BMI1 drives metastasis of prostate cancer in Caucasian and African-American men and is a potential therapeutic target: hypothesis tested in race-specific models

Purpose: Metastasis is the major cause of mortality in prostate cancer (CaP) patients. Factors such as genetic makeup and race play critical role in the outcome of therapies. This study was conducted to investigate the relevance of BMI1 in metastatic CaP disease in Caucasian and African-Americans. Experimental Design: We employed race-specific CaP models, clinical specimens, clinical data mining, gene-microarray, transcription-reporter assay, chromatin-immunoprecipitation (ChIP), immunohistochemistry, transgenic-(tgfl/fl) zebrafish and mouse metastasis models. Results: BMI1 expression was observed to be elevated in metastatic tumors (lymph nodes, lungs, bones, liver) of Caucasian and African-American CaP patients. The comparative analysis of stage III/IV tumors showed an increased BMI1 expression in African-Americans than Caucasians. TCGA and NIH/GEO clinical data corroborated to our findings. We show that BMI1 expression (i) positively correlates to metastatic (MYC, VEGF, cyclin D1) and (ii) negative correlates to tumor suppressor (INKF4A/p16, PTEN) levels in tumors. The correlation was prominent in African-American tumors. We show that BMI1 regulates the transcriptional activation of MYC, VEGF, INKF4A/p16, and PTEN. We show the effect of pharmacological inhibition of BMI1 on the metastatic genome and invasiveness of tumor cells. Next, we show the anti-metastatic efficacy of BMI1-inhibitor in transgenic zebrafish and mouse metastasis models. Docetaxel as monotherapy has poor outcome on the growth of metastatic tumors. BMI1 inhibitor as an adjuvant improved the taxane therapy in race-based in vitro and in vivo models. Conclusion: BMI1, a major driver of metastasis, represents a promising therapeutic target for treating advanced CaP in patients (including those belonging to high-risk group).

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