Wilms’ tumor susceptibility: possible involvement of FOXP3 and CXCL12 genes
© The Author(s). 2016
Received: 8 August 2016
Accepted: 18 October 2016
Published: 10 November 2016
Wilms’ tumor is an embryonal neoplasm of the kidney that accounts for approximately 6 % of all childhood tumors. The chemokine CXCL12 (C-X-C chemokine ligand 12) and its ligand CXCR4 (C-X-C chemokine receptor type 4) are involved in the development of several organs, including the kidney, and are also associated with tumor growth and metastasis. FOXP3 (forkhead transcription factor 3) was initially described as a marker for regulatory T cells; however, its expression in several types of tumor cells has already been described and may have prognostic significance. The aim of the present study was to analyze rs3761548 and rs2232365 FOXP3 polymorphisms, as well as evaluate rs1801157 CXCL12 polymorphism in Wilms’ tumor samples.
Polymorphisms were evaluated in 32 patients and 78 neoplasia-free controls. Genotypes of rs1801157 were determined using PCR-restriction fragment length polymorphism (PCR-RFLP) method, and genotypes of rs2232365 and rs3761548 were determined using allele-specific PCR (AS-PCR).
The case-control study indicated a significant association for allele A carriers of rs1801157 polymorphism in relation to Wilms’ tumor susceptibility (OR = 5.261; 95 % CI 2.156 to 12.84; p = 0.0002). The opposite was observed in male carriers of G allele for rs2232365 polymorphism (OR 0.1164; 95 % CI 0.0227 to 0.5954; p = 0.0091) or when male and female subjects were analyzed (OR = 0.1304; 95 % CI 0.05013 to 0.3394; p < 0.0001).
All in all, these markers may contribute to this neoplasia susceptibility and progression; however, further studies are needed to real clarify their role in Wilms’ tumor pathogenesis.
KeywordsWilms’ tumor FOXP3 CXCL12 Genetic polymorphism
Childhood cancers differ from adult malignant neoplasia in several aspects, such as in primary and histological origins and, also, in clinical outcomes, suggesting they have to be studied independently from adult cancer . Besides, their early onset suggest a low exposition to risk factors, indicating that genetic alterations may have major influences in childhood tumor development .
The Wilms’ tumor (WT) develops from nephroblastic remnants, and it is characterized as an embryonal tumor, composed of persistent blastema, dysplastic tubules, and supporting mesenchyme or stroma . It accounts for approximately 6 % of all childhood tumors , and its incidence corresponds to 1 in 10,000 children. The majority of WT are usually unilateral and sporadic, with only 1 % considered hereditary .
The tumor microenvironment is composed of neoplastic and stromal cells and a great number of immune cells. Interactions among tumor microenvironment components are an emerging issue in tumor progression, influencing growth, invasiveness, and metastatic process . Understanding these complex networks is extremely important for prognostic markers discovery and development of new therapeutic strategies .
Chemokines play a major role in several homeostatic , pathological , and developmental processes . Among them, C-X-C chemokine ligand 12 (CXCL12) and its receptor C-X-C chemokine receptor type 4 (CXCR4) seem to be involved in the development of several organs [11, 12], including kidney , and they are also related to tumor growth  and metastatic process in many types of cancer . Some authors have investigated polymorphisms of CXCL12 in disease pathogenesis, including cancer,  but its value as a susceptibility marker is not well determined.
The forkhead box protein 3 (FOXP3) is a transcription factor that has a fundamental role on the regulation and development of the immune system [17, 18]. Although it was first described as restricted to hematopoietic lineages, recent studies have shown FOXP3 expression in several tissues, including tumor cells [19–21], and it has also been suggested a nuclear or cytoplasmic localization, which can be related with patient prognosis .
Genetic analysis of some diseases like psoriasis  and breast cancer  showed significant association with the single nucleotide polymorphisms (SNP) rs3761548 (−3279 C/A) and rs2232365 (−924 A/G) of FOXP3 gene . The study of these allelic variants can elucidate the role of such polymorphisms in several pathologies, including cancer, concerning to susceptibility, and prognosis.
