Involvement of the Androgen and Glucocorticoid Receptors in Bladder Cancer

Abstract

Bladder cancer is encountered worldwide having been associated with a host of environmental and lifestyle risk factors. The disease has a male to female prevalence of 3 : 1. This disparity has raised the possibility of the androgen receptor (AR) pathway being involved in the genesis of the disease; indeed, research has shown that AR is involved in and is likely a driver of bladder cancer. Similarly, an inflammatory response has been implicated as a major player in bladder carcinogenesis. Consistent with this concept, recent work on anti-inflammatory glucocorticoid signaling points to a pathway that may impact bladder cancer. The glucocorticoid receptor- (GR-) α isoform has an important role in suppressing inflammatory processes, which may be attenuated by AR in the development of bladder cancer. In addition, a GR isoform that is inhibitory to GRα, GRβ, is proinflammatory and has been shown to induce cancer growth. In this paper, we review the evidence of inflammatory mediators and the relationship of AR and GR isoforms as they relate to the propensity for bladder cancer.

Immunoexpression of glucocorticoid receptor alpha (GRα) isoform and apoptotic proteins (Bcl‐2 and Bax) in actinic cheilitis and lower lip squamous cell carcinoma

“…High expression of GRα has been associated with indicators of less aggressive biological behavior in malignant neoplasms, such as smaller tumor size, early clinical stages, and higher survival rates of patients . These results have been attributed to the participation of GRα in immunoinflammatory responses, as well as cell proliferation and apoptosis . The mechanisms whereby GR modulates programmed cell death are poorly understood.…”

“…5,10,11 These results have been attributed to the participation of GRα in immunoinflammatory responses, as well as cell proliferation and apoptosis. 8,12,13 The mechanisms whereby GR modulates programmed cell death are poorly understood. It has been shown that overexpression of GR triggers the death of tumor cells, 14,15 possibly by inhibiting the expression of the antiapoptotic proteins Bcl-2 and Bcl-xL.…”

Glucocorticoid receptor beta increases migration of human bladder cancer cells

“…Two drugs for the treatment of type II diabetes, rosiglitazone and pioglitazone, have been shown to induce bladder cancer [ 56 , 57 ], but their effect on miR144 or GRβ expression is unknown. Recent studies have revealed that there is a 3:1 incidence in men compared to women for bladder cancer, which may be mediated by the androgen receptor (AR) [ 4 ]. Presumably, there may be an interaction between AR and GRβ in prostate cancer.…”

“…Recently, glucocorticoids (GCs) have been used in bladder cancer for their protective properties against the toxic effects of chemotherapy [ 2 ]. GCs may cause resistance to cisplatin, which is a treatment commonly used for bladder cancer [ 3 , 4 ]. The GC receptor (GR) is expressed as different isoforms, GRα and GRβ, which are a result of alternative splicing of a single gene [ 5 – 9 ].…”

“…GCs are commonly used to inhibit growth in hematological cancers [ 20 ] and solid tumors [ 21 ]. Long-term GC treatment can increase the risk of bladder cancer, possibly through immunosuppression [ 2 , 4 ], or by causing GC resistance through elevated GRβ [ 4 , 9 ]. The later remains to be elucidated.…”