Abstract P5-12-06: Nuclear p-ser394-FOXO3a/FOXO3a ratio is associated with an improved survival and response to therapy in breast cancer
Authors: Hou MF , Dai HY , Yan LY , Yang SF , Chen FM , Yeh YT 
Published: May 2019

Background:Forkhead box O (FOXO) transcription factors, one of large forkhead family members, control a wide spectrum of carcinogenesis, therapy response and progression in human cancer. Phosphorylation of FOXO3a by ERK1/2 at ser294, ser344, and ser425 induces its nuclear exclusion and sequestration in the cytosol, therefore avoiding FOXO3a transcriptional activity and consequently promoting cell proliferation and tumorigenesis. We aimed to explore the prognostic significance of subcellular p-ser294-FOXO3a distribution patterns in breast cancer.

Methods: Immunohistochemistry was used to explore expression patterns of ERK1/2, FOXO3a and p-Ser294-FOXO3a in 216 breast cancer lesions. The obtained information was statistically correlated with clinicopathological parameters including tumor size, lymph node metastasis, tumor stage, histological grade, estrogen receptor α (ER), progesterone receptor (PR), HER2 and patients' follow-up data. The median follow-up period was 118 months. Kaplan-Meier survival curves were analyzed using with log-rank test and Cox-regression model was used to determine their independent prognosis values.

Results: Our results showed that nuclear FOXO3a and p-ser394-FOXO3a expression were progressively increased from normal, early to advanced breast tumor. Nuclear p-ser394-FOXO3a and FOXO3a expression was positively correlated (p=0.021). Nerveless, cytoplasmic ERK expression was inversely correlated with nuclear FOXO3a expression (p=0.037), but not its phosphorylation at the ser394 residue. To determine the real impact of p-ser394-FOXO3a, we redefined the ratio of p-ser394-FOXO3a over FOXO3a as p-FOXO3a index. Using χ2 analysis, we found nuclear p-FOXO3a index in tumor tissue was positively associated with lymph node metastasis (p=0.035) and inversely correlated with recurrence rate (p=0.035) in breast cancer patients. The Kaplen-Meier survival curve showed that nuclear p-FOXO3a index, but not cytoplasmic p-FOXO3a index, improved the overall survival rate (p=0.037). In addition, those patients who received hormone therapy would have a better survival rate when they had high nuclear p-FOXO3a index (p=0.005), suggesting that nuclear p-ser394-FOXO3a expression might be required for the response of hormone therapy. Intriguingly, low nuclear p-FOXO3a index significantly associated with the worse overall survival rate of patients who didn't receive chemotherapy or radiotherapy (p=0.049 and p=0.049, respectively), implicating that nuclear p-ser394-FOXO3a expression might also modulate the response of chemotherapy and radiotherapy. Multivariate Cox regression analysis demonstrated that the nuclear p-FOXO3a index (HR=0.46, 95% CI=0.22-0.97, p=0.040), stage (HR=2.48, 95% CI=1.04-5.96, p=0.041), and recurrence (HR=5.69, 95% CI=2.69-12.04, p&lt;0.001) were independent prognostic factors for the overall survival rate of breast cancer patients.

Conclusions: In conclusion, this study highlights that the phosphorylation of FOXO3a at the ser394 residue may play a crucial role in treatment response of breast cancer. Increased p-FOXO3a index may serve as a prognostic factor for an improved survival rate of breast cancer patients.

Citation Format: Hou MF, Dai HY, Yan LY, Yang SF, Chen FM, Yeh YT. Nuclear p-ser394-FOXO3a/FOXO3a ratio is associated with an improved survival and response to therapy in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-12-06.