Recently, a crosstalk between FOXP3 and CXCR4 has been described by Douglass et al. . They demonstrated that downregulated FOXP3 cells have increased CXCR4 expression, and their migration toward CXCL12 gradient is higher when compared with cells who expressed higher FOXP3 levels.
The present study aimed to analyze two polymorphisms in FOXP3 and one polymorphism in CXCL12 in WT samples, in a search for new possible molecular markers to this childhood neoplasia.
A total of 32 paraffin-embedded samples containing normal and tumor tissues was obtained at University Hospital of the State University of Londrina, Londrina, Paraná, Brazil. Clinical data presented (age, tumor size, and gender) were obtained from clinical pathological reports. For control group, blood samples from 78 neoplasia-free individuals were collected at the same region, with an informed consent signed by their parents. This study was conducted following approval from the Human Ethics Committee of State University of Londrina (CEP/UEL 189/2013 – CAAE 17123113400005231), which was in compliance with the declaration of Helsinki.
Genomic DNA was isolated from formalin-fixed paraffin-embedded samples, according to innuPREP DNA Mini Kit (Analytik Jena AG, Jena, Germany) protocol, following manufacturer’s instructions. For neoplasia-free control group, DNA was obtained from peripheral blood white cells using the extraction kit Mini Spin (Biometrix, Curitiba, PR, Brazil), according to manufacturer’s instructions. All DNA samples were quantified in NanoDrop 2000® (NanoDrop Technologies, Wilmington, DE, USA).
Genotyping of CXCL12 and FOXP3 polymorphisms
Primer sequences of FOXP3 and CXCL12 genes
Allele A 334 bp
Allele C 333 bp
Allele A 442 bp
Allele G 427 bp
AS-PCR for FOXP3 polymorphisms were confirmed by randomly sequencing in 15 % of the samples. After amplification, PCR products were purified using PureLink™ PCR Purification Kit (Invitrogen), following manufacturer instructions. The sequencing reaction was performed using BigDye® Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems®, Foster City, CA, USA), 50 ng of DNA template and 5 ρM of primer (forward or reverse) in a final volume of 10 μl. PCR conditions were as follows: 5 min denaturing at 95 °C, 30 cycles of 20 s at 95 °C, 20 s at 50 °C, and 1 min at 60 °C. The amplicons were sequenced in a 24-capillary 3500xl Genetic Analyzer (Applied Biosystems).
Case-control study association was assessed through odds ratio (OR) analysis, adopting 95 % confidence interval (CI), and Fisher’s exact test, performed using Prism 6 for Windows (GraphPad Software, San Diego, CA, USA). Since FOXP3 gene in humans is located in the p-arm of the X-chromosome at Xp.11.23, polymorphism analysis was performed separately for genders. p value <0.05 was considered statistically significant.
This retrospective study evaluated 32 tissue samples of pathologically confirmed patients diagnosed with WT between January 1990 and December 2013. The mean age at diagnosis was 45 months (range 1 year–13 years), and more than 76 % of cases diagnosed before the age of 5 years old, which is in accordance with literature data .
Nineteen (59.37 %) tumoral tissues were obtained from female patients and 13 (40.63 %) were from male patients. Information regarding tumor size was recovered from 25 (78.12 %) samples, once records available through the hospital were not necessarily historically complete or present. This parameter ranged from 6 to 20.5 cm, with an average of 8 cm, which was used to perform the analysis in relation to genetic variants. From 25 samples, seven (28 %) had tumor size less than or equal to 8 cm and 18 (72 %) had tumor size larger than 8 cm.
Histopathological parameters of Wilms’ tumor samples
Lymph node involvement
Considering WT histology, ten samples were classified as blastemal, six samples presented mixed type, four samples were epithelial, and two monophasic tumors (cells with vesicular nuclei, visible nucleoli, and acidic cytoplasm). It has not been possible to obtain ten samples data regarding tumor histological classification. The preoperative chemotherapy was used in four samples.
