oncogenic stimulus. Therefore, we investigated whether exogenous testosterone (TS) exacerbates early-stage, pre-neoplastic lesions in the prostate of NKX3.1 KO mice. Alterations in prostate weights of male reproductive organs (testis, seminal vesicles, and prostate lobes), histopathological lesion scores, apoptotic proteins, and angiogenic proteins were analyzed in C57BL/6 NKX3.1/Korl KO (NKX3.1 KO) mice injected with TS for six weeks. Results The weight of testis, seminal vesicles and ventral prostate was commonly changed in TS-treated mice of wild type (WT) and NKX3.1 KO group, while those of the dorsolateral and anterior prostate were only increased in TS-treated NKX3.1 KO group compared to those of WT. Histopathological lesion severity was greater in TS-treated NKX3.1 KO mice, with the highest lesion scores observed in the high-dose TS (HiTS)-treated KO group, and a similar pattern was observed for p53 staining. The expression levels of apoptotic and angiogenic proteins were significantly increased in TS-treated NKX3.1 KO mice compared to the same group of WT mice. Conclusions These findings suggest that the exogenous TS exacerbates early-stage, pre-neoplastic lesions in the prostate of NKX3.1 KO mice, consistent with a gene–hormone synergistic interaction. The mechanistic basis of this synergy remains to be defined. Supplementary information The online version contains supplementary material available at 10.1186/s42826-026-00284-8. Abs1