Complex regulation of LCoR signaling in breast cancer cells

International audienceLigand-dependent corepressor (LCoR) is a transcriptional repressor of ligand-activated estrogen receptors (ERs) and other transcription factors that acts both by recruiting histone deacetylases and C-terminal binding proteins. Here, we first studied LCOR gene expression in breast cancer cell lines and tissues. We detected two mRNAs variants, LCoR and LCoR2 (which encodes a truncated LCoR protein). Their expression was highly correlated and localized in discrete nuclear foci. LCoR and LCoR2 strongly repressed transcription, inhibited estrogen-induced target gene expression and decreased breast cancer cell proliferation. By mutagenesis analysis, we showed that the helix-turn-helix domain of LCoR is required for these effects. Using in vitro interaction, coimmunoprecipitation, proximity ligation assay and confocal microscopy experiments, we found that receptor-interacting protein of 140 kDa (RIP140) is a LCoR and LCoR2 partner and that this interaction requires the HTH domain of LCoR and RIP140 N- and C-terminal regions. By increasing or silencing LCoR and RIP140 expression in human breast cancer cells, we then showed that RIP140 is necessary for LCoR inhibition of gene expression and cell proliferation. Moreover, LCoR and RIP140 mRNA levels were strongly correlated in breast cancer cell lines and biopsies. In addition, RIP140 positively regulated LCoR expression in human breast cancer cells and in transgenic mouse models. Finally, their expression correlated with overall survival of patients with breast cancer. Taken together, our results provide new insights into the mechanism of action of LCoR and RIP140 and highlight their strong interplay for the control of gene expression and cell proliferation in breast cancer cells

Substance-Use Disorders and Violence

© Springer International Publishing AG 2018.Substance use seems to be associated with increased prevalence levels of violent behaviour in both general population and psychiatric patients, with ‘dual-diagnosis’ clients showing high rates of risky and criminal behaviour and worse therapy compliance. Cases of drug-related aggressiveness mostly involve a number of molecules, e.g. ethanol, stimulants, cannabinoids, opiates, benzodiazepines, synthetic cannabinoids and synthetic cathinones. Consumers of the virtually few hundred, and up to a few thousand, substances currently available may present to the emergency departments without providing information about the substances(s) ingested and it is likely that standard drug tests will show negative results. An appropriate treatment/management plan to cope with the related acute behavioural and psychopathological disturbances is here discussed. Because of the complex behavioural and medical toxicity issues associated with drug intake, raising awareness and education of healthcare professionals on drugs’ health harms, interventions, harm reduction techniques and referral pathways are here deemed of particular relevance