Abstract A30: FOXP3 regulates metastatic spread of breast cancer via control of expression of CXCR4 chemokine receptor

Overbeck-Zubrzycka, Dorota; Kirby, John A.; Ali, Simi; Lennard, T. W. J.

doi:10.1158/1940-6207.prev-10-a30

Cited by 4 publications

(6 citation statements)

References 216 publications

(433 reference statements)

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“…Therefore, a separate analysis by nuclear and cytoplasmic FOXP3 is required in future studies. A recent report showed that normal breast epithelia expressed nucleus FOXP3 and failed to express CXCR4, whereas diminished levels of nuclear FOXP3 was significantly associated with higher levels of membrane CXCR4 in breast tumors and metastases [60,61]. As supported by evidence in our gene target analysis, FOXP3 can reduce CXCR4 expression in MCF7 cells by more than three-fold [11].…”

Section: Transcriptional Regulation In the Context Of Foxp3supporting

confidence: 83%

“…This phenotype may be caused by either that FOXP3 reduced expression of MMP2 and uPA or that FOXP3 inhibits the activation of mTOR and NF-κB signaling [28] (Figure 2). Likewise, transfection of FOXP3 into the CXCR4 expressed MDA-MB-231 breast cancer cells resulted in a decreased expression of CXCR4, that is a tumor metastatic processassociated protein to promote metastasis in breast cancer [58,59], and the chemotactic response of these cells to a CXCL12 gradient was effectively inhibited [60,61], suggesting a repressive function of tumor metastasis by FOXP3. Recently, we identified that FOXP3 can directly bind the BRCA1 to down-regulates the transcriptional activity of this gene, suggesting that FOXP3 repress the BRCA1-mediated DNA repair program [62] (Figure 2).…”

Section: Transcriptional Regulation In the Context Of Foxp3mentioning

confidence: 99%

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IPEX Syndrome, FOXP3 and Cancer

Liu

Yang

et al. 2013

J Syndr

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In this review, we introduce the IPEX syndrome and its relationship with germline mutations of the FOXP3 gene. We then describe the multiple functional roles of FOXP3 in regulatory T cells and epithelial cells as well as in IPEX syndrome and tumor progression. Potential mechanisms of FOXP3 inactivation and transcriptional regulation are discussed with recent advances. Finally, we point out current issues and a potential FOXP3-mediated therapeutic strategy as well as the reactivation of FOXP3 in patients with IPEX syndrome and cancer. ImmuneDysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) SyndromeIn 1982, Powell and his colleagues first reported an X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in a family of 8 males within 3 generations [1]. Later studies identified that this X-linked syndrome is a rare genetic auto-immune disease called IPEX syndrome, characterized by the development of systemic autoimmune disorders which affect multiple organs, including the intestines, skin, and various endocrine glands/organs [2,3]. The clinical and molecular features of IPEX syndrome include severe diarrhea, diabetes, eczema, erythroderma, psoriasis, and thyroiditis, etc. Most patients with X syndrome are males, typically beginning in the first few months of life and dying within the first one to two years of life from metabolic derangements or sepsis [2,3]. IPEX syndrome is considered to be directly caused by the proliferation of autoaggressive T cells and autoantibody-producing B cells [4]. However, the molecular mechanism for IPEX syndrome has not been fully elucidated. As well as evidenced by genetic analysis, approximately 25% of males with IPEX syndrome have been identified to have germline mutations in an X-linked Forkhead box P3 (FOXP3) gene (Figure 1), which may cause some cases of IPEX syndrome [3,[5][6][7][8].Thus, the role of FOXP3 in the immune system is essential for understanding the molecular mechanism of IPEX syndrome. Mutation of the FOXP3 results in the Dysfunction of Regulatory T Cells (Treg) and Leads to the IPEX SyndromeThe Human FOXP3 gene at Xp11.23 is a member of the forkheadbox/winged-helix transcription factor family. This gene was identified during the positional cloning of Scurfin, and functional loss of this gene causes X-linked autoimmune diseases similar to IPEX syndrome in mice and humans [5][6][7][8]. As a transcription factor, FOXP3 can bind to specific regions of DNA and controls the activation and repression of target genes [9][10][11]. FOXP3 is essential for the maintenance of self-tolerance, the development and normal function of Treg cells, as well as the control off the immune system and the prevention of autoimmune disorders [12]. Inactivating mutations of this gene leads to the absence of Treg cells that can increase activation of T cells and immune responses to multiple self-tissues and organs, causing the multiple autoimmune disorders present in mouse as well as in patients with IPEX syndrome [5,6,8]. In males, one mutant allele of t...

