title: 14-3-3zeta overexpression defines high risk for breast cancer recurrence and promotes cancer cell survival.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Neal
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.forename: Wentao
authors.initials: W
authors.lastname: Yang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhou
authors.forename: Nina T
authors.initials: NT
authors.lastname: Nguyen
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Danes
authors.forename: Hua
authors.initials: H
authors.lastname: Guo
authors.forename: Keng-Hsueh
authors.initials: KH
authors.lastname: Lan
authors.forename: Joe
authors.initials: J
authors.lastname: Ensor
authors.forename: Walter
authors.initials: W
authors.lastname: Hittelman
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Dihua
authors.initials: D
authors.lastname: Yu