www.companyofscientists.com/index.php/chd e1 Cancer Health Disparities  RESEARCH Androgen metabolism genes in prostate cancer health disparities Wei Liu1,2, Runhua Liu2,3, Lizhong Wang2,3* 1Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun 130041, PR China 2Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294 3Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294 *Corresponding author e-mail: lwang12@uab.edu ABSTRACT For men in the United States, prostate cancer is common, and newly diagnosed cases of prostate cancer outnumber those of all other cancer types. For prostate cancer, there are racial disparities between Caucasian Americans and African Americans. Androgens and androgen metabolism may be involved in these disparities as well as in the initiation and progression of prostate cancer. Here, we analyzed, in the Cancer Genome Atlas (TCGA) database, the mRNA expression of genes involved in androgen metabolism in prostate cancer based on the patient’s race. The results revealed that expressions of UGT2B15 and CYP3A5 are higher but that SRD5A2, CYP17A1, HSD3B2, and AKR1C3 are lower in African American prostate cancers than in those of Caucasian Americans. These genes may relate to the racial disparities associated with prostate cancer. However, the evidence require validation and functional analysis. KEYWORDS: prostate cancer; racial disparity; androgen; metabolism; gene expression Citation: Liu W. Liu R, Wang L (2017). Androgen metabolism genes in prostate cancer health disparities Cancer Health Disparities;1:e1-e6. doi:10.9777/rr.2017.10003           www.companyofscientists.com/index.php/chd e2 Cancer Health Disparities  RESEARCH INTRODUCTION According to the latest statistics provided by the American Cancer Society (ACS), there are 161,360 incident cases newly diagnosed with prostate cancer, accounting for 19% of all new cancer cases in 2017 and, for males, leading all other cancers (Siegel et al., 2017). The incidence varies with race. The rate for African American (AA) men is 198.4/100,000, higher than 114.8/100,000 for Caucasian American (CA) men. Although the racial disparities in prostate cancer are related to lifestyle, dietary, socioeconomic, and clinical factors, genetic factors are also substantial (Chang et al., 2014; Cooper and Page, 2014; Plata Bello and Concepcion Masip, 2014; Schaid, 2004; Singh et al., 2017). For most prostate cancers, which are generally androgen-sensitive, androgen withdrawal can produce initial regressions (Cooper and Page, 2014). Lower levels of intraprostatic androgens are associated with a lower incidence of prostate cancer (Cooper and Page, 2014). Androgen deprivation therapy, a common treatment, can block progression of metastatic prostate cancer (Welsh and Hentz, 2017; Yang et al., 2017; Young et al., 2017). Further, differences in androgen metabolism may relate to the racial disparities in this disease (Singh et al., 2017). Thus, for prostate cancer, androgen metabolism may be involved in racial disparities as well as in tumor imitation and progression. For CA and AA men in the United States, there are differences in androgen levels. Serum testosterone levels of AA men (aged 31 to 50) are about 15% higher than those of CA men (Ellis and Nyborg, 1992; Singh et al., 2017). In prostate tissues of AA men, androgens, androstenedione, and sex hormone-binding globulin levels are greater than those in tissues of CA men (Singh et al., 2017). Likewise, for AA men, expression of the androgen receptor (AR) protein is 22% higher in benign prostate tissue and 81% higher in prostate cancer tissue relative to CA men (Gaston et al., 2003). These differences may contribute to racial disparities for prostate cancer. Other factors, such as age, body mass index, prostate specific antigen, and pathologic Gleason grade, may be involved in these disparities (Plata Bello and Concepcion Masip, 2014; Schaid, 2004). However, whether genes involved in androgen metabolism are primary factors for these racial disparities is not known. Therefore, with the Cancer Genome Atlas (TCGA) database, we conducted an expression analysis of genes involved in androgen metabolism in prostate cancer based on the