title: FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes is associated with breast cancer prognosis.
abstract: The forkhead box protein 3 (FOXP3) transcription factor is highly expressed in tumor cells as well as in regulatory T cells (Tregs). It plays a tumor-enhancing role in Tregs and suppresses carcinogenesis as a potent repressor of several oncogenes. The clinical prognostic value of FOXP3 expression has not yet been elucidated. In this study, immunohistochemistry was used to investigate the prognostic significance of FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes (TILs) in breast cancer patients. Of the 100 tumor specimens obtained from primary invasive breast carcinoma, 63 and 57% were evaluated as FOXP3+tumor cells and as being highly infiltrated by FOXP3+lymphocytes, respectively. Although FOXP3 expression in tumor cells was of no prognostic significance, FOXP3+lymphocytes were significantly associated with poor overall survival (OS) (n=98, log-rank test P=0.008). FOXP3 exhibited a heterogeneous subcellular localization in tumor cells (cytoplasm, 31%; nucleus, 26%; both, 6%) and, although cytoplasmic FOXP3 was associated with poor OS (P= 0.058), nuclear FOXP3 demonstrated a significant association with improved OS (P=0.016). Furthermore, when patients were grouped according to their expression of tumor cytoplasmic FOXP3 and lymphocyte FOXP3, there were notable differences in the Kaplan-Meier curves for OS (P<0.001), with a high infiltration of FOXP3+lymphocytes accompanied by a cytoplasmic FOXP3+tumor being the most detrimental phenotype. These findings indicated that FOXP3 expression in lymphocytes as well as in tumor cells may be a prognostic marker for breast cancer. FOXP3 in tumor cells may have distinct biological activities and prognostic values according to its localization, which may help establish appropriate cancer treatments.
authors.affiliation: Departments of Pathology, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan ; ; Surgery, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan ;
authors.forename: Miki
authors.initials: M
authors.lastname: Takenaka
authors.affiliation: Research Center for Innovative Cancer Therapy, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan ;
authors.forename: Naoko
authors.initials: N
authors.lastname: Seki
authors.affiliation: Surgery, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan ;
authors.forename: Uhi
authors.initials: U
authors.lastname: Toh
authors.affiliation: Biostatistical Center, Kurume University, Kurume, Fukuoka 830-0011, Japan ;
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hattori
authors.affiliation: Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Fukuoka 830-0011, Japan ;
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kawahara
authors.affiliation: Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Fukuoka 830-0011, Japan ;
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Departments of Pathology, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan ; ; Surgery, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan ;
authors.forename: Keiko
authors.initials: K
authors.lastname: Koura
authors.affiliation: Surgery, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan ;
authors.forename: Ryuji
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: Surgery, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan ;
authors.forename: Hiroko
authors.initials: H
authors.lastname: Otsuka
authors.affiliation: Surgery, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan ;
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Surgery, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan ;
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Iwakuma
authors.affiliation: Surgery, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan ;
authors.forename: Shino
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Surgery, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan ; ; Multidisciplinary Treatment Center, Kurume University Hospital, Kurume, Fukuoka 830-0011, Japan ;
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Department of Immunology, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Sasada
authors.affiliation: Departments of Pathology, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan ;
authors.forename: Rin
authors.initials: R
authors.lastname: Yamaguchi
authors.affiliation: Departments of Pathology, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan ;
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Yano
authors.affiliation: Surgery, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan ;
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shirouzu
authors.affiliation: Research Center for Innovative Cancer Therapy, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan ; ; Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Fukuoka 830-0011, Japan ;
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kage
keywords: breast cancer; clinical prognosis; forkhead box protein 3; regulatory T-cells; tumor-infiltrating lymphocytes