Breast cancer metastasis: demonstration that FOXP3 regulates CXCR4 expression and the response to CXCL12

Abstract

The X-linked transcription factor FOXP3 is expressed by epithelial cells of organs including the breast, where it is considered a tumour suppressor. The chemokine receptor CXCR4 also regulates the development of breast cancer by stimulating cell migration towards CXCL12-expressing sites of metastatic spread. During activation, human T cells show reciprocal regulation of FOXP3 and CXCR4. This study was designed to examine the role FOXP3 plays in metastatic breast cancer, with a particular focus on its potential to regulate CXCR4. Human breast cancer samples showed significantly decreased FOXP3 protein expression but an increased number of CXCR4 transcripts. In comparison with normal primary breast epithelial cells, FOXP3 was down-regulated at both transcript and protein levels in the breast cancer cell lines MCF-7 and MDA-MB-231. In the invasive MDA-MB-231 cells, the remaining FOXP3 was located predominately within the cytoplasm. Following stable FOXP3 overexpression in MDA-MB-231 cells, significant decreases were observed in the expression of ErbB2/HER2, SKP2, c-MYC, and CXCR4. In contrast, an increase in p21 expression led to inhibition of cell proliferation, with a greater proportion in the G1 phase of the cell cycle suggesting the induction of senescence. Specific knockdown of FOXP3 in normal human breast epithelial cells with siRNA significantly increased ErbB2/HER2, SKP2, c-MYC, and CXCR4, and decreased p21 expression. These cells also showed a significantly increased chemotactic response towards CXCL12, consistent with a role for FOXP3 in the regulation of cell migration. Results from this study are consistent with FOXP3 functioning as an important tumour suppressor in breast cancer. Indeed, the potential functions of FOXP3 in breast epithelium can now be extended to include regulation of CXCR4 expression and response to the pro-metastatic chemokine CXCL12.

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

“…In contrast, specific knockdown of FOXP3 in normal breast epithelial cells increased HER2, SKP2, c-MYC and CXCR4 expression (37). These results suggest FOXP3 functions as a tumor suppressor in BC.…”

“…The subcellular location of a protein is related to function especially in the case of FOXP3, which as a transcription factor originally was believed to be limited to a nuclear location (37). In tumor cells, cytoplasmic localization has been explained by failure in translocation to the nucleus (35,38).…”

The Role of Tumoral FOXP3 on Cell Proliferation, Migration, and Invasion in Gastric Cancer

“…Previous studies indicated that FOXP3 can reduce the migratory and invasive capacity of malignant ovarian cells by downregulating MMP-2 and uPA, as well as mTOR and NF-κB [15]. Another study in breast cancer showed that FOXP3 may regulate cancer invasion and metastasis by regulating the expression of chemokine receptors, such as CXCR4 [40, 41]. A study in gastric cancer revealed that FOXP3 is a tumor-suppressor that inhibits NFκB activity, and thereby inhibits COX2 expression [29].…”

Exosome secretion promotes chemotaxis of cancer cells

“…26 Another example is metastasis of breast cancer cells to the lung, driven by SDF-1 and its receptor CXC chemokine receptor 4 (CXCR4). [27][28][29] Recently, exosome secretion was shown to enhance chemotaxis of neutrophils and macrophages. 21,30,31 However, the role of exosome secretion in cancer cell chemotaxis is unknown.…”