patient’s race. From the findings, we have presented a potential mechanism underlying androgen metabolism in racial disparities for prostate cancer. RESULTS AND DISCUSSION We analyzed the mRNA expression of 20 genes involved in androgen metabolism, including AKR1C2, AKR1C3, CYP3A4, CYP3A5, CYP7B1, CYP11A1, CYP17A1, CYP19A1, HSD3B1, HSD3B2, HSD17B3, HSD17B6, HSD17B10, RDH5, RDH16, SRD5A1, SRD5A2, SRD5A3, UGT2B7, and UGT2B15, by use of a web-portal UALCAN tool (Chandrashekar et al., 2017) for analyses of TCGA gene expression data in 52 normal prostate tissues, 147 CA prostate cancer tissues, and 6 AA prostate cancer tissues. For AA tissues, there were significantly higher expressions of 5 genes, including HSD3B2 (cancer/normal fold change = 1.11; p = 4.31x10-2), HSD17B3 (fold change = 3.22; p = 1.11x10-16), HSD17B10 (fold change = 1.27; p = 1.79x10-12), SRD5A1 (fold change = 1.27; p = 4.02x10-5), and SRD5A3 (fold change = 1.14; p = 2.58x10-3), but significantly lower expressions of 9 genes, including AKR1C2 (fold change = 0.32; p = 9.42x10-3), CYP3A5 (fold change = 0.14; p = 1.32x10-3), CYP11A1 (fold change = 0.21; p = 3.85x10-8), CYP19A1 (fold change = 0.27; p = 4.32x10-2), CYP7B1 (fold change = 0.52; p = 2.20x10-4), HSD17B6 (fold change = 0.59; p = 6.56x10-4), RDH5 (fold change = 0.50; p = 5.76x10- 5), SRD5A2 (fold change = 0.23; p = 5.73x10-10), and UGT2B7 (fold change = 0.00; p = 1.83x10-2). Of note, expressions of AKR1C3, CYP3A5, CYP17A1,           www.companyofscientists.com/index.php/chd e3 Cancer Health Disparities  RESEARCH HSD3B2, SRD5A2, and UGT2B15 showed significant differences in prostate cancer tissues between CA men and AA men (Figure 1). Expressions of CYP3A5 (fold change = 1.38; p = 4.32x10-2) and UGT2B15 (fold change = 1.87; p = 4.32x10-2) in AA prostate cancers were higher than those for CA prostate cancers, but expressions of AKR1C3 (fold change = 0.58; p = 4.32x10-2), CYP17A1 (fold change = 0.50; p = 4.32x10-2), HSD3B2 (fold change = 0.77; p = 4.32x10-2), and SRD5A2 (fold change = 0.71; p = 4.32x10-2) were lower in AA prostate cancers than in CA prostate cancers (Figure 1). Figure 1. mRNA expression of genes involved in androgen metabolism in normal prostate tissues and prostate cancers based on the race of patients as determined with the TCGA database. CA, Caucasian American; AA, African American. AKR1C3 is associated with a reduction of androstenedione and lower (Mostaghel and Nelson, 2008) production of testosterone and dihydrotestosterone (DHT) (Yepuru et al., 2013). Higher expression of AKR1C3 enhances survival of prostate cancer cells and formation of endothelial cell tubes, and is positively correlated with a higher Gleason score (Dozmorov et al., 2010). However, there were lower expressions of AKR1C3 in AA prostate cancers than in CA prostate cancers, which suggests a contradictory function of AKR1C3 in racial disparities between AA and CA men. CYP3A5, which is involved in hydroxylation of testosterone and dehydroepiandrosterone (Zeigler-Johnson et al., 2013), enhances growth of prostate cancer cells through facilitating the nuclear translocation of AR (Mitra and Goodman, 2015). The higher expression CYP3A5 in AA men may be associated with higher AR levels and a higher risk of prostate cancer (Singh et al., 2017). As shown here, there were higher expression levels           www.companyofscientists.com/index.php/chd e4 Cancer Health Disparities  RESEARCH of CYP3A5 in AA prostate cancers compared with CA prostate cancers, supporting the previous observation and hypothesis. In the gonads and adrenals, CYP17A1 is involved in various pathways of androgen biosynthesis (Bremmer et al., 2014). Although greater expression of CYP17A1 appears to correlate with higher stages and shorter relapse-free times in prostate cancer (Bremmer et al., 2014; Gomez et al., 2015; Salvi et al., 2016), expression of the CYP17A1 gene was lower in primary prostate cancers than in normal prostate tissue and was lower in AA prostate cancers than in CA prostate cancers. Although, for AA men, a dysfunction of CYP17A1 may affect the susceptibility to prostate cancer, the present data do not support the concept that CYP17A1 is a regulator