Role of oestrogen receptors in bladder cancer development

Early studies documented the existence of sexual dimorphism in bladder cancer occurrence and progression, with a greater bladder cancer incidence in males than females. However, the progression of bladder cancer after diagnosis is much quicker in females than males. These findings can be explained by the effects of female hormones (predominantly oestrogens) and their binding receptors, including oestrogen receptor 1 (ESR1; also known as ERa), oestrogen receptor 2 (ESR2; also known as ER beta), and GPR30 protein on bladder cancer incidence and progression. Results from studies using various in vitro cell lines and in vivo mouse models demonstrate differential roles of oestrogen receptors in cancer initiation and progression. ERa suppresses bladder cancer initiation and invasion, whereas ER beta promotes bladder cancer initiation and progression. Mechanistic studies suggest that ER alpha and ER beta exert these effects via modulation of the AKT pathway and DNA replication complex, respectively. Targeting these signalling pathways-for example, with ER alpha agonists, ER beta antagonists, or selective oestrogen receptor modulators such as 4-[2-phenyl-5,7-bis(trifluoromethyl) pyrazolo[1,5-a] pyrimidin-3-yl] phenol (also known as PHTPP)-could lead to the development of new therapeutic approaches for controlling bladder cancer progression.