Rotinen Díaz, Mirja Sofia
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Rotinen Díaz
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Mirja Sofia
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Ciencias de la Salud
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IMAB. Research Institute for Multidisciplinary Applied Biology
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Publication Open Access ONECUT2 is a druggable driver of luminal to basal breast cancer plasticity(Sringer, 2024-05-31) Zamora Álvarez, Irene; Gutiérrez Núñez, Mirian; Pascual, Alex; Pajares Villandiego, María Josefa; Barajas Vélez, Miguel Ángel; Perez, Lillian M.; You, Sungyong; Knudsen, Beatrice S.; Freeman, Michael R.; Encío Martínez, Ignacio; Rotinen Díaz, Mirja Sofia; Ciencias de la Salud; Osasun Zientziak; Institute for Multidisciplinary Research in Applied Biology - IMAB; Gobierno de Navarra / Nafarroako GobernuaPurpose: tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer (BC), resulting in tumor progression, therapeutic failure and metastatic spread. The transcription factor ONECUT2 (OC2) has been shown to be a master regulator protein of metastatic castration-resistant prostate cancer (mCRPC) tumors that promotes lineage plasticity to a drug-resistant neuroendocrine (NEPC) phenotype. Here, we investigate the role of OC2 in the dynamic conversion between different molecular subtypes in BC. Methods: we analyze OC2 expression and clinical significance in BC using public databases and immunohistochemical staining. In vitro, we perform RNA-Seq, RT-qPCR and western-blot after OC2 enforced expression. We also assess cellular effects of OC2 silencing and inhibition with a drug-like small molecule in vitro and in vivo. Results: OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and tamoxifen-resistant models, and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. OC2 inhibits ER expression and activity, suppresses a gene expression program associated with luminal differentiation and activates a basal-like state at the gene expression level. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors. Conclusions: the transcription factor OC2 is a driver of BC heterogeneity and a potential drug target in distinct cell states within the breast tumors.Publication Open Access 'Defining the independence of the liver circadian clock' & 'BMAL1-driven tissue clocks respond independently to light to maintain homeostasis'(Frontiers Media, 2020) Rotinen Díaz, Mirja Sofia; Ciencias de la Salud; Osasun ZientziakThese studies demonstrate that peripheral tissues and organs can detect changes in environmental light and are capable of maintaining some basic functions, independently from our brain clock. The liver can autonomously ensure glucose homeostasis even if there is a glitch in the feedback system to the central clock (SCN). This could be of critical importance in environmentally challenging conditions to the organism. Our body needs to find a fine balance between diving into adjust its clocks in response to environmental stimuli and opposing change; otherwise we would live in a constant jet lag state. These studies provide evidence of the existence of at least two pathways regulating peripheral circadian clocks to reach that equilibrium. The first is an 'immediate and autonomous' response that allows organs to adjust to changes in light, without any input from other circadian clocks. The latter works as a 'fail safe copy' of past light regime that guarantees a certain degree of resistance and robustness to environmental changes, which is sustained by signals coming from other organs. Future studies will need to examine how the autonomous circadian clocks become deregulated in pathological contexts (obesity, metabolic disease, diabetes…).