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1.  Overexpression of 14-3-3ζ in cancer cells activates PI3K via binding the p85 regulatory subunit 
Oncogene  2011;31(7):897-906.
The ubiquitously expressed 14-3-3 proteins regulate many pathways involved in transformation. Previously, we found that 14-3-3ζ overexpression increased Akt phosphorylation in human mammary epithelial cells. Here, we investigated the clinical relevance and molecular mechanism of 14-3-3ζ overexpression-mediated Akt phosphorylation and the potential impact on breast cancer progression. We found that 14-3-3ζ overexpression was significantly (P = 0.005) associated with increased Akt phosphorylation in human breast tumors. Additionally, 14-3-3ζ overexpression combined with strong Akt phosphorylation was significantly (P=0.01) associated with increased cancer recurrence in patients. In contrast, knockdown of 14-3-3ζ expression by siRNA in cancer cell lines and tumor xenografts reduced Akt phosphorylation. Furthermore, 14-3-3ζ enhanced Akt phosphorylation through activation of PI3K. Mechanistically, 14-3-3ζ bound to the p85 regulatory subunit of PI3K and increased PI3K translocation to the cell membrane. A single 14-3-3 binding motif encompassing serine 83 on p85 is largely responsible for 14-3-3ζ-mediated p85 binding and PI3K/Akt activation. Mutation of serine 83 to alanine on p85 inhibited 14-3-3ζ binding to the p85 subunit of PI3K, reduced PI3K membrane localization and activation, impeded anchorage independent growth and enhanced stress induced apoptosis. These findings revealed a novel mechanism by which 14-3-3ζ overexpression activates PI3K, a key node in the mitogenic signaling network known to promote malignancies in many cell types.
PMCID: PMC3193867  PMID: 21743495
14-3-3ζ; breast cancer; PI3K; Akt
2.  14-3-3ζ as a prognostic marker and therapeutic target for cancer 
Expert opinion on therapeutic targets  2010;14(12):1343-1354.
Importance of the field
The ubiquitously expressed 14-3-3ζ protein is involved in numerous important cellular pathways involved in cancer. Recent research suggests 14-3-3ζ may play a central role regulating multiple pathways responsible for cancer initiation and progression. This review will provide an overview of 14-3-3 proteins and address the role of 14-3-3ζ overexpression in cancer.
Areas covered in this review
The review covers the basic role of 14-3-3 in regulation of multiple pathways with a focus on 14-3-3ζ as a clinically relevant biomarker for cancer recurrence.
What the reader will gain
14-3-3ζ overexpression has been found in multiple cancers; however, the clinical implications were unclear. Recently, 14-3-3ζ has been identified as a biomarker for poor prognosis and chemoresistance in multiple tumor types, indicating a potential clinical application for using 14-3-3ζ in selecting treatment options and predicting cancer patients’ outcome.
Take home message
14-3-3ζ is a potential prognostic marker of cancer recurrence and predictive marker for therapeutic resistance. The overexpression of 14-3-3ζ in multiple cancers suggests that it may be a common target to intervene tumor progression; therefore, more efforts are needed for the development of 14-3-3 inhibitors.
PMCID: PMC3017465  PMID: 21058923
14-3-3 zeta; apoptosis; cancer; chemoresistance; prognostic marker
3.  Upregulation of Neutrophil Gelatinase-Associated Lipocalin by ErbB2 Through NF-κB Activation 
Cancer research  2009;69(24):9163-9168.
ErbB2 (HER2, neu) is a receptor tyrosine kinase overexpressed in about 25% of invasive breast carcinomas. Neutrophil gelatinase-associated lipocalin (NGAL) is a secreted glycoprotein expressed in a variety of cancers including breast carcinomas. NGAL can inhibit erythroid cell production leading to anemia. Anemia usually occurs in cancer patients and negatively impacts quality of life. However, current treatment for cancer-related anemia has potential complications. ErbB2, NGAL, and anemia have all been associated with increased metastasis and poor prognosis in breast cancer patients, although the relationship between ErbB2 and NGAL expression is not clear. Here, using breast cancer cell lines in vitro and transgenic mice carrying the activated c-neu oncogene driven by a mouse mammary tumor virus (MMTV-neu) in vivo, we demonstrate that ErbB2 overexpression leads to NGAL upregulation, which is dependent on nuclear factor kappa B (NF-κB) activity. MMTV-neu transgenic mice developed anemia after tumor onset, and anemia progression could be partially arrested by an NF-κB inhibitor and an ErbB2-targeted therapy. Taken together, upregulation of NGAL by ErbB2 through NF-κB activation is involved in cancer-related anemia, and ErbB2, NF-κB, NGAL pathway may serve as potential therapeutic targets for cancer-related anemia.
