FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes is associated with breast cancer prognosis

Takenaka,Miki; Seki,Naoko; Toh,Uhi; Hattori,Satoshi; Kawahara,Akihiko; Yamaguchi,Tomohiko; Koura,Keiko; Takahashi,Ryuji; Otsuka,Hiroko; Takahashi,Hiroki; Iwakuma,Nobutaka; Nakagawa,Shino; Fujii,Teruhiko; Sasada,Tetsuro; Yamaguchi,Rin; Yano,Hirohisa; Shirouzu,Kazuo; Kage,Masayoshi

doi:10.3892/mco.2013.107

FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes is associated with breast cancer prognosis

Authors:
- Miki Takenaka
- Naoko Seki
- Uhi Toh
- Satoshi Hattori
- Akihiko Kawahara
- Tomohiko Yamaguchi
- Keiko Koura
- Ryuji Takahashi
- Hiroko Otsuka
- Hiroki Takahashi
- Nobutaka Iwakuma
- Shino Nakagawa
- Teruhiko Fujii
- Tetsuro Sasada
- Rin Yamaguchi
- Hirohisa Yano
- Kazuo Shirouzu
- Masayoshi Kage
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Affiliations: Department of Pathology, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka 830-0011, Japan, Department of Surgery, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan, Biostatistical Center, Kurume University, Kurume, Fukuoka 830-0011, Japan, Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Fukuoka 830-0011, Japan, Multidisciplinary Treatment Center, Kurume University Hospital, Kurume, Fukuoka 830-0011, Japan, Department of Immunology, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan
Published online on: April 26, 2013 https://doi.org/10.3892/mco.2013.107
Pages: 625-632

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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.