In the control group, children and adolescents (age average 12 years old) were included according to negative hematological, biochemical, and serological tests for infectious or chronic diseases and consisted of 37 (47.4 %) females and 41 (52.6 %) males.
CXCL12 genetic polymorphism
The genotype frequency observed for CXCL12 polymorphism for WT patients and controls is represented in Fig. 1c, in which 78 % (22/32) are carriers of the variant allele A. The case-control study indicated a strong positive association of more than fivefold, for A allele carriers, with WT susceptibility (p = 0.0002) (Fig. 1d).
FOXP3 genetic polymorphisms
In this work, no significant association was observed for AA homozygotes or A allele carriers in relation to WT susceptibility (p > 0.05; Fig. 2c). Moreover, A allelic frequency of rs3761548 was higher in WT patients (62.5 %) than in the control group (58.97 %).
The case-control study indicated that G allele carriers of FOXP3 polymorphism rs2232365 were negatively associated with WT susceptibility, comparing male individuals (OR 0.1164; 95 % CI 0.0227 to 0.5954; p = 0.0091), and when male and female subjects were analyzed together (OR = 0.1304; 95 % CI 0.05013 to 0.3394; p < 0.0001) (Fig. 3c).
Studies have shown that WT cells express markers of early kidney development [28, 29]. In addition, several studies have highlighted the presence and importance of CXCL12 and CXCR4 during kidney maturation [13, 30–32]. In this context, genotype frequencies of CXCL12 polymorphism rs1801157 have been investigated in order to address its possible role in tumor pathogenesis in different conditions, including acute lymphoblastic leukemia , chronic myelogenous leukemia , breast cancer [34, 35], and Hodgkin’s lymphoma and non-Hodgkin’s lymphoma . However, there was no study in literature indicating the frequency of this polymorphism in WT patients. In the present case-control study, it was verified a strong positive association for A allele carriers and WT susceptibility (Fig. 1).
Polymorphisms in regulatory regions can change protein expression and may be associated with susceptibility to certain diseases . In fact, the rs1801157 polymorphism is located at a regulatory region of CXCL12; however, there are conflicting results about the influence of this polymorphism in protein expression. Some studies have shown that A allele carriers have increased CXCL12 protein levels [27, 36]; on the other hand, de Oliveira et al.  observed that A allele carriers had low levels of CXCL12 messenger RNA (mRNA) compared to GG genotype.
These contrast CXCL12 expression patterns might represent different techniques (serum ELISA, mRNA expression, blot analysis) or biological samples tested (peripheral blood, cultured cells). Moreover, prospective studies should be developed in order to provide rational conclusions on how CXCL12 rs1801157 genotypes would influence gene transcription and/or translation.
It is known that spatial and temporal relationship between CXCL12- and CXCR4-positive cells are required for a regular kidney development . In light of our results, the authors would suggest that A allele carriers, which may express altered CXCL12 levels, could be more susceptible to kidney development disruption.
FOXP3 is an X-linked gene that encodes a transcription factor, which is essential in CD4+CD25+FOXP3 regulatory T (Treg) cells . Treg cells may contribute to tumorigenesis by suppressing immune responses from host, and mutations of this gene have already been reported in cancer patients . To date, there are no studies investigating FOXP3 polymorphisms in WT patients. Regarding the abovementioned, investigation of possible association of FOXP3 genetic variants in WT may shed light on the molecular pathogenesis of this neoplasia, opening up new paths to screening susceptible individuals.
Although AA homozygotes for rs3761548 FOXP3 polymorphism have been considered susceptible to breast neoplasia , no significant association was observed for AA homozygotes or A allele carriers in relation to WT susceptibility (Fig. 2c). Furthermore, allelic distribution of rs3761548 A allele in WT patients was slightly different from that in the control group. Concerning FOXP3 rs2232365 polymorphism, the case-control study indicated that G allele is negatively associated with WT susceptibility in male individuals and when males and females subjects were analyzed together (Fig. 3c).
