7534

YWHAZ

tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta;YWHAZ;tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta

14-3-3 delta|14-3-3 protein zeta/delta|14-3-3 protein/cytosolic phospholipase A2|14-3-3 zeta|epididymis luminal protein 4|epididymis secretory protein Li 3|phospholipase A2|protein kinase C inhibitor protein 1|protein kinase C inhibitor protein-1|tyrosine

8q23.1

protein-coding

The 14-3-3zeta gene, on 8q22, is often amplified in breast cancer and encodes a survival factor that interacts with and stabilizes many key signaling proteins. We examined the relationship between the expression of 14-3-3zeta, estrogen receptor alpha (ERalpha), and other parameters ( tumor size, grade, nodal status, progesterone receptor, HER2, EGFR, and p53) in matched primary and recurrence tumor tissue and how these factors impact time to recurrence, properties of the recurred tumors, and site of metastasis. In this cohort of over 100 patients, median time to recurrence was 3 years (range 1-17 years). Our analyses of primary tumor microarray cores revealed that 14-3-3zeta status was significantly correlated with tumor grade, size, and ERalpha. Women with 14-3-3zeta-positive and ERalpha-negative tumors had the earliest time to recurrence (median 1 yr, p < 0.001, hazard ratio 2.89), while median time to recurrence was 7 years for 14-3-3zeta-negative and ER-positive tumors. Of recurred tumors, 70-75 % were positive for 14-3-3zeta, up from the 45 % positivity of primary tumors. High expression of 14-3-3zeta also correlated with site of recurrence and showed a propensity for distant metastases to lung and chest wall. Multifactor correlation regression analysis revealed 14-3-3zeta to be a non-redundant, independent variable that adds clinical strength in predicting risk for early recurrence in ER-positive and -negative breast cancers, providing information beyond that of all other clinical pathological features examined. Thus, high expression of 14-3-3zeta in the primary tumor was significantly associated with earlier time to recurrence and with distant metastasis. Furthermore, even when the primary breast cancers were negative-low for 14-3-3zeta, the majority acquired increased expression in the recurrence. The findings underscore the detrimental role played by 14-3-3zeta in tumor aggressiveness and suggest that reducing its expression or interfering with its actions might substantially improve the clinical outcome for breast cancer patients.

Peritoneal implantation is the most common metastatic pattern of epithelial ovarian cancer, and the five-year survival rate of patients is dramatically decreased when large-scale peritoneal metastasis occurs. This study aimed to determine serum proteins that could be used to detect early peritoneal metastasis of ovarian cancer. The secreted (or shed) proteins of the ovarian cancer cell line SKOV-3 were analyzed using LC-MS/MS, and 97 proteins were identified in the SKOV-3 culture supernatant. After the SKOV-3 cells were xenografted into the peritoneal cavities of nude mice, 3 of the 97 proteins were detected in animal sera. Following enzyme-linked immunosorbent assay (ELISA)-based screening of clinical blood samples, one of the three proteins, 14-3-3 zeta, was identified as a candidate biomarker. The average serum levels of 14-3-3 zeta in patients with epithelial ovarian cancer and benign gynecological diseases were significantly different. The expression of 14-3-3 zeta was associated with the degree of cancer peritoneal metastasis, the emergence of ascites, bilateral involvement, and the clinical stage and substage. Using 14-3-3 zeta, the overall diagnostic accuracy for ovarian cancer was greatly improved. Furthermore, siRNA-based experiments demonstrated that 14-3-3 zeta was responsible for approximately 62, 65, and 30% of the migratory, invasive, and implantation abilities of SKOV-3 cells, respectively. The present results demonstrated that the nude mouse xenograft model is an efficient system for performing function-oriented biomarker discovery, which can be used for a variety of research tasks in future molecular diagnoses, targeted therapies, and ovarian cancer vaccine development.