Assessing the Role of the Interleukin-12/STAT4 Axis in Breast Cancer by a Bioinformatics Approach
Keywords:
Breast cancer, breast cancer subtypes, cytokines, immunotherapy, Interleukin-12, IL-12/STAT4 axis, tumor microenvironmentAbstract
Interleukin-12 (IL-12) is an anti-tumor cytokine that promotes biological actions through the IL-12/STAT4 axis. Genetic variation and tumor microenvironment dynamics have been identified as critical elements for impaired immune anti-tumor responses. Breast cancer (BC) is a heterogeneous disease classified at the molecular level in several subtypes, each having unique biological and clinical traits. Despite research identifying the relevance of IL-12 in many cancer types, no studies have assessed the role of the IL-12/STAT4 axis in BC. The goal of this study was to evaluate the correlation of the IL-12/STAT4 signaling axis and BC patients’ survival in general and in the context of the BC molecular subtypes. Bioinformatics analyses using TCGA data were completed to evaluate the correlation of the IL-12/STAT4 axis and BC. A high expression of important IL-12/STAT4 axis molecules such as the IL-12 receptor genes (IL12RB1 and IL12RB2), STAT4, IFNG and TBX21 were found to significantly increase BC patients’ survival rates, especially in the most aggressive BC subtypes such as the luminal B (LumB), HER-2+ and basal like (BL). A possible relevant role of the IL-12/STAT4 axis in BC is suggested by this bioinformatics-study, which might also be subtype-specific. Further studies such as molecular and tumor microenvironment analyses will be required to clarify better the specific role of the IL-12 /STAT4 axis in BC. The results from these additional analyses may potentially improve IL-12 related immunotherapeutic approaches to BC.
References
B. E. Lippitz, “Cytokine patterns in patients with cancer: A systematic review,” The Lancet Oncology. 2013.
D. Duluc et al., “Interferon-γ reverses the immunosuppressive and protumoral properties and prevents the generation of human tumor-associated macrophages,” Int. J. Cancer, 2009.
T. Floros and A. A. Tarhini, “Anticancer Cytokines: Biology and Clinical Effects of Interferon-α2, Interleukin (IL)-2, IL-15, IL-21, and IL-12,” Semin. Oncol., 2015.
W. Lasek, R. Zagozdzon, and M. Jakobisiak, “Interleukin 12: Still a promising candidate for tumor immunotherapy?,” Cancer Immunology, Immunotherapy. 2014.
W. T. Watford, M. Moriguchi, A. Morinobu, and J. J. O’Shea, “The biology of IL-12: Coordinating innate and adaptive immune responses,” Cytokine and Growth Factor Reviews. 2003.
S. P. Kerkar and N. P. Restifo, “The power and pitfalls of IL-12,” Blood. 2012.
S. Zundler and M. F. Neurath, “Interleukin-12: Functional activities and implications for disease,” Cytokine and Growth Factor Reviews. 2015.
D. A. A. Vignali and V. K. Kuchroo, “IL-12 family cytokines: immunological playmakers,” Nature Immunology. 2012.
S. Tugues et al., “New insights into IL-12-mediated tumor suppression,” Cell Death and Differentiation. 2015.
S. P. Kerkar et al., “Tumor-specific CD8+T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts,” Cancer Res., 2010.
V. G. Vogel, “Epidemiology of breast cancer,” in The Breast: Comprehensive Management of Benign and Malignant Diseases, 2017.
C. E. DeSantis, J. Ma, A. Goding Sauer, L. A. Newman, and A. Jemal, “Breast cancer statistics, 2017, racial disparity in mortality by state,” CA. Cancer J. Clin., 2017.
T. Cancer and G. Atlas, “Comprehensive molecular portraits of human breast tumours.,” Nature, 2012.
X. Dai et al., “Breast cancer intrinsic subtype classification, clinical use and future trends,” American Journal of Cancer Research. 2015.
M. Ignatiadis and C. Sotiriou, “Luminal breast cancer: From biology to treatment,” Nature Reviews Clinical Oncology. 2013.
F. Ades et al., “Luminal B breast cancer: Molecular characterization, clinical management, and future perspectives,” Journal of Clinical Oncology. 2014.
H. G. Russnes, O. C. Lingjærde, A. L. Børresen-Dale, and C. Caldas, “Breast Cancer Molecular Stratification: From Intrinsic Subtypes to Integrative Clusters,” American Journal of Pathology. 2017.
S. G. Ahn, S. J. Kim, C. Kim, and J. Jeong, “Molecular Classification of Triple-Negative Breast Cancer,” J. Breast Cancer, 2016.
L. A. Emens, “Breast cancer immunotherapy: Facts and hopes,” Clinical Cancer Research. 2018.
T. Hamza, J. B. Barnett, and B. Li, “Interleukin 12 a key immunoregulatory cytokine in infection applications,” International Journal of Molecular Sciences. 2010.
I. Ohs, L. Ducimetière, J. Marinho, P. Kulig, B. Becher, and S. Tugues, “Restoration of natural killer cell antimetastatic activity by IL12 and checkpoint blockade,” Cancer Res., 2017.
