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 14-3-3Z is overexpressed in >40% of advanced breast cancers, and this overexpression predicts poor patient survival. Here, we examined at what stage of breast disease 14-3-3Z overexpression occurs, and we found that increased expression of 14-3-3Z begins at

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... typical ductal hyperplasia, an early stage of breast disease. To determine whether 14-3-3Z overexpression is a decisive early event in breast cancer, we overexpressed 14-3-3Z in MCF10A cells and examined its effect in a three-dimensional culture model. We discovered that 14-3-3Z 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 14-3-3Z overexpression conferred resistance to anoikis. Additionally, 14-3-3Z overexpression in MCF10A cells and in mammary epithelial cells (MEC) from 14-3-3Z transgenic mice reduced expression of p53, which is known to mediate anoikis. Mechanistically, 14-3-3Z 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 14-3-3Z-overexpressing MCF10A acini in threedimensional cultures. These data suggest that 14-3-3Z overexpression is a critical event in early breast disease, and down-regulation of p53 is one of the mechanisms by which 14-3-3Z alters MEC acini structure and increases the risk of breast cancer.