Fig 8. Regulation of SC genome endoreplication by cell cycle regulators parallels control of tumour cell growth in CRPC.

(A) CycD/Rbf/E2F1/CycE are all essential for the endoreplication in SCs that is induced by mating. Hormone-independent EcR signalling appears to be required for E2F1-dependent induction of endoreplication and associated growth, an effect that is at least partly mediated by increasing EcR levels. In turn, the EcR, in a complex with its partner Usp ², is at least partly dependent on CycE to perform its functions in endoreplication. BMP signalling interacts with the cell cycle regulatory axis downstream of Rbf, but upstream of E2F1, although our data do not eliminate the possibility that it may also act on the EcR in an E2F1-independent fashion to control endoreplication-independent growth. The signalling network that controls endoreplication and associated growth has not been identified in other Drosophila cells to date. (B) However, mirroring this regulation in SCs, activation of CycD/Rbf/E2F1 during ADT, leads to an increase in AR expression and hormone-independent AR signalling that drive growth and proliferation in CRPC. BMP-6 signalling may also be involved in this process. Therefore, in SCs after mating and in CRPC, the cell cycle machinery performs a distinct role involving elevated steroid receptor expression and hormone-independent, steroid receptor-dependent signalling to drive DNA replication and growth. Cdk4/2- cyclin dependent kinase 4/2; CycD- Cyclin D; CycE- Cyclin E; Dp- Dumpy; Dpp- Decapentaplegic; Ec-Ecdysone; EcR- Ecdysone receptor; Med- Medea (Drosophila co-Smad); P- Phosphate group; Rbf- Retinoblastoma; Tkv- Thickveins (type I BMP receptor); Usp- Ultraspiracle (EcR binding partner); Wit- Wishful thinking (type II BMP receptor); AR- Androgen Receptor; Smad5- human receptor Smad; Smad4- human co-Smad. Red arrows depict the pathways that regulate SC endoreplication and associated growth, and the dotted arrows show probable signalling interactions.