title: BEX2 regulates mitochondrial apoptosis and G1 cell cycle in breast cancer.
abstract: We have recently demonstrated that BEX2 is differentially expressed in primary breast tumors and BEX2 expression is required for the Nerve Growth factor inhibition of ceramide-induced apoptosis in breast cancer. In this study we investigate the functional role of BEX2 in the survival and growth of breast cancer cells. We demonstrate that BEX2 downregulation induces mitochondrial apoptosis and sensitizes breast cancer cells to the pro-apoptotic effects of ceramide, doxorubicin and staurosporine. In addition, BEX2 overexpression protects the breast cancer cells against mitochondrial apoptosis. We show that this effect of BEX2 is mediated through the modulation of Bcl-2 protein family, which involves the positive regulation of anti-apoptotic member Bcl-2 and the negative regulation of pro-apoptotic members BAD, BAK1 and PUMA. Moreover, our data suggests that BEX2 expression is required for the normal cell cycle progression during G1 in breast cancer cells through the regulation of cyclin D1 and p21. To further support the significance of BEX2 in the pathogenesis of breast cancer we demonstrate that BEX2 overexpression is associated with a higher activation of the Bcl-2/NF-kappaB pathway in primary breast tumors. Furthermore, we show that BEX2 downregulation results in a higher expression and activity of protein phosphatase 2A. The modulation of protein phosphatase 2A, which is also known to mediate the cellular response to ceramide, provides a possible mechanism to explain the BEX2-mediated cellular effects. This study demonstrates that BEX2 has a significant role in the regulation of mitochondrial apoptosis and G1 cell cycle in breast cancer.
authors.affiliation: The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane Qld 4102, Australia. a.naderi@uq.edu.au
authors.forename: Ali
authors.initials: A
authors.lastname: Naderi
authors.forename: Ji
authors.initials: J
authors.lastname: Liu
authors.forename: Ian C
authors.initials: IC
authors.lastname: Bennett
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016193:G1 Phase; D006801:Humans; D007124:Immunoenzyme Techniques; D008928:Mitochondria / Q000473:pathology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050863:Synaptotagmin I / Q000235:genetics / Q000378:metabolism
chemical_list: C530662:BEX2 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050863:Synaptotagmin I; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2