The FOXP3 rs2232365 polymorphism is located within a putative DNA-binding site of another transcription factor, GATA-3, that directly regulates FOXP3 expression, in addition to controlling Treg cell function via interaction with the regulatory regions of the FOXP3 locus. GATA-3 is essential to Th2 immune response  and can only bind the FOXP3 promoter region if the A allele is present . The GG genotype of rs2232365 was observed to decrease FOXP3 expression, affecting Treg cell function by disruption of the Th1/Th2 balance . Conventionally, Th2-mediated immunity has been considered to favor tumor growth, by promoting angiogenesis as well inhibiting cell-mediated immunity and tumor cell killing [41, 42]. Hence, we inferred that high frequencies of G allele might affect Treg function and decrease Th2 immune response, leading to a protective effect against tumor development.
FOXP3 transcription factor has different expression patterns in a great variety of cell types, and its role in cancer remains unclear. Nowadays, it is well established that this protein can be expressed by different cell types, aside from its expression in Tregs, which include normal  and tumor [20, 43] cells. Studies have supported that FOXP3 protein also has different roles, acting as a tumor suppressor protein , or as evading mechanisms for tumors, when expressed by Tregs . In breast cancer, the FOXP3 has been described as a transcriptional repressor of genes involved in tumor development, like HER2 and SKP2 , and also in cancer progression, like CXCR4 .
Notwithstanding, AA homozygous samples for rs3761548 and rs2232365 of FOXP3 polymorphisms, considered variant and ancestral genotypes, respectively, presented larger tumor size (>8 cm). This could suggest that certain genotypes of FOXP3 gene might contribute, in some way, to disease prognosis.
In another study , the variant genotype AA of FOXP3 was also positively associated with tumor size, in triple negative breast cancer. Taken together, these results may indicate a role for this marker in cancer progression, raising new possibilities for research, targeting FOXP3.
In conclusion, the present study demonstrated that FOXP3 rs2232365 is negatively and CXCL12 rs1801157 is positively associated with WT susceptibility. Although the number of WT patients in this case-control study was small, the incidence of this cancer is relatively rare in population. Thus, this study demonstrated, for the first time, an association between FOXP3 and CXCL12 genetic polymorphisms with this cancer, demonstrating that these markers are, somehow, involved in WT pathogenesis. Further studies are needed to define the precise roles in this process.
C-X-C chemokine ligand 12
C-X-C chemokine receptor type 4
Forkhead box protein 3
Polymerase chain reaction
PCR-restriction fragment length polymorphism
Single nucleotide polymorphisms
Regulatory T cell
The authors would like to acknowledge Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação Araucária do Paraná, Secretaria da Ciência, Tecnologia e Ensino Superior (SETI), Fundo Estadual para a Infância e Adolescência (FIA/PR), Secretaria da Família e Desenvolvimento Social (SEDS), and Pró reitoria de Pós-Graduação da Universidade Estadual de Londrina (PROPPG-UEL).
PMMO collected the samples, performed the PCR-RFLP and AS-PCR, analyzed the results, and wrote the manuscript. CBA collected the samples, performed the statistical analysis, and wrote the manuscript. RLG, ALG, CECO, and MOK interpreted the clinical data and contributed to the writing of the manuscript. BKBH and DLP performed the PCR-RFLP and AS-PCR and wrote the manuscript. MAEW, an advisor, designed the structure of the manuscript, supervised the details, and wrote the final version of the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Informed consent was obtained from all parents of individuals included in the control group of this study.
The protocol was approved by the Institutional Human Research Ethics Committee of the State University of Londrina, Paraná, Brazil (n°.171231134.0000.5231).
