FOXP3 suppresses breast cancer metastasis through downregulation of CD44

Abstract

Forkhead box protein 3 (FOXP3) plays an important role in breast cancer as an X-linked tumor suppressor gene. However, the biological functions and significance of FOXP3 in breast cancer metastasis remain unclear. Here, we find that, clinically, nuclear FOXP3 expression is inversely correlated with breast cancer metastasis. Moreover, we demonstrate that FOXP3 significantly inhibits adhesion, invasion and metastasis of breast cancer cells in vivo and in vitro. In addition, the adhesion molecule CD44 is found to be suppressed by FOXP3 through transcriptome sequence analysis (RNA-seq). A luciferase reporter assay, chromatin immunoprecipitation and electrophoretic mobility shift assay identify CD44 as a direct target of FOXP3. The expression of CD44 is downregulated by FOXP3 in breast cancer cells. Importantly, anti-CD44 antibody reverses the FOXP3 siRNAinduced effects on the breast cancer cells in vitro and FOXP3 expression level in the nucleus of breast cancer cells is inversely correlated with CD44 expression level in clinic breast cancer tissues. Taken together, the results from the present study suggest that FOXP3 is a suppressor of breast cancer metastasis. FOXP3 directly binds to the promoter of CD44 and inhibits its protein expression, thereby suppressing adhesion and invasion of human breast cancer cells. This finding highlights the therapeutic potential of FOXP3-CD44 signaling to inhibit breast cancer metastasis.Breast cancer is the most common female cancer in Western countries, accounting for the second most common cause of cancer-related death in women.1-3 Although recent advances in early diagnosis and treatment options for breast cancer, tumor metastasis still leads to poor survival of the patients.2,4,5 Because metastasis is so crucial in breast cancer prognosis and mortality, more innovative research has been completed to better understand the molecules or mechanisms responsible for metastasis. However, the molecular mechanisms involved in breast cancer metastasis remains to be fully unraveled.FOXP3 is a member of the forkhead/winged helix family of the transcription factors and the mutation in this gene is responsible for X-linked autoimmune diseases in mice (scurfy mice) and humans (Immune dysregulation, polyendopathy, enterophathy, X-linked, IPEX).6-8 Until a few years ago, it was thought that the expression of FOXP3 was restricted to lymphocytes and research focused on defining the functions of FOXP3 in these immune cells. Research indicated that FOXP3 is essential for the development and function of CD4 1 CD25 1 regulatory T cells (Treg). 9-12 However, it has been discovered recently that FOXP3 is also expressed in epithelial cells of the normal human breast, 13-15 ovary, 16 lung 17 and prostate. 18 Aggressive cancer of these epithelial tissues often correlates with abnormal expression of FOXP3, which can be either absent or reduced at the transcript and protein level. 13,16,18 It is becoming clear that FOXP3 can play an important role in controlling the expression of numerous genes involved in...

Intratumoral FoxP3 expression is associated with angiogenesis and prognosis in malignant canine mammary tumors

“…In human studies increased numbers of Treg cells have been associated with tumor aggressiveness and poor survival in many solid tumors, (Griffiths et al, 2007;Wolf et al, 2003) including breast cancer (Bates et al, 2006;Gao et al, 2015;Zhu et al, 2015).…”

“…However, in breast tumors some groups have showed the association of Treg cells with good clinical outcome, (Zhang et al, 2015) highlighting the complexity of Tregs as a biomarker.…”

Critical Role of a Novel Biological Marker GALNT14 Expression in Different Cancer Types

“…Tumor metastasis of breast cancer stil significantly reduces survival [9]. One of the proteins that cause metastasis is the GALNT family.…”

Hydroquinone-induced FOXP3-ADAM17-Lyn-Akt-p21 signaling axis promotes malignant progression of human leukemia U937 cells

“…1e, f). Previous studies revealed that FOXP3 overexpression induced apoptosis of glioma, breast, prostate, and ovarian cancer (Zuo et al 2007a, b;Zhang and Sun 2010;Frattini et al 2012;Douglass et al 2014;Zhang et al 2015;Liu et al 2015a, b). Nevertheless, under serum deprivation, the number of apoptotic U937 cells was higher than that of U937/HQ cells (Fig.…”

“…FOXP3 expression in breast cancer, colorectal cancer, and non-small cell lung cancer is found to be associated with poor overall survival (Merlo et al 2009;Dimitrakopoulos et al 2011;Kim et al 2013). In contrast, some in vitro and in vivo studies suggest that FOXP3 functions as a tumor suppressor in breast cancer, prostate cancer, ovarian cancer, and glioblastoma (Zuo et al 2007a, b;Zhang and Sun 2010;Frattini et al 2012;Douglass et al 2014;Zhang et al 2015;Liu et al 2015a, b). Although Tan et al (2014) reported that overexpression of FOXP3 inhibits proliferation and induces apoptosis in melanoma cells, they suggested that tight regulation of FOXP3 expression should balance its effect on tumor growth and immune escape in melanoma.…”