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Section: Transcriptional Regulation In the Context Of Foxp3supporting

confidence: 83%

Section: Transcriptional Regulation In the Context Of Foxp3mentioning

confidence: 99%

IPEX Syndrome, FOXP3 and Cancer

Liu

Yang

et al. 2013

J Syndr

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“…The increased expression of HER2 in turn induced CXCR4 expression, which has been recently reported to play an important role in cancer invasion and metastasis including in breast cancer cells . Another study demonstrated an inverse correlation between diminished expression of FOXP3 and CXCR4 expression . Normal FOXP3 expression and localization inhibited migration of cancer cells toward their metastatic sites expressing CXCR4.…”

Section: Discussionmentioning

confidence: 99%

“…37 Another study demonstrated an inverse correlation between diminished expression of FOXP3 and CXCR4 expression. 38 Normal FOXP3 expression and localization inhibited migration of cancer cells toward their metastatic sites expressing CXCR4. 38 Thus, FOXP3 might regulate chemokine receptor expression through suppression of HER2.…”

Section: Discussionmentioning

confidence: 99%

FOXP3 suppresses breast cancer metastasis through downregulation of CD44

Zhang

Hao

et al. 2015

Int. J. Cancer

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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...

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“…Preclinical studies have reported that FOXP3 acts as an X-linked tumor suppressor gene by downregulating HER2/ErbB2 and Skp2 oncogenes and upregulating p21 expression [3,4,5]. FOXP3 is also involved in chemotherapy and radiotherapy sensitivity [6,7], and the metastatic potential of cancer cells by regulating chemokine receptor expression [8]. Although many preclinical studies have demonstrated an important role of FOXP3 in the pathogenesis of breast cancer, the prevalence and clinical indications of FOXP3 expression in breast cancer cells are not yet clearly defined.…”

Section: Introductionmentioning

confidence: 99%

FOXP3 Expression Is Related to High Ki-67 Index and Poor Prognosis in Lymph Node-Positive Breast Cancer Patients

Kim¹,

Koo

Lee³

2013

Oncology

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Background: Recent preclinical studies have shown that Forkhead box protein 3 (FOXP3) is an important tumor suppressor gene. The clinical and prognostic implication of FOXP3 expression in breast cancer cells still remains controversial. Methods: We evaluated the FOXP3 expression status of 183 patients who underwent curative surgery for breast cancer using the immunohistochemical assay of tissue microarray. Results: We found FOXP3 expression in 51 out of 183 (27.9%) surgically resected breast cancer tumors, and 33 patients were scored as weak positive and 18 as strong positive. FOXP3-positive tumors were associated with significantly higher nuclear grade, higher histologic grade and a more negative estrogen receptor status. The FOXP3 expression level was independently associated with high Ki-67 index in a logistic regression model. In the node-positive subgroup, strong FOXP3 positivity was related to poor disease-free survival and disease-specific survival compared to FOXP3-negative patients, whereas there was no survival difference between FOXP3-negative and FOXP3-weak-positive patients. Multivariate analysis with adjustment for patient age and human epidermal growth factor receptor 2 status demonstrated significantly poor survival of FOXP3-strong-positive patients in node-positive patients. Conclusion: Our results suggest that strong FOXP3 expression in breast cancer cells is associated with poor prognosis and high Ki-67 index.

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Abstract A30: FOXP3 regulates metastatic spread of breast cancer via control of expression of CXCR4 chemokine receptor

Cited by 4 publications

References 216 publications

IPEX Syndrome, FOXP3 and Cancer

IPEX Syndrome, FOXP3 and Cancer

FOXP3 suppresses breast cancer metastasis through downregulation of CD44

FOXP3 Expression Is Related to High Ki-67 Index and Poor Prognosis in Lymph Node-Positive Breast Cancer Patients

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