Suchergebnisse

El pdf del artículo es la versión de autor. ; Vitamin D receptor (VDR) mediates the antitumoral action of the active vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). VDR expression is lost during colon cancer progression causing unresponsiveness to 1,25(OH)2D3 and its analogs. Previously, Snail1, an inducer of epithelial-to-mesenchymal transition (EMT), was reported to inhibit VDR expression. Here, we show that Snail2/Slug, but not other EMT inducers such as Zeb1, Zeb2, E47 or Twist1, represses VDR gene promoter. Moreover, Snail2 and Snail1 show additive repressing effect on VDR promoter. Snail2 inhibits VDR RNA and protein and blocks the induction of E-cadherin and an adhesive phenotype by 1,25(OH)2D3. Snail2 reduces the ligand-induced VDR transcriptional activation of a consensus response element and of the CYP24 promoter. Concordantly, Snail2 inhibits the induction of CYP24 RNA and p21CIP1, filamin A and vinculin proteins and the repression of c-MYC by 1,25(OH)2D3. Additionally, Snail2 abrogates β-catenin nuclear export and the antagonism of the transcriptional activity of β-catenin–T-cell factor complexes by 1,25(OH)2D3. SNAI2 expression is upregulated in 58% of colorectal tumors and correlates inversely with that of VDR. However, VDR downregulation is higher in tumors coexpressing SNAI2 and SNAI1 than in those expressing only one of these genes. Together, these data indicate that Snail2 and Snail1 cooperate for VDR repression in colon cancer. ; Ministerio de Ciencia e Innovación (SAF2007-60341, ISCIII-RETIC RD06/0020/0009); Comunidad de Madrid (S-GEN-0266-2006); European Union (MRTN-CT-2005-019496, NucSys). ; Peer Reviewed

et al. ; [Background]: Pharmacological activation of cannabinoid receptors elicits antitumoral responses in different cancer models. However, the biological role of these receptors in tumor physio-pathology is still unknown. [Methods]: We analyzed CB2 cannabinoid receptor protein expression in two series of 166 and 483 breast tumor samples operated in the University Hospitals of Kiel, Tübingen, and Freiburg between 1997 and 2010 and CB2 mRNA expression in previously published DNA microarray datasets. The role of CB2 in oncogenesis was studied by generating a mouse line that expresses the human V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (HER2) rat ortholog (neu) and lacks CB2 and by a variety of biochemical and cell biology approaches in human breast cancer cells in culture and in vivo, upon modulation of CB2 expression by si/shRNAs and overexpression plasmids. CB2-HER2 molecular interaction was studied by colocalization, coimmunoprecipitation, and proximity ligation assays. Statistical tests were two-sided. [Results]: We show an association between elevated CB2 expression in HER2+ breast tumors and poor patient prognosis (decreased overall survival, hazard ratio [HR] = 0.29, 95% confidence interval [CI] = 0.09 to 0.71, P = .009) and higher probability to suffer local recurrence (HR = 0.09, 95% CI = 0.049 to 0.54, P = .003) and to develop distant metastases (HR = 0.33, 95% CI = 0.13 to 0.75, P = .009). We also demonstrate that genetic inactivation of CB2 impairs tumor generation and progression in MMTV-neu mice. Moreover, we show that HER2 upregulates CB2 expression by activating the transcription factor ELK1 via the ERK cascade and that an increased CB2 expression activates the HER2 pro-oncogenic signaling at the level of the tyrosine kinase c-SRC. Finally, we show HER2 and CB2 form heteromers in cancer cells. [Conclusions]: Our findings reveal an unprecedented role of CB2 as a pivotal regulator of HER2 pro-oncogenic signaling in breast cancer, and they suggest that CB2 may be a biomarker with prognostic value in these tumors. ; This work was supported by grants from Spanish Ministry of Economy and Competitiveness (PI11/00295 and PI14/01101, supported with European Regional Development (FEDER) funds, to CS, SAF2012-36566 to JFP, SAF2010-22198 to SOG, and Ramón y Cajal fellowship to PJM); GW Pharmaceuticals (to CS); Madrid Regional Government (S2010/BMD-2308 to MG, S2010/BMD-2353 to SOG and S2011/BMD-2470 to JFP); Fundación Mutua Madrileña; Sandra Ibarra Foundation; and Instituto de Salud Carlos III (CIBERER-3–749/172.03 and ACCI-CIBERER-16 to JFP). EPG and EMV are recipients of Postdoctoral Research Contracts from Fundación Científica Asociación Española Contra el Cáncer. MA is a recipient of a Formación de Profesorado Universitario (FPU) fellowship (from the Spanish Ministry of Economy and Competitiveness), and EPG was a recipient of a Federation of the Societies of Biochemistry and Molecular Biology (FEBS) Short-term Fellowship. ; Peer Reviewed