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1.	Coffer PJ and Burgering BM: Forkhead-box transcription factors and their role in the immune system. Nat Rev Immunol. 4:889–899. 2004. View Article : Google Scholar : PubMed/NCBI
2.	Hori S, Nomura T and Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science. 299:1057–1061. 2003. View Article : Google Scholar : PubMed/NCBI
3.	Lopes JE, Torgerson TR, Schubert LA, et al: Analysis of FOXP3 reveals multiple domains required for its function as a transcriptional repressor. J Immunol. 177:3133–3142. 2006. View Article : Google Scholar : PubMed/NCBI
4.	Martin F, Ladoire S, Mignot G, Apetoh L and Ghiringhelli F: Human FOXP3 and cancer. Oncogene. 29:4121–4129. 2010. View Article : Google Scholar : PubMed/NCBI
5.	Sakaguchi S, Ono M, Setoguchi R, et al: Foxp3⁺CD25⁺CD4⁺natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 212:8–27. 2006.
6.	Liyanage UK, Moore TT, Joo HG, et al: Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 169:2756–2761. 2002. View Article : Google Scholar : PubMed/NCBI
7.	Woo EY, Chu CS, Goletz TJ, et al: Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 61:4766–4772. 2001.
8.	Bates GJ, Fox SB, Han C, et al: Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 24:5373–5380. 2006. View Article : Google Scholar : PubMed/NCBI
9.	Bohling SD and Allison KH: Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target. Mod Pathol. 21:1527–1532. 2008. View Article : Google Scholar : PubMed/NCBI
10.	Curiel TJ, Coukos G, Zou L, et al: Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 10:942–949. 2004. View Article : Google Scholar : PubMed/NCBI
11.	Gobert M, Treilleux I, Bendriss-Vermare N, et al: Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res. 69:2000–2009. 2009. View Article : Google Scholar
12.	Ohara M, Yamaguchi Y, Matsuura K, Murakami S, Arihiro K and Okada M: Possible involvement of regulatory T cells in tumor onset and progression in primary breast cancer. Cancer Immunol Immunother. 58:441–447. 2009. View Article : Google Scholar : PubMed/NCBI
13.	Ebert LM, Tan BS, Browning J, et al: The regulatory T cell-associated transcription factor FoxP3 is expressed by tumor cells. Cancer Res. 68:3001–3009. 2008. View Article : Google Scholar : PubMed/NCBI
14.	Hinz S, Pagerols-Raluy L, Oberg HH, et al: Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Cancer Res. 67:8344–8350. 2007. View Article : Google Scholar : PubMed/NCBI
15.	Karanikas V, Speletas M, Zamanakou M, et al: Foxp3 expression in human cancer cells. J Transl Med. 6:192008. View Article : Google Scholar : PubMed/NCBI
16.	Zuo T, Wang L, Morrison C, et al: FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell. 129:1275–1286. 2007. View Article : Google Scholar : PubMed/NCBI
17.	Wang L, Liu R, Li W, et al: Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate. Cancer Cell. 16:336–346. 2009. View Article : Google Scholar : PubMed/NCBI
18.	Zuo T, Liu R, Zhang H, et al: FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2. J Clin Invest. 117:3765–3773. 2007.PubMed/NCBI
19.	Zhang HY and Sun H: Up-regulation of Foxp3 inhibits cell proliferation, migration and invasion in epithelial ovarian cancer. Cancer Lett. 287:91–97. 2010. View Article : Google Scholar : PubMed/NCBI
20.	Jung DJ, Jin DH, Hong SW, et al: Foxp3 expression in p53-dependent DNA damage responses. J Biol Chem. 285:7995–8002. 2010. View Article : Google Scholar : PubMed/NCBI
21.	Ladoire S, Arnould L, Mignot G, et al: Presence of Foxp3 expression in tumor cells predicts better survival in HER2-overexpressing breast cancer patients treated with neoadjuvant chemotherapy. Breast Cancer Res Treat. 125:65–72. 2011. View Article : Google Scholar
22.	Liang YJ, Liu HC, Su YX, et al: Foxp3 expressed by tongue squamous cell carcinoma cells correlates with clinicopathologic features and overall survival in tongue squamous cell carcinoma patients. Oral Oncol. 47:566–570. 2011. View Article : Google Scholar : PubMed/NCBI
23.	Merlo A, Casalini P, Carcangiu ML, et al: FOXP3 expression and overall survival in breast cancer. J Clin Oncol. 27:1746–1752. 2009. View Article : Google Scholar : PubMed/NCBI
24.	Tao H, Mimura Y, Aoe K, et al: Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-infiltrating regulatory T cells. Lung Cancer. 75:95–101. 2012. View Article : Google Scholar : PubMed/NCBI
25.	Winerdal ME, Marits P, Winerdal M, et al: FOXP3 and survival in urinary bladder cancer. BJU Int. 108:1672–1678. 2011. View Article : Google Scholar : PubMed/NCBI
26.	Elston CW and Ellis IO: Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 19:403–410. 1991. View Article : Google Scholar
27.	Badoual C, Hans S, Rodriguez J, et al: Prognostic value of tumor-infiltrating CD4⁺T-cell subpopulations in head and neck cancers. Clin Cancer Res. 12:465–472. 2006. View Article : Google Scholar : PubMed/NCBI
28.	Carreras J, Lopez-Guillermo A, Fox BC, et al: High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood. 108:2957–2964. 2006. View Article : Google Scholar : PubMed/NCBI
29.	Salama P, Phillips M, Grieu F, et al: Tumor-infiltrating FOXP3⁺ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol. 27:186–192. 2009.
30.	Zhou Z, Song X, Li B and Greene MI: FOXP3 and its partners: structural and biochemical insights into the regulation of FOXP3 activity. Immunol Res. 42:19–28. 2008. View Article : Google Scholar : PubMed/NCBI
31.	Yu H, Kortylewski M and Pardoll D: Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol. 7:41–51. 2007. View Article : Google Scholar : PubMed/NCBI
32.	Knupfer H and Preiss R: Significance of interleukin-6 (IL-6) in breast cancer (review). Breast Cancer Res Treat. 102:129–135. 2007. View Article : Google Scholar : PubMed/NCBI
33.	Nicolini A, Carpi A and Rossi G: Cytokines in breast cancer. Cytokine Growth Factor Rev. 17:325–337. 2006. View Article : Google Scholar