for racial disparities between AA men and CA men. HSD3B2 is involved in catalyzing androstendione and DHT metabolites (Simard et al., 1996). Higher expression of HSD3B2 accelerates the degradation of DHT metabolites and leads to lower DHT levels (Simard et al., 1996). However, the relationship between high DHT levels and prostate cancer risk is controversial. For CA men and AA men, there are no significant differences in DHT levels in sera and tissues (Singh et al., 2017). The present data also showed higher expression of HSD3B2 in AA prostate cancers compared with CA prostate cancers, results that are inconsistent with racial disparities between AA and CA men. SRD5A2 is responsible for the conversion of testosterone into DHT (Fang et al., 2017). Genetic analyses suggest that there are SRD5A2 TA repeat alleles in AA men at high risk for prostate cancer but not in CA men (Singh et al., 2017), indicating that genetic variants of SRD5A2 may be associated with racial disparities. Variants of the enzyme may enhance the activity and result in higher levels of DHT, leading to cancer progression. However, higher expression of SRD5A2 appears to be inconsistent with higher levels of DHT (Singh et al., 2017). The present data showed that expression of SRD5A2 was lower in AA prostate cancers compared with those of CAs, which does not support a role of SRD5A2 in the racial disparities between AA men and CA men. In the androgen biosynthesis pathway, UGT2B15 is a regulator for androstenedione glucuronidate (Gauthier-Landry et al., 2015). High androstenedione levels may require more glucuronosyltransferases encoded by UGT2B15 (Singh et al., 2017). Of note, there are higher androstenedione levels in normal prostate tissues and greater expression of UGT2B15 in AA prostate cancers than in those of CAs (Singh et al., 2017). As shown here, there was higher expression of UGT2B15 in AA prostate cancers compared with CA prostate cancers, supporting a function of UGT2B15 in racial disparities of prostate cancers. Since prostate cancer is a pathophysiologic disease involving a variety of genetic factors (Chang et al., 2014; Cooper and Page, 2014), the change of a single gene may be insufficient to produce racial disparities. Further, the functions of genes in racial disparities in prostate cancer are associated with mRNA and protein expression. Moreover, the AA cohort of prostate cancers in this TCGA database includes only six cases, which limits the statistical power to detect significant differences in our analysis. Therefore, a larger sample cohort is needed to establish the relationship between the genes and racial disparities in prostate cancer. In summary, in the United States, the incidences of prostate cancer are different for CA and AA men. Genes, such as CYP3A5 and UGT2B15, which are involved in androgen metabolism, appear to be associated with racial disparities between AA and CA prostate cancers. Due to a limitation of sample size, however, the results need to be validated in further studies. Acknowledgements We thank Dr. Donald L. Hill for editorial assistance in preparing this manuscript. This work was supported by the National Institutes of Health/National Cancer Institute (CA179282 and           www.companyofscientists.com/index.php/chd e5 Cancer Health Disparities  RESEARCH CA118948) and the Department of Defense (PC130594 and PC140308). Conflict of interest statement The author has declared that no competing or conflict of interests exist. The funders had no role in study design, writing of the manuscript and decision to publish. Authors’ contributions WL performed the analyses. RL and LW wrote the manuscript. References Bremmer, F., Jarry, H., Strauss, A., Behnes, C.L., Trojan, L., and Thelen, P. (2014). Increased expression of CYP17A1 indicates an effective targeting of the androgen receptor axis in castration resistant prostate cancer (CRPC). Springerplus 3, 574. Chandrashekar, D.S., Bashel, B., Balasubramanya, S.A.H., Creighton, C.J., Ponce-Rodriguez, I., Chakravarthi, B., and Varambally, S. (2017). UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses. Neoplasia 19, 649-658. Chang, K.H., Ercole, C.E., and Sharifi, N. (2014). Androgen