Abstract A97: Loss of function for FOXO1A contributes to poor outcome in African American and Latina women with breast cancer

Abstract

Abstract Background: FKHR transcription factor FOXO1A plays a pivotal role in the regulation of cell differentiation and apoptosis. Deregulation of FOXO1A contributes to resistance to different chemotherapeutic drugs in cancer patients. In vitro studies from our laboratory (Cancer Research 2010) demonstrated that overexpressing FOXO1A in HER2 overexpressing breast cancer cells improved sensitivity of trastuzumab. The purpose of this study is to determine the prognostic relevance of FOXO1A in African American and Latina women with breast cancer. Methods: The Association of FOXO1A expression with clinicopathological features of breast cancer and disease outcome was conducted in a cohort of 131 patients. The patients were retrospectively selected from our data base. Kaplan-Meier survival curves and Cox regression with multivariate analysis were used for accessing the disease-free survival. The FOXO1A expression and localization in malignant breast tissues, fibroadenoma and normal breast tissues were determined by immunohistochemistry analysis. Results: The FOXO1A protein was observed in both nuclear and cell membranes of normal breast tissue; in cell membranes of fibroadenoma, and in cytoplasm of malignant breast tissue. FOXO1A was significantly reduced in poorly differentiated tumors compared to well and moderately differentiated tumors. FOXO1A expression was inversely correlated between lymph node metastasis and HER2 status. FOXO1A is not associated with tumor size, stage and ER/PR status in our current cohort of patients. Interestingly, the loss of FOXO1A in breast cancer tissue was significantly associated with increased tissue pAkt and loss of PTEN. The relative risk (RR) for decrease in disease-free survival (DFS) was 2.0 in pAkt-/FOXO1 A-group compared to pAkt-/FOXO1A+ group. The RR for decrease in DFS increased to 4.2 in pAkt+/FOXO1A+ and further increased to 5.8 in pAkt+/FOXO1A-group. Compared to HER2+/FOXO1A+ tumors, a more than 30% further reduction in 5-year DFS was seen in patients with HER2+/FOXO1A-tumors. However, the Cox regression with multivariate analysis demonstrated that FOXO1A was not an independent contributor for the reduction of DFS. We did not find any association among ethnicity, age and the FOXO1A expression in this cohort of patients. Conclusion: Analysis of FOXO1A expression in clinical cancer tissues may provide important prognosis for DFS and OS. It also suggests that FOXO1A could be an important therapeutic target regulated by the PI3K/Akt pathway. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A97.