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.

Different Expression Patterns of CXCR4, CCR7, Maspin and FOXP3 in Luminal Breast Cancers and Their Sentinel Node Metastases

“…In previous reports, FOXP3 positivity has been associated with higher tumor grade, higher Ki-67 expression and LN metastases (17,39,40). In these studies FOXP3 expression was mostly cytoplasmic or combined cytoplasmic/nuclear.…”

“…In our study, luminal B tumors were more often FOXP3-positive than were luminal A tumors. Predominance of nuclear FOXP3 location in our material might be explained by exclusively ER-positive, HER2-negative PTs, as nuclear FOXP3 expression has been associated with ER-positive PTs and a favorable clinical outcome (39).…”

Immunohistochemical Estimation of Foxp3 Expression in T-Reg and Cancer Cells in Iraqi Lung Cancer Tissue.

“…[30,33] had both confirmed the expression of FOXP3 in the nuclei and cytoplasm of lung cancer. The association between cancer cell expression (nuclear or cytoplasmic) and lymphocytic expression was not signifigant [34].By this, it is regarded as non-specific reaction offcorse unless the protein(marker) has a functional cytoplasmic localization [23].On the other hand, synthesize of the protein in any particular cell is a reflection of gene expression in that cell [22].…”

“…The number of FOXP3+ cells present within tumorcell nuclei were counted and scored manually in 10 high-power fields (HPFs; magnification, x400).No nuclear staining cells (0),1-5 cell(+1), 6-19 cell(+2) , 20 and amore cell (+3) according to [31] , lymphocyte infilterating cells were scored as no staining cells(0), 1-25%cells (+1), 26-50% cells(+2), 51-100% cells(+3) according to [23,7]. Cytoplasm FOXP3 expression was scored as no staining Intensity was scored negative staining, low, moderate, and high or strong staining according to deep of brown color of the marker.…”

“…These observations hint are interpretation of previous studies in which T-reg prevalence in tumors was investigated by measuring FOXP3 transcripts in the tumor tissue, as some of these transcripts may have originated from the tumor cells themselves and not from T-reg. Clearly, these explanations raise the possibility of inducing tumor immunogenicity by knocking down FOXP3 expression [21].Unequivocal proof that FOXP3 is expressed both at the protein and transcript protein level by tumour cells of various types (lung cancer, colon cancer, breast cancer, melanoma, erythroidleukemia, acute T-cell leukemia) correlated with the expression levels of TGFb1 and IL-10 [22] .Also the expression of FOXP3 in patients with tumor tissues of breast [23], pancreas [13], ovarian [24],melanoma [25], lung( [26], colorectal [27] oesophageal [28]and gastric cancer [29] have been reported.…”