metabolism in prostate cancer: from molecular mechanisms to clinical consequences. Br J Cancer 111, 1249-1254. Cooper, L.A., and Page, S.T. (2014). Androgens and prostate disease. Asian J Androl 16, 248- 255. Dozmorov, M.G., Azzarello, J.T., Wren, J.D., Fung, K.M., Yang, Q., Davis, J.S., Hurst, R.E., Culkin, D.J., Penning, T.M., and Lin, H.K. (2010). Elevated AKR1C3 expression promotes prostate cancer cell survival and prostate cell- mediated endothelial cell tube formation: implications for prostate cancer progression. BMC Cancer 10, 672. Ellis, L., and Nyborg, H. (1992). Racial/ethnic variations in male testosterone levels: a probable contributor to group differences in health. Steroids 57, 72-75. Fang, C., Guo, Z.Q., Chen, X.Y., Liu, T.Z., Zeng, X.T., and Wang, X.H. (2017). Relationship between SRD5A2 rs9282858 polymorphism and the susceptibility of prostate cancer: A meta-analysis based on 20 publications. Medicine (Baltimore) 96, e6791. Gaston, K.E., Kim, D., Singh, S., Ford, O.H., 3rd, and Mohler, J.L. (2003). Racial differences in androgen receptor protein expression in men with clinically localized prostate cancer. J Urol 170, 990-993. Gauthier-Landry, L., Belanger, A., and Barbier, O. (2015). Multiple roles for UDP- glucuronosyltransferase (UGT)2B15 and UGT2B17 enzymes in androgen metabolism and prostate cancer evolution. J Steroid Biochem Mol Biol 145, 187-192. Gomez, L., Kovac, J.R., and Lamb, D.J. (2015). CYP17A1 inhibitors in castration-resistant prostate cancer. Steroids 95, 80-87. Mitra, R., and Goodman, O.B., Jr. (2015). CYP3A5 regulates prostate cancer cell growth by facilitating nuclear translocation of AR. Prostate 75, 527-538. Mostaghel, E.A., and Nelson, P.S. (2008). Intracrine androgen metabolism in prostate cancer progression: mechanisms of castration resistance and therapeutic implications. Best Pract Res Clin Endocrinol Metab 22, 243-258. Plata Bello, A., and Concepcion Masip, T. (2014). Prostate cancer epidemiology. Arch Esp Urol 67, 373-382. Salvi, S., Casadio, V., Burgio, S.L., Conteduca, V., Rossi, L., Menna, C., Carretta, E., Costantini, M., Zoli, W., and De Giorgi, U. (2016). CYP17A1 polymorphisms and clinical outcome of castration-resistant prostate cancer patients treated with abiraterone. Int J Biol Markers 31, e264-269. Schaid, D.J. (2004). The complex genetic epidemiology of prostate cancer. Hum Mol Genet 13 Spec No 1, R103-121. Siegel, R.L., Miller, K.D., and Jemal, A. (2017). Cancer Statistics, 2017. CA Cancer J Clin 67, 7- 30.           www.companyofscientists.com/index.php/chd e6 Cancer Health Disparities  RESEARCH Simard, J., Durocher, F., Mebarki, F., Turgeon, C., Sanchez, R., Labrie, Y., Couet, J., Trudel, C., Rheaume, E., Morel, Y., et al. (1996). Molecular biology and genetics of the 3 beta- hydroxysteroid dehydrogenase/delta5-delta4 isomerase gene family. J Endocrinol 150 Suppl, S189-207. Singh, S.K., Lillard, J.W., Jr., and Singh, R. (2017). Molecular basis for prostate cancer racial disparities. Front Biosci (Landmark Ed) 22, 428- 450. Welsh, J.S., and Hentz, C. (2017). Androgen Deprivation Therapy and Subsequent Dementia. JAMA Oncol 3, 1000-1001. Yang, D.D., Muralidhar, V., Mahal, B.A., Nezolosky, M.D., Labe, S.A., Vastola, M.E., Boldbaatar, N., King, M.T., Martin, N.E., Orio, P.F., 3rd, et al. (2017). Low rates of androgen deprivation therapy use with salvage radiation therapy in patients with prostate cancer after radical prostatectomy. Urol Oncol 35, 542 e525-542 e532. Yepuru, M., Wu, Z., Kulkarni, A., Yin, F., Barrett, C.M., Kim, J., Steiner, M.S., Miller, D.D., Dalton, J.T., and Narayanan, R. (2013). Steroidogenic enzyme AKR1C3 is a novel androgen receptor- selective coactivator that promotes prostate cancer growth. Clin Cancer Res 19, 5613-5625. Young, J.W.S., Sutradhar, R., Rangrej, J., Marras, C., Fleshner, N., and Alibhai, S.M.H. (2017). Androgen deprivation therapy and the risk of parkinsonism in men with prostate cancer. World J Urol 35, 1417-1423. Zeigler-Johnson, C., Morales, K.H., Spangler, E., Chang, B.L., and Rebbeck, T.R. (2013). Relationship of early-onset baldness to prostate cancer in African-American men. Cancer Epidemiol Biomarkers Prev 22, 589- 596.