PUBLICATION
BMI1 Drives Metastasis of Prostate Cancer in Caucasian and African-American Men and Is A Potential Therapeutic Target: Hypothesis Tested in Race-specific Models.
- Authors
- Ganaie, A., Beigh, F.H., Astone, M., Ferrari, M.G., Maqbool, R., Umbreen, S., Parray, A.S., Siddique, H.R., Hussain, T., Murugan, P., Morrissey, C., Koochekpour, S., Deng, Y., Konety, B.R., Hoeppner, L.H., Saleem, M.
- ID
- ZDB-PUB-180809-2
- Date
- 2018
- Source
- Clinical cancer research : an official journal of the American Association for Cancer Research 24(24): 6421-6432 (Journal)
- Registered Authors
- Hoeppner, Luke
- Keywords
- none
- MeSH Terms
-
- Animals
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Biomarkers, Tumor*
- Black or African American*
- Cell Line, Tumor
- Disease Models, Animal
- Docetaxel/pharmacology
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Humans
- Male
- Mice
- Molecular Targeted Therapy
- Neoplasm Metastasis
- Neoplasm Staging
- Polycomb Repressive Complex 1/antagonists & inhibitors
- Polycomb Repressive Complex 1/genetics*
- Polycomb Repressive Complex 1/metabolism
- Prostatic Neoplasms/drug therapy
- Prostatic Neoplasms/genetics*
- Prostatic Neoplasms/metabolism
- Prostatic Neoplasms/pathology
- White People
- Zebrafish
- PubMed
- 30087142 Full text @ Clin. Cancer Res.
Citation
Ganaie, A., Beigh, F.H., Astone, M., Ferrari, M.G., Maqbool, R., Umbreen, S., Parray, A.S., Siddique, H.R., Hussain, T., Murugan, P., Morrissey, C., Koochekpour, S., Deng, Y., Konety, B.R., Hoeppner, L.H., Saleem, M. (2018) BMI1 Drives Metastasis of Prostate Cancer in Caucasian and African-American Men and Is A Potential Therapeutic Target: Hypothesis Tested in Race-specific Models.. Clinical cancer research : an official journal of the American Association for Cancer Research. 24(24):6421-6432.
Abstract
Purpose: Metastasis is the major cause of mortality in prostate cancer 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 prostate cancer disease in Caucasian and African-Americans.Experimental Design: We employed race-specific prostate cancer models, clinical specimens, clinical data mining, gene-microarray, transcription-reporter assay, chromatin-immunoprecipitation (ChIP), IHC, 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 prostate cancer 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.Conclusions: BMI1, a major driver of metastasis, represents a promising therapeutic target for treating advanced prostate cancer in patients (including those belonging to high-risk group). Clin Cancer Res; 1-12. ©2018 AACR.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping