دورية أكاديمية
14-3-3 zeta down-regulates p53 in mammary epithelial cells and confers luminal filling.
| العنوان: | 14-3-3 zeta down-regulates p53 in mammary epithelial cells and confers luminal filling. |
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| المؤلفون: | Danes CG; Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA., Wyszomierski SL, Lu J, Neal CL, Yang W, Yu D |
| المصدر: | Cancer research [Cancer Res] 2008 Mar 15; Vol. 68 (6), pp. 1760-7. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Baltimore, Md. : American Association for Cancer Research Original Publication: Chicago [etc.] |
| مواضيع طبية MeSH: | 14-3-3 Proteins/*biosynthesis , Breast Diseases/*metabolism , Breast Neoplasms/*metabolism , Cell Transformation, Neoplastic/*metabolism , Tumor Suppressor Protein p53/*metabolism, 14-3-3 Proteins/genetics ; Animals ; Anoikis/physiology ; Breast Diseases/genetics ; Breast Diseases/pathology ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/pathology ; Disease Progression ; Down-Regulation ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Humans ; Mice ; Mice, Transgenic ; Neoplasm Staging ; Phosphatidylinositol 3-Kinases/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-mdm2/metabolism ; Signal Transduction ; Transfection ; Tumor Suppressor Protein p53/biosynthesis ; Tumor Suppressor Protein p53/genetics |
| مستخلص: | Recent progress in diagnostic tools allows many breast cancers to be detected at an early preinvasive stage. Thus, a better understanding of the molecular basis of early breast cancer progression is essential. Previously, we discovered that 14-3-3 zeta is overexpressed in >40% of advanced breast cancers, and this overexpression predicts poor patient survival. Here, we examined at what stage of breast disease 14-3-3 zeta overexpression occurs, and we found that increased expression of 14-3-3 zeta begins at atypical ductal hyperplasia, an early stage of breast disease. To determine whether 14-3-3 zeta overexpression is a decisive early event in breast cancer, we overexpressed 14-3-3 zeta in MCF10A cells and examined its effect in a three-dimensional culture model. We discovered that 14-3-3 zeta overexpression severely disrupted the acini architecture resulting in luminal filling. Proper lumen formation is a result of anoikis, apoptosis due to detachment from the basement membrane. We found that 14-3-3 zeta overexpression conferred resistance to anoikis. Additionally, 14-3-3 zeta overexpression in MCF10A cells and in mammary epithelial cells (MEC) from 14-3-3 zeta transgenic mice reduced expression of p53, which is known to mediate anoikis. Mechanistically, 14-3-3 zeta induced hyperactivation of the phosphoinositide 3-kinase/Akt pathway which led to phosphorylation and translocation of the MDM2 E3 ligase resulting in increased p53 degradation. Ectopic expression of p53 restored luminal apoptosis in 14-3-3 zeta-overexpressing MCF10A acini in three-dimensional cultures. These data suggest that 14-3-3 zeta overexpression is a critical event in early breast disease, and down-regulation of p53 is one of the mechanisms by which 14-3-3 zeta alters MEC acini structure and increases the risk of breast cancer. |
| معلومات مُعتمدة: | 1R01-CA109570 United States CA NCI NIH HHS; 1R01-CA119127 United States CA NCI NIH HHS; P01-CA0099031 United States CA NCI NIH HHS; P30-CA 16672 United States CA NCI NIH HHS; P50 CA116199 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (14-3-3 Proteins) 0 (TP53 protein, human) 0 (Tumor Suppressor Protein p53) EC 2.3.2.27 (MDM2 protein, human) EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2) EC 2.7.1.- (Phosphatidylinositol 3-Kinases) EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) EC 3.4.25.1 (Proteasome Endopeptidase Complex) |
| تواريخ الأحداث: | Date Created: 20080315 Date Completed: 20080409 Latest Revision: 20161124 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1158/0008-5472.CAN-07-3177 |
| PMID: | 18339856 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-7445 |
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| DOI: | 10.1158/0008-5472.CAN-07-3177 |