Continuous AhR Activity Accelerates Prostate Cancer Progression in African American Men
Abstract
Objective/Rationale: African American (AA) men are 60% more likely than white men to be diagnosed with prostate cancer during their lifetimes and are more than twice as likely to die from the disease. Black men are also diagnosed at a younger age and present with higher-grade tumors at the time of diagnosis. Recent studies demonstrate that AA men with clinically localized, non-metastatic prostate cancer do not respond as favorably to long-term androgen deprivation therapy (ADT) as Caucasian-American (CA) males. The elevated prostate-specific antigen (PSA) levels seen in non-responsive patients are a direct result of sustained androgen receptor signaling despite ADT. AA men would benefit greatly from more potent anti-androgenic therapies in combination with radiation. The molecular mechanisms responsible for sustained androgen receptor signaling in castration-resistant prostate cancer (CRPC) are not clearly understood. Additional studies are needed to identify all modulators of androgen receptor signaling to develop targeted therapeutic strategies. The studies outlined in this proposal provide novel insight into androgen-independent signaling and will establish the aryl hydrocarbon receptor (AhR) as a key modulator of androgen receptor signaling. AhR is a cellular protein that is well studied for mediating the carcinogenic responses to environmental toxins. Currently accepted understanding states that AhR requires direct interaction with environmental toxins to elicit its effects. However, evidence is emerging that AhR may promote cancer progression in the absence of environmental toxins. We have previously reported that AhR is overexpressed and constitutively active in prostate cancer cells that do not respond to anti-androgens. Reducing AhR activity in these cells decreases androgen receptor levels and reduces expression of PSA. AhR reduction also resulted in these cells growing slower and regaining a significant response to anti-androgens. What types of patients will this help? Identification of this unidentified mechanism of androgen receptor activation will help all men who are diagnosed with CRPC. Since AA men are more often diagnosed with these higher-grade tumors, these studies will directly address the health disparities associated with prostate cancer. The broad objective of these studies is to compare the level and effect of AhR activity in AA and Caucasian-American prostate cancer cells and tissues. We hypothesize that constitutive AhR signaling is responsible for the sustained androgen receptor signaling seen in CRPC and that AA men have elevated AhR activity compared to CA men. Our preliminary studies already show that AA prostate cancer cells have a higher baseline amount of AhR than non-responsive CA prostate cancer cells, suggesting that the AA cells may have higher AhR activity. Interim Outcomes: The studies will identify a novel therapeutic target to control androgen receptor signaling that is not achieved by current therapies. Previous studies have not considered the existence of constitutive AhR signaling in prostate cancer or its ability to promote prostate cancer progression. Short term, this study will increase our understanding of the role AhR serves in cancer biology and the impact it has on prostate cancer progression. We are proposing that AA men have enhanced AhR activity beyond the level seen in CA men. Based on our previously published work, we know that enhanced AhR activity maintains androgen receptor signaling and decreases the response to anti-androgens. Additionally, by confirming AhR expression in patient tissue samples, these studies will validate AhR as a prognostic biomarker and therapeutic target. Long term, this work could provide a launching pad to investigate if the higher AhR activity seen in AA men is related to particular environmental factors, such as diet, since many of the ligands for AhR can be found in fried and grilled foods. It can also l
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710274
Entities
People
- Joann Powell
Organizations
- Clark Atlanta University
- United States Army