Abstract 434: Identification of 14-3-3α as a predictor of early time to recurrence and a molecular target in metastatic hormone receptor-positive and -negative breast cancers
Authors: Bergamaschi Anna , Frasor Jonna M. , Borgen Kristina , Stanculescu Adina , Johnson Patricia , Rowland Kendrith , Wiley Elizabeth L. , Katzenellenbogen Benita S. 
Published: August 2012

Introduction: The 14-3-3α gene, on 8q22, is often amplified in breast cancer. It encodes a survival factor that interacts with many key signaling proteins, thereby increasing cell proliferation and invasiveness, and contributing to therapy resistance and poor clinical outcome. We examined the relationship between the expression of 14-3-3α, FOXM1, and EGFR in matched primary and recurrence tumor tissue and how this impacts time to recurrence, properties of the recurrent tumors, and site of metastasis. Findings: In this cohort of 130 patients, median time to recurrence 3 years (range 1-17 yrs), our analysis of primary tumor microarray cores showed 45% were 14-3-3α -positive, 53% were hormone receptor-positive, and 20% were triple negative. Examination of 14-3-3α and ER status indicated that tumors 14-3-3α-positive and ER-negative had the earliest time to recurrence [p &lt;0.001, hazard ratio of 2.89 (95% CI of 2.37-3.41)]. To assess the prognostic importance of 14-3-3α, we stratified primary tumors based on 14-3-3α IHC and compared these to levels in the matched recurred tumors. Of recurred tumors, 65% were positive for 14-3-3α, showing an increase in positive cases of 20% compared to the primary tumors. Thus, a significant proportion of primary tumors negative for 14-3-3α became positive in the recurrence (P=0.0001). Positive 14-3-3α status was correlated with site of recurrence, with a propensity for metastases to lung and chest wall. Multifactor correlation regression analysis revealed 14-3-3α status to be a non-redundant, i.e. independent, variable that adds clinical strength in predicting recurrence in ER-positive and -negative breast cancers and provides information in addition to all other clinical pathological features examined (tumor size, grade, receptor status, FOXM1, CERB2, EGFR, p53, positive lymph nodes). Conclusions: High expression of 14-3-3α in the primary tumor or its acquisition in the recurrence was significantly associated with earlier time to recurrence and with distant metastasis. 14-3-3α is an independent variable that can alone improve the prediction of clinical outcome. FOXM1, while not being an independent variable, showed strong correlation with 14-3-3α positivity, and tumors positive for both factors showed the shortest time to recurrence. The findings underscore the very detrimental roles played by 14-3-3α and FOXM1 in tumor aggressiveness and metastasis, and suggest that reducing their expression or interfering with their actions might substantially improve the clinical outcome for breast cancer patients. (Supported by grants from The Breast Cancer Research Foundation to BSK and The Sirazi Foundation to BSK and JF, and DOD postdoctoral fellowship (W81XWH-09-1-0398) to AB)

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 434. doi:1538-7445.AM2012-434