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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]

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