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The 14-3-3ζ 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 14-3-3ζ, estrogen receptor α (ERα), 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 14-3-3ζ status was significantly correlated with tumor grade, size, and ERα. Women with 14-3-3ζ-positive and ERα-negative tumors had the earliest time to recurrence (median 1 yr, p &lt; 0.001, hazard ratio 2.89), while median time to recurrence was 7 years for 14-3-3ζ-negative and ER-positive tumors. Of recurred tumors, 70-75 % were positive for 14-3-3ζ, up from the 45 % positivity of primary tumors. High expression of 14-3-3ζ also correlated with site of recurrence and showed a propensity for distant metastases to lung and chest wall. Multifactor correlation regression analysis revealed 14-3-3ζ 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 14-3-3ζ 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 14-3-3ζ, the majority acquired increased expression in the recurrence. The findings underscore the detrimental role played by 14-3-3ζ in tumor aggressiveness and suggest that reducing its expression or interfering with its actions might substantially improve the clinical outcome for breast cancer patients.

14-3-3ζ as a predictor of early time to recurrence and distant metastasis in hormone receptor-positive and -negative breast cancers