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14-3-3 Overexpression Defines High Risk for Breast Cancer Recurrence and Promotes Cancer Cell Survival

Departments of ¹ Molecular and Cellular Oncology, ² Biostatistics, and ³ Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Dihua Yu, Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 108, Houston, TX 77030. Phone: 713-792-3636; Fax: 713-792-4454; E-mail: dyu{at}mdanderson.org.

Key Words: 14-3-3 • breast cancer • apoptosis resistance • disease recurrence • prognostic marker

The ubiquitously expressed 14-3-3 proteins are involved in numerous important cellular functions. The loss of 14-3-3 is a common event in breast cancer; however, the role of other 14-3-3s in breast cancer is unclear. Recently, we found that 14-3-3 overexpression occurs in early stage breast diseases and contributes to transformation of human mammary epithelial cells. Here, we show that 14-3-3 overexpression also persisted in invasive ductal carcinoma and contributed to the further progression of breast cancer. To examine the clinical effect of 14-3-3 overexpression in advanced stage breast cancer, we performed immunohistochemical analysis of 14-3-3 expression in primary breast carcinomas. 14-3-3 overexpression occurred in 42% of breast tumors and was determined to be an independent prognostic factor for reduced disease-free survival. 14-3-3 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 14-3-3 overexpression causally promotes breast cancer progression, we overexpressed 14-3-3 by stable transfection or reduced 14-3-3 expression by siRNA in cancer cell lines. Increased 14-3-3 expression enhanced anchorage-independent growth and inhibited stress-induced apoptosis, whereas down-regulation of 14-3-3 reduced anchorage-independent growth and sensitized cells to stress-induced apoptosis via the mitochondrial apoptotic pathway. Transient blockade of 14-3-3 expression by siRNA in cancer cells effectively reduced the onset and growth of tumor xenografts in vivo. Therefore, 14-3-3 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 14-3-3. [Cancer Res 2009;69(8):3425–32]