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|Title:||FOXP3 regulates metastatic spread of breast cancer via control of expression of CXCR4 chemokine receptor|
|Abstract:||The FOXP3 transcription factor can regulate T cell migration by inhibiting expression of CXCR4, the receptor for the chemokine CXCL12. The increased expression of CXCR4 by breast cancer cells can drive metastatic migration towards sites that express CXCL12. Intracellular trafficking of FOXP3 to the nucleus is required in order for this factor to function. The presence of alternative splicing forms, mutations and post-translationally modified forms may disrupt FOXP3 nuclear localization. We hypothesised that FOXP3 tumour suppressor is inactive in breast cancer causing an increase in CXCR4 expression and the development of metastasis. The expression of FOXP3 and CXCR4 were measured at mRNA and protein (immunohistochemistry, immunofluorescence, FACS) levels. FOXP3 DNA sequences of normal and cancer cells were analysed. Stable FOXP3 overexpressing breast cancer transfectants were used to investigate the potential of FOXP3 to regulate chemotaxis. Normal breast epithelial cells (both patient-derived tissues and laboratory cultured cell lines) expressed FOXP3 in their nuclei but did not express CXCR4. Breast cancer cells overexpressed CXCR4 (p<0.05), whereas FOXP3 expression was decreased (p<0.05) and confined to the cytoplasm with negligible nuclear expression. Metastases expressed less FOXP3 and more CXCR4 than primary cancers (p<0.05). FOXP3 sequencing in breast cancer cell lines did not reveal mutations. However, there were at least three bands on the PCR electrophoreses gel. The predominant form in breast cancer cells contained an insertion of 120bp within the forkhead domain. Transfection of breast cancer cells with wild-type FOXP3 restored its nuclear expression, reduced CXCR4 expression and inhibited cell migration. This study demonstrated failure of nuclear localisation of FOXP3 in breast cancer cells and an inverse correlation between this failure and CXCR4 expression. Disruption of FOXP3 nuclear localisation may be due to abnormal co-expression of FOXP3 splice variants leading to increased CXCR4 expression and acquisition of the capacity to metastasize.|
|Appears in Collections:||Institute of Cellular Medicine|
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