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FOXO3a expression is associated with lymph node metastasis and poor disease-free survival in triple-negative breast cancer
  1. Abdul Rehman1,
  2. Yeseul Kim1,
  3. Hyunsung Kim1,
  4. Jongmin Sim1,
  5. Hyein Ahn2,
  6. Min Sung Chung3,
  7. Su-Jin Shin1,
  8. Kiseok Jang1
  1. 1 Department of Pathology, Hanyang University College of Medicine, Seoul, South Korea
  2. 2 Department of Pathology, College of Medicine, Konyang University, Daejeon, South Korea
  3. 3 Department of Surgery, Hanyang University College of Medicine, Seoul, South Korea
  1. Correspondence to Professor Kiseok Jang, Department of Pathology, Hanyang University College of Medicine, Seoul 04763, South Korea; medartisan{at}


Aims Forkhead box O (FOXO) transcription factors, consisting of FOXO1, FOXO3a, FOXO4 and FOXO6, are involved in carcinogenesis and tumour progression. Recent studies have suggested that FOXOs act as tumour suppressors in a variety of human cancers. This study investigated the clinicopathological significance of FOXOs in triple-negative breast cancer (TNBC).

Methods FOXO protein expressions were assessed by immunohistochemistry in 125 TNBC tissues. Correlations between FOXO protein expression and various clinicopathological parameters, including patients’ survival, were investigated. MDA-MB-468 cell line was used for in vitro cell proliferation and migration assay.

Results FOXO1 protein expression was not observed in all 125 TNBC tissues. FOXO4 and FOXO6 protein expressions were detected in 11 (8.8%) and 14 (11.2%) TNBC tissues, respectively. Loss of FOXO4 expression was significantly associated with high histological grade (P=0.014, χ2 test), and TNBCs with positive FOXO6 expression correlated with high grade (P=0.020, χ2 test). FOXO3a expression was detected in 40 (32%) TNBC cases and correlated with adverse clinicopathological features, such as lymph node metastasis (P=0.021, χ2 test), perineural invasion (P=0.013, χ2 test) and higher Ki-67 proliferation index (P=0.048, t-test). Additionally, FOXO3a expression was significantly associated with poor disease-free survival (P=0.015, log-rank test). In the in vitro study, siRNA-mediated FOXO3a knockdown in the MDA-MB-468 cell line inhibited cell proliferation and migration.

Conclusion Among FOXO members, FOXO3a may have a potential role in promoting tumour cell migration and proliferation and may serve as a prognostic biomarker and a potential therapeutic target for TNBC.

  • breast cancer
  • metastasis
  • immunohistochemistry

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  • Handling editor Cheok Soon Lee.

  • Contributors AR, YK, HK, JS, HA, MSC and S-JS contributed to acquisition and analysis of clinicopathological information, construction of tissue microarray and statistical analyses. AR and KJ performed pathological evaluation and in vitro experiments. AR drafted manuscript. KJ contributed to study design and data interpretation and supervised the study.

  • Funding This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (No. 2015R1C1A1A01056091).

  • Competing interests None declared.

  • Ethics approval The study protocol was approved by the Institutional Review Board of Hanyang University Hospital (HYUH-2015-12-023).

  • Provenance and peer review Not commissioned; externally peer reviewed.