Glucocorticoid Receptor Beta as a Contributor to Prostate Cancer Growth and Migration

Abstract

Adenocarcinoma of the prostate is commonly diagnosed in the United States. Prostate cancer (PC) is second only to lung cancer as a leading cause of male cancer deaths (CDC & NCI). African‐Americans (AA) are nearly 1.6 times more likely to be diagnosed with PC than Caucasian‐American (CA) men and 2.4 times more likely to die from the disease. There are known growth‐inhibitory roles of glucocorticoid (GC) hormones in PC. However, eventually, the PC growth and the disease “escapes” become refractory to hormone therapy. Glucocorticoid receptor (GR) consists of two isoforms, GRα, which has been the most studied, and another isoform, GRβ, is less understood. The role of GRβ or GRα in the spectrum of the disease of prostate adenocarcinoma is unknown. Previously, our lab discovered the GRβ gene in mice and found that GRβ has a role in enhancing the growth of cancer cells via the PTEN/Akt1 pathway. In our studies, we found high levels of GRβ in adenocarcinomas from prostate cancer specimens and no change in the GRα level. Analysis of E006AA prostate cancer cells from African Americans showed significantly higher GRβ levels (p<0.01) compared to cells from Caucasian Americans. We, therefore, used lentivirus to overexpress GRβ in LNCaP cells that are derived from Caucasian men. We found that GRβ induces growth pathways and sensitizes to androgen‐induced growth. Migration studies in the E006AA prostate cancer cells from African Americans showed that antagonizing GRβ by lentiviral shRNA or by the Sweet‐P inhibitor significantly (p<0.05) decreased migration rates of the prostate cancer cells. Our findings here indicate that GRβ inhibits GRα to cause GC resistance, which may cultivate hormone‐refractory PC for growth and migration. The research findings may impact PC treatment by allowing for the development of strategies for rational drug design that may lead to novel treatments targeting GRβ and provide the basis for studies in the management of prostate cancer.