title: An evaluation of the clinical significance of FOXP3+ infiltrating cells in human breast cancer.
abstract: Studies in mice have shown that thymic-derived CD4+ CD25+ regulatory T cells (T reg; FOXP3(+) lymphocytes) inhibit an antitumour immune response. Additional studies have also reported that the T reg population increases in peripheral blood and tumour tissues from patients with cancer. However, the relationship between the T reg population and the patient prognosis remains controversial. Our aim was to determine the prognostic value of T reg cell density in breast cancer using immunohistochemical assessment of FOXP3, which has been shown to be the optimal marker for T regs. Tissue microarrays were used, and the density of FOXP3(+) cells was determined in a series of 1445 cases of well-characterised primary invasive breast carcinoma cases with long-term follow up. FOXP3(+) cell numbers were counted in tumour nests, in tumour-adjacent stroma, and in distant stroma. The total number of FOXP3(+) cells significantly correlated with higher tumour grade (r (s) = 0.37, P < 0.001) and ER negativity (Mann-Whitney U test, P < 0.001). In addition, FOXP3 infiltration positively correlated with HER2 expression and basal phenotype subclass. On univariate analysis, FOXP3(+) cells were associated with a worse prognosis (P = 0.012, log rank = 6.36). This association was found for intratumoural FOXP3(+) and for tumour-adjacent stromal FOXP3(+)-cells (tumour-cell associated FOXP3, P = 0.001 and log rank 10.35). However, the number of FOXP3(+) cells was not found to be an independent prognostic factor in multivariate analysis. We therefore conclude that FOXP3(+) infiltrating cells do not have a dominant role in breast cancer prognosis and suggest that other inflammatory cell subsets may be more critical variables.
authors.affiliation: Division of Pathology, School of Molecular Medical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK.
authors.forename: Sahar M A
authors.initials: SM
authors.lastname: Mahmoud
authors.forename: Emma C
authors.initials: EC
authors.lastname: Paish
authors.forename: Desmond G
authors.initials: DG
authors.lastname: Powe
authors.forename: R Douglas
authors.initials: RD
authors.lastname: Macmillan
authors.forename: Andrew H S
authors.initials: AH
authors.lastname: Lee
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D017024:Chemotherapy, Adjuvant; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism*; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D011960:Receptors, Estrogen