Abstract

Abstract Background: The transcription factor FOXP3 can regulate T cell migration by inhibiting expression of CXCR4, the receptor for the chemokine CXCL12. Increased expression of CXCR4 by breast cancer cells can drive metastatic migration towards sites which express CXCL12. Intracellular trafficking of FOXP3 to the nucleus is required in order for this protein to function. We hypothesised that FOXP3 gene is inactivated in breast cancer causing failure of nuclear localisation with subsequent increase in CXCR4 and potential for metastasis. Methods: The expression patterns of FOXP3 and CXCR4 were measured at mRNA (PCR, real-time PCR) and protein (immunohistochemistry, immunofluorescence, flow cytometry) levels. A hundred sections of benign breast tissue, cancers, lymph node metastases and seven breast cell lines were examined with traditional and digital microscopy techniques. The results were correlated with pathological and clinical prognostic indicators of breast cancer. Results: “Normal” breast epithelial cells (both patient-derived tissues and laboratory cultured cell lines) expressed FOXP3 in their nuclei and at the same time fail to express CXCR4. Breast cancer cells significantly overexpressed CXCR4 (P<0.05), whereas FOXP3 expression was significantly decreased (P<0.05) and confined to the cytoplasm with negligible nuclear expression [Figure 1]. Metastases expressed significantly less FOXP3 and more CXCR4 than primaries (P<0.05). Transfection of cancer cells with wild-type FOXP3 cDNA expressing plasmid restored physiological nuclear FOXP3 expression. Discussion: We have found failure of FOXP3 nuclear localisation in breast cancer cells and an inverse correlation between this failure and CXCR4 expression [Figure 2]. Increased CXCR4 expression may adversely affect signalling pathways in favour of metastasis. Expression of wild type FOXP3 reverses this suggesting that breast cancer cells have mutations in the FOXP3 gene resulting in cytoplasmic localisation of the protein. Our findings suggest that disruption of FOXP3 nuclear localisation due to dysfunctional FOXP3 transcription factor may be a novel explanation for breast cancer invasion and metastases. Figures available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-05-03.

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