The Expression Landscape of FOXP3 and Its Prognostic Value in Breast Cancer

Overview

Journal Ann Transl Med

Publisher AME Publishing Company

Date 2022 Aug 15

PMID 35965804

Authors

Jingping Li

Xiangmei Zhang

Beichen Liu

Chao Shi

Xindi Ma

Shuguang Ren

Xiaohan Zhao

Yunjiang Liu

Affiliations

Soon will be listed here.

Abstract

Background: Forkhead Box Protein 3 (FOXP3), as an essential marker of regulatory T cell (Treg) development, is reportedly overexpressed in invasive breast carcinoma (BRCA) and could be a potential prognostic factor for BRCA. However, the biological function of FOXP3 in BRCA is still unclear. In this study, we comprehensively explored the expression landscape of FOXP3 and its prognostic value in BRCA.

Methods: FOXP3 transcriptomic expression data were mainly obtained from The Cancer Genome Atlas (TCGA). The Kaplan-Meier plotter and receiver operating characteristic (ROC) curve were used to assess the prognostic and diagnostic value of FOXP3 in BRCA. UALCAN, cBio-Portal, and MethSurv were used to evaluate the genomic variation of FOXP3. Gene set enrichment analysis (GSEA) was performed to explore the FOXP3 pathways involved in BRCA. Morover, we detected the expression of FOXP3 in 123 BRCA specimens and 5 BRCA cell lines to verify the biological value of FOXP3 in BRCA. The Kaplan-Meier method was adopted for the overall survival (OS) analysis, and a Cox proportional hazards model was used to estimate the hazard ratio (HR) for OS.

Results: FOXP3 was more highly expressed in BRCA than in normal tissues (2.808±1.020 1.409±0.656, P<0.001), and overexpressed FOXP3 was associated with a better prognosis. The ROC curve demonstrated a significant diagnostic value of FOXP3 in BRCA (area under the ROC curve, AUC: 0.877). Genomic analysis revealed that promoter hypomethylation of FOXP3 may be the underlying mechanism of FOXP3's upregulation in BRCA. GSEA found that FOXP3 coexpressed genes were mainly involved in the Toll-like receptor pathway, JAK/STAT pathway, cell cycle, and apoptosis. Moreover, high FOXP3 expression was an independent protective factor for OS in our 123 BRCA tissues (HR: 0.367; P=0.036). , we found that FOXP3 knockdown with siRNA promoted migration and invasion in MCF-7 cells.

Conclusions: This study demonstrated that FOXP3 shows prognostic and diagnostic value for BRCA. We provided evidence that promoter hypomethylation and a high expression of FOXP3 were both related to a favorable prognosis in BRCA, which maybe associated with the Toll-like receptor pathway, JAK/STAT pathway, cell cycle, and apoptosis.

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References

Grinda T, Antoine A, Jacot W, Blaye C, Cottu P, Dieras V . Evolution of overall survival and receipt of new therapies by subtype among 20 446 metastatic breast cancer patients in the 2008-2017 ESME cohort. ESMO Open. 2021; 6(3):100114. PMC: 8095121. DOI: 10.1016/j.esmoop.2021.100114. View

Merlo A, Casalini P, Carcangiu M, Malventano C, Triulzi T, Menard S . FOXP3 expression and overall survival in breast cancer. J Clin Oncol. 2009; 27(11):1746-52. DOI: 10.1200/JCO.2008.17.9036. View

Ueno T . Biomarkers of neoadjuvant/adjuvant endocrine therapy for ER-positive/HER2-negative breast cancer. Chin Clin Oncol. 2020; 9(3):35. DOI: 10.21037/cco-20-165. View

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

Liang Y, Zhang H, Song X, Yang Q . Metastatic heterogeneity of breast cancer: Molecular mechanism and potential therapeutic targets. Semin Cancer Biol. 2019; 60:14-27. DOI: 10.1016/j.semcancer.2019.08.012. View

