Rbf/E2F1-mediated transition from steroid-dependent to steroid-independent ecdysone receptor signalling in Drosophila prostate-like secondary cells
Authors: Aashika Sekar 1,2; Mark Wainwright 2; Aaron Leiblich 2; Claudia Mendes 2; Clive Wilson 2
Affiliations: 1) Centre for Tumour Biology, Barts Cancer Institute, London, United Kingdom; 2) Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom
Keywords: h. tumorigenesis; n. hormonal control
Castration-resistant prostate cancer (CRPC) is an incurable, androgen-independent form of prostate cancer that emerges in the hormone-depleted environment of androgen deprivation therapy (ADT). However, CRPC growth still frequently depends on Androgen Receptor (AR) signalling. Unusually, loss of the tumour suppressor gene, Retinoblastoma (Rb), and consequent activation of transcription factor E2F1 have been linked to late-stage tumour progression to CRPC, rather than early-stage events. We have previously shown that binucleate secondary cells (SCs) of the Drosophila melanogaster male accessory gland (AG) share several functional and signalling similarities with human prostate epithelial cells. Upon mating, SC growth regulation switches from a steroid-dependent to a steroid-independent form of Ecdysone Receptor (EcR) control that induces genome endoreplication. Here, we demonstrate that the Drosophila Rb homologue, Rbf, and E2F1, as well as cell cycle regulators, Cyclin D (CycD) and Cyclin E (CycE), are key mediators of SC growth and endoreplication both in virgin and mated males. Importantly, we show that the CycD/Rbf/E2F1 axis requires the EcR, but not ecdysone, to trigger CycE-dependent endoreplication and associated growth in SCs after mating, mirroring changes in CRPC. We also demonstrate that excess Rbf activity reversibly suppresses binucleation in adult SCs. Overall, our work reveals mechanistic parallels between the physiological switch to hormone-independent EcR signalling in SCs and the pathological switch seen in CRPC, and suggests that the latter may represent the dysregulation of a currently unidentified physiological process, which permits AR signalling when androgen levels are low.