14-3-3ζ overexpression defines high risk for breast cancer recurrence and promotes cancer cell survival

Christopher L. Neal, Jun Yao, Wentao Yang, Xiaoyan Zhou, Nina T. Nguyen, Jing Lu, Christopher G. Danes, Hua Guo, Keng Hsueh Lan, Joe Ensor, Walter Hittelman, Mien Chie Hung, Dihua Yu

Research output: Contribution to journalArticle

141 Scopus citations

Abstract

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 effect 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

Original languageEnglish (US)
Pages (from-to)3425-3432
Number of pages8
JournalCancer research
Volume69
Issue number8
DOIs
StatePublished - Apr 15 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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