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
- Malkin D (1997) Cancer of childhood. In: Vita VT Jr, Hellman S, Rosenberg SA (eds) Cancer: principles and practice of oncology, 5th edn. Lippincott-Raven, New YorkGoogle Scholar
- Davidoff AM (2012) Wilms tumor. Adv Pediatr 59:247–267. doi:10.1016/j.yapd.2012.04.001 View ArticlePubMedPubMed CentralGoogle Scholar
- Beckwith JB (1994) Renal pathology with clinical and functional correlations. J B. Lippincott Company, PhiladelphiaGoogle Scholar
- Ries L, Eisner M, Kosary C, Hankey B, Miller B, Clegg L et al (2004) SEER cancer statistics review, 1975-2001. National Cancer Institute, Bethesda, http://seer.cancer.gov/csr/1975_2001/ Google Scholar
- Breslow NE, Beckwith JB, Perlman EJ, Reeve AE (2006) Age distributions, birth weights, nephrogenic rests, and heterogeneity in the pathogenesis of Wilms tumor. Pediatr Blood Cancer 47:260–267. doi:10.1002/pbc.20891 View ArticlePubMedPubMed CentralGoogle Scholar
- Yaqub S, Aandahl EM (2009) Inflammation versus adaptive immunity in cancer pathogenesis. Crit Rev Oncog 15:43–63View ArticlePubMedGoogle Scholar
- Fridman WH, Galon J, Dieu-Nosjean MC, Cremer I, Fisson S, Damotte D et al (2011) Immune infiltration in human cancer: prognostic significance and disease control. Curr Top Microbiol Immunol 344:1–24. doi:10.1007/82_2010_46 PubMedGoogle Scholar
- Viola A, Luster AD (2008) Chemokines and their receptors: drug targets in immunity and inflammation. Annu Rev Pharmacol Toxicol 48:171–197. doi:10.1146/annurev.pharmtox.48.121806.154841 View ArticlePubMedGoogle Scholar
- Balkwill F (2003) Chemokine biology in cancer. Semin Immunol 15:49–55View ArticlePubMedGoogle Scholar
- Klein RS, Rubin JB, Gibson HD, DeHaan EN, Alvarez-Hernandez X, Segal RA et al (2001) SDF-1 alpha induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells. Development 128:1971–1981PubMedGoogle Scholar
- Nagasawa T, Tachibana K, Kishimoto T (1998) A novel CXC chemokine PBSF/SDF-1 and its receptor CXCR4: their functions in development, hematopoiesis and HIV infection. Semin Immunol 10:179–185. doi:10.1006/smim.1998.0128 View ArticlePubMedGoogle Scholar
- Salcedo R, Oppenheim JJ (2003) Role of chemokines in angiogenesis: CXCL12/SDF-1 and CXCR4 interaction, a key regulator of endothelial cell responses. Microcirculation 10:359–370. doi:10.1038/sj.mn.7800200 View ArticlePubMedGoogle Scholar
- Takabatake Y, Sugiyama T, Kohara H, Matsusaka T, Kurihara H, Koni PA et al (2009) The CXCL12 (SDF-1)/CXCR4 axis is essential for the development of renal vasculature. J Am Soc Nephrol 20:1714–1723. doi:10.1681/ASN.2008060640 View ArticlePubMedPubMed CentralGoogle Scholar
- Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R et al (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121:335–348. doi:10.1016/j.cell.2005.02.034 View ArticlePubMedGoogle Scholar
- Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME et al (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56. doi:10.1038/35065016 View ArticlePubMedGoogle Scholar
- de Lourdes PA, Guembarovski RL, Oda JM, Lopes LF, Ariza CB, Amarante MK et al (2013) CXCL12 and TP53 genetic polymorphisms as markers of susceptibility in a Brazilian children population with acute lymphoblastic leukemia (ALL). Mol Biol Rep 40:4591–4596. doi:10.1007/s11033-013-2551-1 View ArticleGoogle Scholar
