Endocrine Abstracts

We recently generated a transgenic reporter mouse, ERE-Luc, to study ER transcriptional activity in pathophysiological states. In this model, luciferase synthesis is strictly associated with transcriptional activity of both ERα and ERβ, independent from the activity of receptors related to ERs. This enables to apply non-invasive imaging technologies to visualize ERs transcriptional activity in vivo, allowing to follow ERs activity in time in several organs in physiological or pharmacological settings. Initial studies focussed on ERs activity in sexually mature, adult female mice. By bioluminescence imaging, we showed that ERs activity extent in cycling females is proportional to circulating estradiol levels only in reproductive organs. In non-reproductive organs, other factors appear to be responsible for ER transcriptional activation. More recently, using pharmacological inhibitors of IGF-1 receptors and mice with ablated liver synthesis of IGF-1, we showed that IGF-1 is involved in the regulation of ER-dependent transcription in several ER-positive tissues, in accordance with previous reports, ours and from other laboratories, showing that intracellular signalling cascades induced by IGF-1 may regulate ERs transcriptional activity in vitro. In view of the major role played by IGF-1 in less evolved organisms (nematodes, insects) in metabolic path selection determining proliferation or increased lifespan, it should not surprise that its signalling includes a receptor relevant for sexual behaviour and reproduction. ERE-Luc mouse has also been used to study the consequences of long-term treatments with natural and synthetic ligands on ER transcriptional activity. These in vivo studies are carried out by daily measurements of bioluminescence emission of female ERE-Luc mice treated with different doses of 17β-estradiol, Raloxifene and Tamoxifen for up to 21 days. Results reveal that therapeutic efficacy is achieved when drugs are administered at concentrations able to reinstate the oscillatory ER transcriptional pattern of naturally cycling mice. Thus, these initial studies point to the physiological relevance of ERs fluctuating activity and to its need, to maintain the tissue-specific protective effects linked to estrogen action.