This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Danes, C. G. Articles by Yu, D. Search for Related Content PubMed PubMed Citation Articles by Danes, C. G. Articles by Yu, D.

14-3-3 Down-regulates p53 in Mammary Epithelial Cells and Confers Luminal Filling

¹ Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center; ² The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas

Requests for reprints: Dihua Yu, Department of Molecular and Cellular Oncology, Unit 108, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3636; E-mail: dyu{at}mdanderson.org.

Key Words: 14-3-3 • p53 • anoikis • luminal filling • early stage breast cancer

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 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 overexpression occurs, and we found that increased expression of 14-3-3 begins at atypical ductal hyperplasia, an early stage of breast disease. To determine whether 14-3-3 overexpression is a decisive early event in breast cancer, we overexpressed 14-3-3 in MCF10A cells and examined its effect in a three-dimensional culture model. We discovered that 14-3-3 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 overexpression conferred resistance to anoikis. Additionally, 14-3-3 overexpression in MCF10A cells and in mammary epithelial cells (MEC) from 14-3-3 transgenic mice reduced expression of p53, which is known to mediate anoikis. Mechanistically, 14-3-3 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–overexpressing MCF10A acini in three-dimensional cultures. These data suggest that 14-3-3 overexpression is a critical event in early breast disease, and down-regulation of p53 is one of the mechanisms by which 14-3-3 alters MEC acini structure and increases the risk of breast cancer. [Cancer Res 2008;68(6):1760–7]

This article has been cited by other articles:

				S.-H. Li, V. S. Hawthorne, C. L. Neal, S. Sanghera, J. Xu, J. Yang, H. Guo, P. S. Steeg, and D. Yu Upregulation of Neutrophil Gelatinase-Associated Lipocalin by ErbB2 through Nuclear Factor-{kappa}B Activation Cancer Res., December 15, 2009; 69(24): 9163 - 9168. [Abstract] [Full Text] [PDF]

				C. L. Neal, J. Yao, W. Yang, X. Zhou, N. T. Nguyen, J. Lu, C. G. Danes, H. Guo, K.-H. Lan, J. Ensor, et al. 14-3-3{zeta} Overexpression Defines High Risk for Breast Cancer Recurrence and Promotes Cancer Cell Survival Cancer Res., April 15, 2009; 69(8): 3425 - 3432. [Abstract] [Full Text] [PDF]