S.-X. Yang et al., “Interleukin-12 activated CD8+ T cells induces apoptosis in breast cancer cells and reduces tumor growth,” Biomed. Pharmacother., 2016.
S. P. Kerkar et al., “IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors,” J. Clin. Invest., 2011.
D. Chinnasamy et al., “Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice,” Clin. Cancer Res., 2012.
J. Casper et al., “The UCSC Genome Browser database: 2018 update,” Nucleic Acids Res., 2018.
J. Gao et al., “Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal,” Sci. Signal., 2013.
W. T. Watford, B. D. Hissong, J. H. Bream, Y. Kanno, L. Muul, and J. J. O’Shea, “Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4,” Immunological Reviews. 2004.
Y. Qu, L. Chen, D. B. Lowe, W. J. Storkus, and J. L. Taylor, “Combined Tbet and IL12 gene therapy elicits and recruits superior antitumor immunity in vivo,” Mol. Ther., 2012.
P. Casbas-Hernandez et al., “Tumor intrinsic subtype is reflected in cancer-adjacent tissue,” Cancer Epidemiol. Biomarkers Prev., 2015.
D. C. Koboldt et al., “Comprehensive molecular portraits of human breast tumours,” Nature, 2012.
K. Andreev et al., “Impaired T-bet-pSTAT1α and perforin-mediated immune responses in the tumoral region of lung adenocarcinoma,” Br. J. Cancer, 2015.
C. Gu-Trantien et al., “CD4+follicular helper T cell infiltration predicts breast cancer survival,” J. Clin. Invest., 2013.
A. G. Rivenbark, S. M. O’Connor, and W. B. Coleman, “Molecular and cellular heterogeneity in breast cancer: Challenges for personalized medicine,” Am. J. Pathol., 2013.
X. Dai et al., “Breast cancer intrinsic subtype classification, clinical use and future trends,” Am J Cancer Res, 2015.
N. Deng, H. Zhou, H. Fan, and Y. Yuan, “Single nucleotide polymorphisms and cancer susceptibility,” Oncotarget, 2017.
J. S. Chang et al., “Genetic polymorphisms in adaptive immunity genes and childhood acute lymphoblastic leukemia,” Cancer Epidemiol. Biomarkers Prev., 2010.
S. W. Chang, G. Q. Xu, and Y. L. Fan, “Association of interleukin-12 gene polymorphisms with cancer susceptibility: A meta-analysis,” Int. J. Clin. Exp. Med., 2015.
Y. Xiao, G. Liu, and L. Gong, “Systematic review and meta-analysis on the association between polymorphisms in genes of IL-12 signaling pathway and hepatocellular carcinoma risk,” J. Cancer, 2018.
Y. Zheng et al., “Role of interleukin-12 gene polymorphisms in the onset risk of cancer: a meta-analysis,” Oncotarget, 2017.
M. L. Slattery et al., “Genetic variation in the JAK/STAT/SOCS signaling pathway influences breast cancer-specific mortality through interaction with cigarette smoking and use of aspirin/NSAIDs: The Breast Cancer Health Disparities Study,” Breast Cancer Res. Treat., 2014.
S. K. Hussain et al., “Nucleotide variation in IL-10 and IL-12 and their receptors and cervical and vulvar cancer risk: A hybrid case-parent triad and case-control study,” Int. J. Cancer, 2013.
M. L. Slattery et al., “Genetic variation in the JAK/STAT/SOCS signaling pathway influences breast cancer-specific mortality through interaction with cigarette smoking and use of aspirin/NSAIDs: The Breast Cancer Health Disparities Study,” Breast Cancer Res. Treat., 2014.
C. M. Moon et al., “Association of signal transducer and activator of transcription 4 genetic variants with extra-intestinal manifestations in inflammatory bowel disease,” Life Sci., 2010.
N. Chanthra et al., “Single nucleotide polymorphisms in STAT3 and STAT4 and risk of hepatocellular carcinoma in Thai patients with chronic hepatitis B,” Asian Pacific J. Cancer Prev., 2016.
Z. Zhang, S. Fye, I. B. Borecki, and J. S. Rader, “Polymorphisms in immune mediators associate with risk of cervical cancer,” Gynecol. Oncol., 2014.
B. Gonzalez, H. Flores-A, D. Sanchez, C. Alaez, and C. Gorodezky, “IL2 polymorphisms have no impact on risk, but genetic variants in IFNG have a protective role in acute lymphoblastic leukemia and are associated with gender in Mexican children,” Hum. Immunol., 2015.
S. K. Larsen, Y. Gao, and P. H. Basse, “NK Cells in the Tumor Microenvironment,” Crit Rev Oncog, 2014.
V. Thorsson et al., “The Immune Landscape of Cancer,” Immunity, 2018.
G. Rahir and M. Moser, “Tumor microenvironment and lymphocyte infiltration,” Cancer Immunology, Immunotherapy. 2012.
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