ABSTRACT
Runx1 participation in epithelial mammary cells is still under review. Emerging data indicates that Runx1 could be relevant for breast tumor promotion. However, to date no studies have specifically evaluated the functional contribution of Runx1 to control gene expression in mammary epithelial tumor cells. It has been described that Runx1 activity is defined by protein context interaction. Interestingly, Foxp3 is a breast tumor suppressor gene. Here we show that endogenous Runx1 and Foxp3 physically interact in normal mammary cells and this interaction blocks Runx1 transcriptional activity. Furthermore we demonstrate that Runx1 is able to bind to R-spondin 3 (RSPO3) and Gap Junction protein Alpha 1 (GJA1) promoters. This binding upregulates Rspo3 oncogene expression and downregulates GJA1 tumor suppressor gene expression in a Foxp3-dependent manner. Moreover, reduced Runx1 transcriptional activity decreases tumor cell migration properties. Collectively, these data provide evidence of a new mechanism for breast tumor gene expression regulation, in which Runx1 and Foxp3 physically interact to control mammary epithelial cell gene expression fate. Our work suggests for the first time that Runx1 could be involved in breast tumor progression depending on Foxp3 availability.
Subject(s)
Adenocarcinoma/metabolism , Breast Neoplasms/metabolism , Connexin 43/metabolism , Core Binding Factor Alpha 2 Subunit/metabolism , Forkhead Transcription Factors/metabolism , Gene Expression Regulation, Neoplastic , Thrombospondins/metabolism , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Animals , Apoptosis , Blotting, Western , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Movement , Cell Proliferation , Chromatin Immunoprecipitation , Female , Fluorescent Antibody Technique , Humans , Immunoenzyme Techniques , Immunoprecipitation , Mice , Mice, Inbred BALB C , Microscopy, Confocal , Microscopy, Fluorescence , Promoter Regions, Genetic/genetics , Tumor Cells, Cultured , Wound Healing , Xenograft Model Antitumor AssaysABSTRACT
The results of this study describe the immunostimulatory properties of Leishmania infantum Hsp83 (83) to elicit humoral and cellular response against the Toxoplasma gondii Rop2 protein in an adjuvant-free vaccination system. The analysis was performed by immunizing three different mice strains (BALB/c, C57BL/6 and C3H). Mice immunized with fusion Rop2-83 elicited a stronger humoral and cellular response in comparison to mice immunized with Rop2 alone, or a mix of LiHsp83 and Rop2. The fusion protein induced a Th1 type response, with predominance of specific IgG2a/IgG2c isotype and IFN-gamma secretions, whereas Rop2 alone or mixed with LiHsp83 produced a Th1/Th2 mixed response. Vaccination with fusion protein conferred a remarkable resistance against oral infection with ME49 cysts in C57BL/6 and C3H mice, in comparison to mice immunized with Rop2 alone or the protein mixture. Following lethal challenge, a significant survival rate was observed in Rop2-83 immunized Balb/c and C57BL/6 mice in comparison to control groups.