- Coffer PJ, Burgering BM (2004) Forkhead-box transcription factors and their role in the immune system. Nat Rev Immunol 4:889–899. doi:10.1038/nri1488 View ArticlePubMedGoogle Scholar
- Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061. doi:10.1126/science.1079490 View ArticlePubMedGoogle Scholar
- Ebert LM, Tan BS, Browning J, Svobodova S, Russell SE, Kirkpatrick N et al (2008) The regulatory T cell-associated transcription factor FoxP3 is expressed by tumor cells. Cancer Res 68:3001–3009. doi:10.1158/0008-5472.CAN-07-5664 View ArticlePubMedGoogle Scholar
- Karanikas V, Speletas M, Zamanakou M, Kalala F, Loules G, Kerenidi T et al (2008) Foxp3 expression in human cancer cells. J Transl Med 6:19. doi:10.1186/1479-5876-6-19 View ArticlePubMedPubMed CentralGoogle Scholar
- Zuo T, Wang L, Morrison C, Chang X, Zhang H, Li W et al (2007) FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell 129:1275–1286. doi:10.1016/j.cell.2007.04.034 View ArticlePubMedPubMed CentralGoogle Scholar
- Takenaka M, Seki N, Toh U, Hattori S, Kawahara A, Yamaguchi T et al (2013) FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes is associated with breast cancer prognosis. Mol Clin Oncol 1:625–632. doi:10.3892/mco.2013.107 PubMedPubMed CentralGoogle Scholar
- Gao L, Li K, Li F, Li H, Liu L, Wang L et al (2010) Polymorphisms in the FOXP3 gene in Han Chinese psoriasis patients. J Dermatol Sci 57:51–56. doi:10.1016/j.jdermsci.2009.09.010 View ArticlePubMedGoogle Scholar
- Lopes LF, Guembarovski RL, Guembarovski AL, Kishima MO, Campos CZ, Oda JM et al (2014) FOXP3 transcription factor: a candidate marker for susceptibility and prognosis in triple negative breast cancer. Biomed Res Int 2014:341654. doi:10.1155/2014/341654 PubMedGoogle Scholar
- Song P, Wang XW, Li HX, Li K, Liu L, Wei C et al (2013) Association between FOXP3 polymorphisms and vitiligo in a Han Chinese population. Br J Dermatol 169:571–578. doi:10.1111/bjd.12377 View ArticlePubMedGoogle Scholar
- Douglass S, Meeson AP, Overbeck-Zubrzycka D, Brain JG, Bennett MR, Lamb CA et al (2014) Breast cancer metastasis: demonstration that FOXP3 regulates CXCR4 expression and the response to CXCL12. J Pathol 234:74–85. doi:10.1002/path.4381 View ArticlePubMedGoogle Scholar
- Winkler C, Modi W, Smith MW, Nelson GW, Wu X, Carrington M et al (1998) Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE Study, Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC). Science 279:389–393View ArticlePubMedGoogle Scholar
- Li CM, Guo M, Borczuk A, Powell CA, Wei M, Thaker HM et al (2002) Gene expression in Wilms’ tumor mimics the earliest committed stage in the metanephric mesenchymal-epithelial transition. Am J Pathol 160:2181–2190. doi:10.1016/S0002-9440(10)61166-2 View ArticlePubMedPubMed CentralGoogle Scholar
- Li W, Kessler P, Williams BR (2005) Transcript profiling of Wilms tumors reveals connections to kidney morphogenesis and expression patterns associated with anaplasia. Oncogene 24:457–468. doi:10.1038/sj.onc.1208228 View ArticlePubMedGoogle Scholar
- Ueland J, Yuan A, Marlier A, Gallagher AR, Karihaloo A (2009) A novel role for the chemokine receptor Cxcr4 in kidney morphogenesis: an in vitro study. Dev Dyn 238:1083–1091. doi:10.1002/dvdy.21943 View ArticlePubMedGoogle Scholar
