Race, CYP27A1, and Estrogen Signaling in Prostate Cancer
Abstract
Black men suffer a disproportionate burden from prostate cancer. Even in an equal access setting, such as within the Department of Veterans Affairs (VA) Health System, we found blacks were more likely to have prostate cancer, especially high-grade prostate cancer, and were more likely to have their cancer recur after surgery compared to white men. This argues strongly that there is a biological basis, at least in part, contributing to more aggressive prostate cancers in black men. However, to date, few studies have gone into depth to understand differences in the tumors between black and white men. Moreover, the few studies that have attempted this are limited by modest numbers (typically 600 samples or less or which half or less are from black men) and have not accounted for the few (but important) known differences in tumor biology between races (for example, tumors in black men are less likely to have a particular gene rearrangement common in white men’s tumors). Thus, whether the differences found to date merely represent the effects of the known differences or are truly novel findings is unclear. In a preliminary analysis of 543 prostate cancer samples from black (n=305) and white (n=238) men treated with surgery at the Durham VA, we found many differences in the genes that were active in tumors of black vs. white men. We found one of the major differences was in the activity of the estrogen response pathway, which was much more active in tumors from black men. Further, we found that one specific gene that is potentially related to estrogen, called CYP27A1, was higher in tumors in black men. CYP27A1 is responsible for converting cholesterol to another molecule, 27-hydroxycholesterol (27HC). 27HC is usually primarily responsible for controlling cholesterol levels within cells, but it can also stimulate activity of the estrogen receptors. Indeed, this gene is elevated in breast cancer samples and contributes to promoting growth of breast cancers. Consistent with the idea that 27HC may have similar functions in prostate cancer (i.e., to drive estrogen activity), we found that tumors with higher CYP27A1 levels had higher estrogen activity using data from over 1,000 prostate cancer samples. As such, this combination of high CYP27A1 expression and high estrogen activity appears to define a novel, never described before subset of prostate cancers, and this subset is more common in black men. As this is a newly defined subset, the specific genes that drive tumor growth in this subset are not known. These specific driver genes, called master regulators, are potential targets for treatment as they control many other genes within the cell. Interestingly, in the analysis of our samples from the Durham VA, the top 50 master regulators in black men were completely different from the top 50 in white men. In addition, 6 of the top 50 master regulators in black men were related to estrogen activity. This provides further evidence that, in a subset of prostate cancer, a CYP27A1-estrogen connection is active that may be driving tumor growth. We propose that further genomic analyses focused on these tumors with high CYP27A1 expression and high estrogen activity using an unprecedentedly large sample size of ~10,000 prostate cancers that have already undergone genomic analysis, along with cell lines from black and white men that can be examined in-depth, will provide unparalleled insights into racial differences. Specifically, we aim to identify unique genes that are more active in black tumors that can be targeted to reduce suffering from prostate cancer in black men. These more active pathways will give tremendous insight into the biological basis for why black men have more aggressive prostate cancer. Such fundamental and comprehensive knowledge is required to design future treatments. Further, we will test whether blocking these pathways can slow or eliminate tumor growth – both in a petri dish and in mice usi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110222
Entities
People
- Stephen J. Freedland
Organizations
- Cedars-Sinai Medical Center
- United States Army