Lam E, Brosens J, Gomes A, Koo C . Forkhead box proteins: tuning forks for transcriptional harmony. Nat Rev Cancer. 2013; 13(7):482-95. DOI: 10.1038/nrc3539. View

Cerami E, Gao J, Dogrusoz U, Gross B, Sumer S, Aksoy B . The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012; 2(5):401-4. PMC: 3956037. DOI: 10.1158/2159-8290.CD-12-0095. View

Ostrow A, Kalhor R, Gan Y, Villwock S, Linke C, Barberis M . Conserved forkhead dimerization motif controls DNA replication timing and spatial organization of chromosomes in . Proc Natl Acad Sci U S A. 2017; 114(12):E2411-E2419. PMC: 5373409. DOI: 10.1073/pnas.1612422114. View

Jia H, Qi H, Gong Z, Yang S, Ren J, Liu Y . The expression of FOXP3 and its role in human cancers. Biochim Biophys Acta Rev Cancer. 2019; 1871(1):170-178. DOI: 10.1016/j.bbcan.2018.12.004. View

10.

Jacob S, Jurinovic V, Lampert C, Pretzsch E, Kumbrink J, Neumann J . The association of immunosurveillance and distant metastases in colorectal cancer. J Cancer Res Clin Oncol. 2021; 147(11):3333-3341. PMC: 8484134. DOI: 10.1007/s00432-021-03753-w. View

11.

Matoba T, Imai M, Ohkura N, Kawakita D, Ijichi K, Toyama T . Regulatory T cells expressing abundant CTLA-4 on the cell surface with a proliferative gene profile are key features of human head and neck cancer. Int J Cancer. 2018; 144(11):2811-2822. DOI: 10.1002/ijc.32024. View

12.

Higuchi Y, Yasunaga J, Mitagami Y, Tsukamoto H, Nakashima K, Ohshima K . HTLV-1 induces T cell malignancy and inflammation by viral antisense factor-mediated modulation of the cytokine signaling. Proc Natl Acad Sci U S A. 2020; 117(24):13740-13749. PMC: 7306771. DOI: 10.1073/pnas.1922884117. View

13.

Lan F, Zhang N, Zhang J, Krysko O, Zhang Q, Xian J . Forkhead box protein 3 in human nasal polyp regulatory T cells is regulated by the protein suppressor of cytokine signaling 3. J Allergy Clin Immunol. 2013; 132(6):1314-21. DOI: 10.1016/j.jaci.2013.06.010. View

14.

Smiline Girija A . Protean role of epigenetic mechanisms and their impact in regulating the Tregs in TME. Cancer Gene Ther. 2021; 29(6):661-664. DOI: 10.1038/s41417-021-00371-z. View

15.

Morikawa H, Sakaguchi S . Genetic and epigenetic basis of Treg cell development and function: from a FoxP3-centered view to an epigenome-defined view of natural Treg cells. Immunol Rev. 2014; 259(1):192-205. DOI: 10.1111/imr.12174. View

16.

Modhukur V, Iljasenko T, Metsalu T, Lokk K, Laisk-Podar T, Vilo J . MethSurv: a web tool to perform multivariable survival analysis using DNA methylation data. Epigenomics. 2017; 10(3):277-288. DOI: 10.2217/epi-2017-0118. View

17.

Li X, Gao Y, Li J, Zhang K, Han J, Li W . FOXP3 inhibits angiogenesis by downregulating VEGF in breast cancer. Cell Death Dis. 2018; 9(7):744. PMC: 6030162. DOI: 10.1038/s41419-018-0790-8. View

18.

Qiu R, Zhou L, Ma Y, Zhou L, Liang T, Shi L . Regulatory T Cell Plasticity and Stability and Autoimmune Diseases. Clin Rev Allergy Immunol. 2018; 58(1):52-70. DOI: 10.1007/s12016-018-8721-0. View

19.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

20.

Wang L, Liu R, Li W, Chen C, Katoh H, Chen G . Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate. Cancer Cell. 2009; 16(4):336-46. PMC: 2758294. DOI: 10.1016/j.ccr.2009.08.016. View