| Summary: | <p>The paired lobes of the male Drosophila accessory gland (AG) contain two epithelial cell types, main cells (MCs) and secondary cells (SCs). SCs are a useful in vivo genetic model system to study fundamental mechanisms regulating cell growth and secretion, and they share several properties with the human prostatic gland. The SCs in adult virgin males grow with age in a BMP-dependent manner, and this growth can be further enhanced upon mating. During my DPhil, I have developed the SC as a model to study steroid receptor-dependent growth regulation. The fly nuclear steroid receptor, the ecdysone receptor (EcR), and the human androgen receptor (AR) share similar structural and functional domains. I show that a complex interplay between the BMP and EcR signalling pathways is involved in the regulation of SC growth in both virgin and mated males, an interaction which may allow mated males to rapidly replenish the expelled contents of their AG. The growth that occurs after mating is partly accounted for by genome endoreplication which is BMP/EcR-dependent, as is the secretory activity of SCs. I show that SCs can synthesise the hormone ecdysone, much like the prostate gland which produces the most active form of androgen. Interestingly, SC growth that occurs in virgin males requires ecdysone, but in mated males, endoreplication-dependent growth occurs independently of this hormone. The switch from hormone-dependent steroid receptor signalling to hormone-independent signalling mirrors the transition from androgen-dependent prostate cancer to the more aggressive and incurable form of prostate cancer, androgen-independent ‘castration-resistant prostate cancer’ (CRPC). I demonstrate that the cell cycle regulators, Cyclin D (CycD), Cyclin E (CycE), Retinoblastoma (Rbf) and E2F1, which are all implicated in prostate cancer, are key regulators of SC growth and endoreplication both in virgin and mated males. Furthermore, CycD/Rbf/E2F1/CycE interacts with the BMP/EcR signalling axis to regulate the transition from hormone-dependent to hormone-independent steroid receptor signalling in SCs, mirroring some of the mechanisms associated with the transition to CRPC. Overall, my work suggests that there are parallels between the physiological roles of the EcR’s switch to hormone-independence in SCs and the pathological changes seen in CRPC, and indicates that further genetic analyses in SCs may unravel the complex signalling mechanisms that mediate the transition to this lethal form of cancer.</p>
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