- Grone HJ, Cohen CD, Grone E, Schmidt C, Kretzler M, Schlondorff D et al (2002) Spatial and temporally restricted expression of chemokines and chemokine receptors in the developing human kidney. J Am Soc Nephrol 13:957–967PubMedGoogle Scholar
- Ding M, Cui S, Li C, Jothy S, Haase V, Steer BM et al (2006) Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice. Nat Med 12:1081–1087. doi:10.1038/nm1460 View ArticlePubMedGoogle Scholar
- de Oliveira CE, Cavassin GG, Perim Ade L, Nasser TF, de Oliveira KB, Fungaro MH et al (2007) Stromal cell-derived factor-1 chemokine gene variant in blood donors and chronic myelogenous leukemia patients. J Clin Lab Anal 21:49–54. doi:10.1002/jcla.20142 View ArticlePubMedGoogle Scholar
- de Oliveira KB, Guembarovski RL, Guembarovski AM, da Silva do Amaral Herrera AC, Sobrinho WJ, Ariza CB et al (2013) CXCL12, CXCR4 and IFNgamma genes expression: implications for proinflammatory microenvironment of breast cancer. Clin Exp Med 13:211–219. doi:10.1007/s10238-012-0194-5 View ArticlePubMedGoogle Scholar
- de Oliveira KB, Oda JM, Voltarelli JC, Nasser TF, Ono MA, Fujita TC et al (2009) CXCL12 rs1801157 polymorphism in patients with breast cancer, Hodgkin’s lymphoma, and non-Hodgkin’s lymphoma. J Clin Lab Anal 23:387–393. doi:10.1002/jcla.20346 View ArticlePubMedGoogle Scholar
- Hirata H, Hinoda Y, Kikuno N, Kawamoto K, Dahiya AV, Suehiro Y et al (2007) CXCL12 G801A polymorphism is a risk factor for sporadic prostate cancer susceptibility. Clin Cancer Res 13:5056–5062. doi:10.1158/1078-0432.CCR-07-0859 View ArticlePubMedGoogle Scholar
- Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336, http://www.nature.com/ni/journal/v4/n4/suppinfo/ni904_S1.html View ArticlePubMedGoogle Scholar
- Li W, Wang L, Katoh H, Liu R, Zheng P, Liu Y (2011) Identification of a tumor suppressor relay between the FOXP3 and the Hippo pathways in breast and prostate cancers. Cancer Res 71:2162–2171. doi:10.1158/0008-5472.can-10-3268 View ArticlePubMedPubMed CentralGoogle Scholar
- Zhu J, Yamane H, Cote-Sierra J, Guo L, Paul WE (2006) GATA-3 promotes Th2 responses through three different mechanisms: induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell-specific factors. Cell Res 16:3–10View ArticlePubMedGoogle Scholar
- Wu Z, You Z, Zhang C, Li Z, Su X, Zhang X et al (2012) Association between functional polymorphisms of Foxp3 gene and the occurrence of unexplained recurrent spontaneous abortion in a Chinese Han population. Clin Dev Immunol 2012:896458. doi:10.1155/2012/896458 PubMedGoogle Scholar
- DeNardo DG, Coussens LM (2007) Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. Breast Cancer Res 9:212–222. doi:10.1186/bcr1746 View ArticlePubMedPubMed CentralGoogle Scholar
- Ellyard JI, Simson L, Parish CR (2007) Th2-mediated anti-tumour immunity: friend or foe? Tissue Antigens 70:1–11. doi:10.1111/j.1399-0039.2007.00869.x View ArticlePubMedGoogle Scholar
- Hinz S, Pagerols-Raluy L, Oberg HH, Ammerpohl O, Grussel S, Sipos B et al (2007) Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Cancer Res 67:8344–8350. doi:10.1158/0008-5472.CAN-06-3304 View ArticlePubMedGoogle Scholar
- Zou W (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6:295–307. doi:10.1038/nri1806 View ArticlePubMedGoogle Scholar