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Role of Forkhead Box Protein 3 Expression in Invasive Breast Cancer

Laboratory of Tumorimmunology, Tyrolean Cancer Research Institute; and the Department of Hematology and Oncology, Innsbruck Medical University, Innsbruck, Austria

Holger Rumpold

Laboratory of Tumorimmunology, Tyrolean Cancer Research Institute; Laboratory of Molecular Genetics, Department of Hematology and Oncology; and the Department of Hematology and Oncology, Innsbruck Medical University, Innsbruck, Austria

Dominik Wolf

Laboratory of Tumorimmunology, Tyrolean Cancer Research Institute; and the Department of Hematology and Oncology, Innsbruck Medical University, Innsbruck, Austria

Guenther Gastl

Department of Hematology and Oncology, Innsbruck Medical University, Innsbruck, Austria

Daniel Reimer, Nina Jenewein, Christian Marth, Alain G. Zeimet

Department of Gynecology and Obstetrics, Innsbruck Medical University, Innsbruck, Austria

To the Editor:

In their report recently published in the Journal of Clinical Oncology, Bates et al¹ identified high regulatory T-cell (Treg) numbers as an important risk factor for inferior relapse-free and overall survival in breast cancer patients. The authors suggest that forkhead box protein 3 (FOXP3)–positive Treg might represent a novel marker to identify patients at risk of late relapse who may benefit from more intensified treatment. The number of FOXP3-positive cells was quantified by means of time consuming immunohistochemistry, the interpretation of which very much depends on the experience of the pathologist. We analyzed FOXP3 mRNA expression by real-time polymerase chain reaction, which has recently been shown to identify ovarian cancer patients with poor outcome² from a total of 116 breast cancer samples (86 invasive ductal, 19 invasive lobular, four mucinous, three medullary, one invasive tubular, one squamous cell carcinoma, one lymphangiosis carcinomatosa and one cystosarcoma phylloides). Ten patients were classified as stage I, 74 as stage II (30 IIA; 44 IIB), 12 as stage III (eight IIIA; four IIIB), and six as stage IV (in 14 patients stages were not classifiable). Sixty-five patients received radiation therapy and 67 received chemotherapy. The median observation period was 96.6 months (range, 7 to 191 months). A plasmid standard for absolute quantification of FOXP3 transcripts was applied. The cutoff value for FOXP3 high and low expression was defined as the mean value of FOXP3 expression in the entire patient cohort. A significant correlation between FOXP3 expression and the appearance of lymph node metastases was observed in the whole patient group (P = .03; FOXP3 as continuous variable). However, we did not find any significant correlation of FOXP3 expression with other important clinical variables, such as tumor grade (P = .13), stage (P = .9), or size (P = .4), appearance of distant metastases (P = .4), menopausal status (P = .3), or expression of hormone receptors (estrogen receptor: n = 83; P = .14; progesterone receptor: n = 74; P = .11). Interestingly, we observed a clear trend (albeit not statistically significant; P = .1) for an inferior overall survival in FOXP3 high patients expressing either estrogen or progesterone receptors (Fig 1). Lack of significance was most likely due to limited patient sample number. However, in the hormone receptor–negative group no survival difference between FOXP3 high and FOXP3 low patients was observed. Thus larger prospective studies are needed to validate real-time polymerase chain reaction as standard method for rapid quantification of tissue FOXP3 content. Together with the data reported by Bates and colleagues, our data suggest that FOXP3 expression might indeed represent an important milieu factor in hormone receptor–positive invasive breast cancer via tipping the balance toward a more immunosuppressive milieu. Especially in this patient group, Treg might represent a valuable target for cancer therapy.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. High forkhead box protein 3 (FOXP3) expression is associated with a trend toward inferior overall survival in (A) estrogen (n = 83) and (B) progesterone (n = 73) receptor–positive invasive breast cancer patients. Survival curves are depicted based on expression of FOXP3: the cases were divided into two groups (ie, FOXP3 high and FOXP3 low). P was determined by log-rank test.

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. 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[Abstract/Free Full Text]

2. Wolf D, Wolf AM, Rumpold H, et al: The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin Cancer Res 11:8326-8331, 2005[Abstract/Free Full Text]

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