Tremendous race disparities exist in prostate cancer incidence and mortality. Reasons for these disparities remain unknown but are likely due to both environmental and biological factors. In vitro studies suggest that the heavy metal cadmium is an endocrine disruptor of the androgen receptor. The androgen receptor is essential for normal prostate growth and development but is also the primary drug target for treatment of prostate cancer as it controls a plethora of downstream targets involved in disease progression. Previous studies indicate that compared to European-Americans, African-Americans have had higher urinary and blood cadmium levels and, have higher androgen receptor protein levels and different patterns of AR-target expression in prostate tissue. Our preliminary data (N=59) suggests that African-Americans may have higher prostate tissue cadmium levels than European-Americans. Our data also suggests that cadmium is associated with androgen receptor protein expression in prostate tumor tissue but that race modifies the association. Therefore, race differences in the association between cadmium and the androgen receptor could lead to differences in expression/signaling of downstream androgen receptor targets involved in tumor aggressiveness and disease recurrence. In this R21 study, we propose to further investigate cadmium as an endocrine disruptor of the androgen receptor by capitalizing on a well-defined, ethnically diverse cohort of prostatectomy cases (N=415, 44% AA, diagnosed 1999-2004) that originally participated in the Gene-Environment Interaction in Prostate Cancer (GECAP) (R01 ES11126) study. In prostate tumor and adjacent non-tumor tissue, we will measure cadmium as well as a panel of additional toxic and essential metals that can affect cadmium toxicity. We will also measure the whole-genome transcriptome in tumor tissue. The transcriptome includes all coding and non-coding RNAs transcriptionally expressed by genes in a population of cells. We will determine whether prostate tumor tissue cadmium level is associated with androgen receptor protein expression in the larger cohort and will determine if race does indeed modify the association between cadmium and androgen receptor expression. Further, we'll determine whether prostate tumor tissue cadmium level is associated with prostate cancer aggressiveness or biochemical recurrence. In addition, we will examine the combined association of cadmium level and androgen receptor protein expression with regard to the prostate tumor transcriptome in African - and European- Americans. From our preliminary data and other existing reports, we hypothesize that race differences in the association of cadmium and the androgen receptor result in differences in expression of downstream androgen receptor targets that play a role in disease progression, and further, that these differences may in part explain race disparities in prostate cancer progression. If our hypothesis is confirmed, the GECAP data set contains an enormous resource of demographic, clinical and medical history, dietary, occupational and genetic information to investigate variables that may explain these findings.
Cadmium is recognized as an endocrine disruptor, a human carcinogen, and an important biological hazard in the U.S. based on its toxicity and abundance. If our hypotheses are supported, this study will provide evidence that cadmium is an endocrine disruptor in the human prostate and will identify a new avenue through which race disparities in prostate cancer progression may occur. Further, our transcriptome related findings may help identify pathways to pursue in future research that could ultimately be used to tailor prostate cancer therapy rather than using broad treatment with androgen deprivation which is accompanied by a wide spectrum of negative side-effects. Most importantly, because steroid receptors have highly conserved promoter and DNA binding domains, our findings will have relevance for other diseases in which cadmium and endocrine disruption have been implicated, and in which race differences exist including breast cancer, neuroendocrinology, cardiovascular disease, thyroid disease, and metabolism and obesity.
|Neslund-Dudas, Christine M; McBride, Russell B; Kandegedara, Ashoka et al. (2018) Association between cadmium and androgen receptor protein expression differs in prostate tumors of African American and European American men. J Trace Elem Med Biol 48:233-238|