DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Uncovering the molecular mechanisms of prostate cancer in African Americans

Posted September 26, 2017

Michael Ittmann, M.D., Ph.D., Baylor College of Medicine, Arun Sreekumar, Ph.D., Baylor College of Medicine, Franklin Huang, M.D., Ph.D., Dana Farber Cancer Institute

Franklin Huang
Dr. Franklin Huang
Dana Farber Cancer Institute

Ittmann Group Picture
Photo left to right: Arun Sreekumar, Nagireddy Putluri, Patricia Castro, Jianghua Wang, Michael Ittmann and Chad Creighton

African American (AA) men have significantly higher incidence and mortality from prostate cancer (PCa) than European American (EA) men. While some of this disparity can be attributed to socioeconomic factors, mortality from PCa is still higher in AA men after these factors are accounted for, indicating that there is also a biological component contributing to the disparity. While a substantial amount of investigation into the genetic and biological causes of PCa has already been done and is still underway, race differences are typically unaccounted for since AA men are typically under-represented in the sample population. Thus, the biology contributing to a more aggressive clinical phenotype of PCa in AA men remains poorly understood.

To help elucidate molecular and genetic mechanisms that contribute to the PCa disparity in AA men, Drs. Michael Ittmann and Arun Sreekumar at Baylor College of Medicine measured gene expression in AA tumors and compared the data to expression profiles from EA men. With support from two separate FY11 Health Disparity Research Awards, they found that the MNX1 gene was upregulated in only the AA PCa tissue samples and not in the EA or normal prostate samples. This gene had been previously shown to be important in pancreas development and in the tumorigenesis of acute myeloid leukemia, but this was the first study to show it may play an important role in PCa. Additional studies are underway to assess the potential of MNX1 as a biomarker for aggressive disease in AA men.

At Dana Farber Cancer Institute, Dr. Franklin Huang also sought to determine tumor genetic factors that may be influencing PCa health disparity. With support from a FY13 Physician Research Training Award, Dr. Huang performed exome sequencing and targeted validation of localized primary PCa in AA men utilizing samples from Weill Cornell Medical Center, Karmanos Cancer Institute, Roswell Park Cancer Institute, and the PCRP-funded Prostate Cancer Biorepository Network. Through this work, he revealed several novel gene mutations in the AA population, including loss-of-function mutations in the ERF gene. Further in vitro studies on the function of ERF showed for the first time that this gene may act as a tumor suppressor gene in AA PCa, and may be associated with more aggressive forms of PCa in this population.

Taken together, these findings demonstrate that there are molecular mechanisms that may be unique to AA PCa that were previously unknown. Additionally, they highlight the importance of inclusion of samples and patients from different ancestral, racial, and ethnic backgrounds in genetic and biological studies of PCa. The investigators hope these discoveries will result in new biomarkers or drug targets for AA PCa, and ultimately lead to new treatments for this high risk population.


Huang Figure
ERF can act as a tumor suppressor gene in prostate cancer cells. Anchorage-independent growth assays of ERF knockdown in PC-3 prostate cancer cell lines were performed in triplicate. Colonies were quantified with CellProfiler, * p<.05, student’s T test. Data shown is representative of two independent experiments. Western blot results are depicted for knockdown of ERF with two short hairpins and control hairpin.

Ittmann Figure
Expression of MNX1 in prostate cancer. MNX1 mRNA levels in EA and AA prostate cancer and benign tissues by qRT-PCR. Asterisks indicate statistically significant differences between cancer and benign tissues.

Publications:

Huang FW, Mosquera JM, Garofalo A, et al. 2017. Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations. Cancer Discov. pii: CD-16-0960

Zhang L, Wang J, Zhang Y, et al. 2016. MNX1 is an androgen regulated oncogene that is upregulated in African-American prostate cancer. Cancer Res 76(21):6290-6298.

Kaushik AK, Shojaie A, Panzitt K, et al. 2016. Inhibition of hexosamine biosynthetic pathway promotes castration-resistant prostate cancer. Nature Comm 7:11612.

Stossi F, Dandekar RD, Bolt MJ, et al. 2016. High throughput microscopy identifies Bisphenol AP, a Bisphenol A Analog, as a novel AR down-regulator. Oncotarget 7(13):16962-16974.

Kaushik AK, Vareed SK, Basu S, et al. 2014. Metabolomic profiling identifies biochemical pathways associated with castration-resistant prostate cancer. J Proteome Res 13(2):1088-1100.

Khan AP, Rajendiran TM, Ateeq B, et al. 2013. The role of sarcosine metabolism in prostate cancer progression. Neoplasia 15(5):491-501.


Links:

Unique Genomic Alteration in Prostate Cancers in African American Men

Metabolomic Profiling to Distinguish Racially Distinct Prognostic Markers in Prostate Cancer

Investigating the Mechanisms of African-American Prostate Cancer

The Prostate Cancer Biorepository Network (PCBN)


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Last updated Tuesday, September 26, 2017