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

Abstract

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 atypical 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. [Cancer Res 2008;68(6):1760-7]

Proteomic Analysis of Potential Breast Cancer Biomarkers

“…As such, these proteins might have the potential to be putative breast cancer markers. As expected, some well-known breast cancer markers, such as 14-3-3 proteins (Danes et al, 2008), annexins (Cao et al, 2008a), calmodulin (Gallo et al, 2008), anterior gradient homolog 2 (AGR-2) (Zweitzig et al, 2007;Fritzsche et al, 2006), Galectin-1 (Jung et al, 2007) and Rho-associated protein kinase-2 (ROCK2) (Fu et al, 2008b), were also identified in this 2D-DIGE experiment, lending credence to the reliability of early phase biomarker detection using this experimental strategy. Fig.…”

Restraining FOXO3-dependent transcriptional BMF activation underpins tumour growth and metastasis of E-cadherin-negative breast cancer

“…11 Several studies have shown that activation of oncogenic growth factor receptor (GFR) signalling can induce aberrant filling of the luminal space. 3,5,12 Similar effects have been observed upon inhibition of pro-apoptotic players such as BIM, BMF and p53, 5,6,13 indicating that either GFR activation and/or the inhibition of distal pro-apoptotic effectors underlie anchorage independence of breast cancer cells. Indeed, mutations in the PI3K and p53 pathway are among the most observed mutations in epithelial cancers, including breast cancer.…”

Genome-scale Reconstruction of Metabolic Network in Bacillus subtilis Based on High-throughput Phenotyping and Gene Essentiality Data

“…This demand function was used as the objective function for flux balance analysis analysis. The growth rates for different substrate uptake rates were computed based on minimal media (see "Experimental Procedures" for simulation conditions) and compared with the experimental results of aerobic chemostat cultivation (13,23). Under these conditions, the model used the caa 3 terminal oxidase activity as part of the optimal flux distribution and resulted in higher in silico growth rates than experimental results (Fig.…”