ERK1/2-RSK regulation of oestrogen homeostasis

The molecular mechanisms regulating oestrogen homeostasis have been primarily studied in the mammary gland, which is the focus of this review. In the non-pregnant adult, the mammary gland undergoes repeated cycles of proliferation and apoptosis in response to the fluctuating levels of oestrogen that occur during the reproductive stage. Oestrogen actions are mediated through the steroid hormone receptors, oestrogen receptor α and β and through a G-protein coupled receptor. In the mammary gland, ERα is of particular importance and thus will be highlighted. Mechanisms regulating oestrogen-induced responses through ERα are necessary to maintain homeostasis given that the signalling pathways that are activated in response to ERα-mediated transcription can also induce transformation. ERK1/2 and its downstream effector, p90 ribosomal S6 kinase (RSK), control homeostasis in the mammary gland by limiting oestrogen-mediated ERα responsiveness. ERK1/2 drives degradation coupled ERα-mediated transcription, whereas RSK2 acts as a negative regulator of ERK1/2 activity to limit oestrogen responsiveness. Moreover, RSK2 acts as a positive regulator of translation. Thus, RSK2 provides both positive and negative signals to maintain oestrogen responsiveness. In addition to transmitting signals through tyrosine kinase receptors, ERK1/2-RSK engages with hedgehog signalling to maintain oestrogen levels and with the HIPPO pathway to regulate ERα-mediated transcription. Additionally, ERK1/2-RSK controls the progenitor populations within the mammary gland to maintain the ERα-positive population. RSK2 is involved in increased breast cancer risk in individuals taking oral contraceptives and in parity-induced protection against breast cancer. RSK2 and ERα may also co-operate in diseases in tissues outside of the mammary gland.