PMCID: PMC2794902  PMID: 19951994
ErbB2; neutrophil gelatinase-associated lipocalin (NGAL); nuclear factor kappa B (NF-κB); anemia; breast cancer
4.  14-3-3ζ Overexpression Defines High Risk for Breast Cancer Recurrence and Promotes Cancer Cell Survival 
Cancer research  2009;69(8):3425-3432.
The ubiquitously expressed 14-3-3 proteins are involved in numerous important cellular functions. The loss of 14-3-3σ is a common event in breast cancer; however, the role of other 14-3-3s in breast cancer is unclear. Recently, we found that 14-3-3ζ overexpression occurs in early stage breast diseases and contributes to transformation of human mammary epithelial cells. Here, we show that 14-3-3ζ overexpression also persisted in invasive ductal carcinoma and contributed to the further progression of breast cancer. To examine the clinical impact of 14-3-3ζ overexpression in advanced stage breast cancer, we performed immunohistochemical analysis of 14-3-3ζ expression in primary breast carcinomas. 14-3-3ζ overexpression occurred in 42% of breast tumors and was determined to be an independent prognostic factor for reduced disease-free survival. 14-3-3ζ overexpression combined with ErbB2 overexpression and positive lymph node status identified a subgroup of patients at high risk for developing distant metastasis. To investigate whether 14-3-3ζ overexpression causally promotes breast cancer progression, we overexpressed 14-3-3ζ by stable transfection or reduced 14-3-3ζ expression by siRNA in cancer cell lines. Increased 14-3-3ζ expression enhanced anchorage independent growth and inhibited stress-induced apoptosis, whereas downregulation of 14-3-3ζ reduced anchorage independent growth and sensitized cells to stress-induced apoptosis via the mitochondrial apoptotic pathway. Transient blockade of 14-3-3ζ expression by siRNA in cancer cells effectively reduced the onset and growth of tumor xenografts in vivo. Therefore, 14-3-3ζ overexpression is a novel molecular marker for disease recurrence in breast cancer patients and may serve as an effective therapeutic target in patients whose tumors overexpress 14-3-3ζ.
PMCID: PMC2671640  PMID: 19318578
14-3-3ζ; breast cancer; apoptosis resistance; disease recurrence; prognostic marker
5.  ErbB2-mediated Src and STAT3 Activation Leads to Transcriptional Upregulation of p21Cip1 and Chemoresistance in Breast Cancer Cells 
Molecular cancer research : MCR  2009;7(4):592-600.
Overexpression of the ErbB2 receptor tyrosine kinase is prevalent in approximately 30% of human breast cancers and confers Taxol resistance. Our previous work has demonstrated that ErbB2 inhibits Taxol induced apoptosis in breast cancer cells by transcriptionally upregulating p21Cip1. However, the mechanism of ErbB2-mediated p21Cip1 upregulation is unclear. Here we show that ErbB2 upregulates p21Cip1 transcription through increased Src activity in ErbB2 overexpressing cells. Src activation further activated STAT3 that recognizes an SIE binding site on the p21Cip1 promoter required for ErbB2-mediated p21Cip1 transcriptional upregulation. Both Src and STAT3 inhibitors restored Taxol sensitivity in resistant ErbB2 overexpressing breast cancer cells. Our data suggest that ErbB2 overexpression can activate STAT3 through Src leading to transcriptional upregulation of p21Cip1 that confers Taxol resistance of breast cancer cells. Our study suggests a potential clinical application of Src and STAT3 inhibitors in Taxol sensitization of ErbB2 overexpressing breast cancers.
PMCID: PMC2689096  PMID: 19372587
ErB2; STAT3; Src; p21Cip1; breast cancer

Results 1-5 (5)