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

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 8; p. 3425
• Main Authors: Neal, Christopher L, Yao, Jun, Yang, Wentao, Zhou, Xiaoyan, Nguyen, Nina T, Lu, Jing, Danes, Christopher G, Guo, Hua, Lan, Keng-Hsueh, Ensor, Joe, Hittelman, Walter, Hung, Mien-Chie, Yu, Dihua
• Format: Journal Article
• Language: English
• Published: United States 15.04.2009
• Subjects: 14-3-3 Proteins - biosynthesis; 14-3-3 Proteins - genetics; Apoptosis - physiology; Biomarkers, Tumor - biosynthesis; Biomarkers, Tumor - genetics; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Adhesion - physiology; Cell Growth Processes - physiology; Cell Line, Tumor; Cell Survival - physiology; Female; Gene Amplification; Humans; Mitochondria - genetics; Mitochondria - metabolism; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Prognosis; Risk Factors
• ISSN: 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-2765

The ubiquitously expressed 14-3-3 proteins are involved in numerous important cellular functions. The loss of 14-3-3sigma is a common event in breast cancer; however, the role of other 14-3-3s in breast cancer is unclear. Recently, we found that 14-3-3zeta overexpression occurs in early stage breast diseases and contributes to transformation of human mammary epithelial cells. Here, we show that 14-3-3zeta overexpression also persisted in invasive ductal carcinoma and contributed to the further progression of breast cancer. To examine the clinical effect of 14-3-3zeta overexpression in advanced stage breast cancer, we performed immunohistochemical analysis of 14-3-3zeta expression in primary breast carcinomas. 14-3-3zeta overexpression occurred in 42% of breast tumors and was determined to be an independent prognostic factor for reduced disease-free survival. 14-3-3zeta 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 14-3-3zeta overexpression causally promotes breast cancer progression, we overexpressed 14-3-3zeta by stable transfection or reduced 14-3-3zeta expression by siRNA in cancer cell lines. Increased 14-3-3zeta expression enhanced anchorage-independent growth and inhibited stress-induced apoptosis, whereas down-regulation of 14-3-3zeta reduced anchorage-independent growth and sensitized cells to stress-induced apoptosis via the mitochondrial apoptotic pathway. Transient blockade of 14-3-3zeta expression by siRNA in cancer cells effectively reduced the onset and growth of tumor xenografts in vivo. Therefore, 14-3-3zeta 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 14-3-3zeta.