The online version of this article (https://doi.org/10.1186/s12935-018-0663-3) contains supplementary material, which is available to authorized users.
Ferial Amira Slim and Geneviève Ouellette are equal first authors
Inflammation is a major player in breast cancer (BC) progression. Allograft-inflammatory factor-1 (AIF1) is a crucial mediator in the inflammatory response. AIF1 reportedly plays a role in BC, but the mechanism remains to be elucidated. We identified two AIF1 isoforms, AIF1v1 and AIF1v3, which were differentially expressed between affected and unaffected sisters from families with high risk of BC with no deleterious BRCA1/BRCA2 mutations (BRCAX). We investigated potential functions of AIFv1/v3 in BC of varying severity and breast adipose tissue by evaluating their expression, and association with metabolic and clinical parameters of BC patients.
AIF1v1/v3 expression was determined in BC tissues and cell lines using quantitative real-time PCR. Potential roles and mechanisms were examined in the microenvironment (fibroblasts, adipose tissue, monocytes and macrophages), inflammatory response (cell reaction in BC subgroups), and metabolism [treatment with docosahexaenoic acid (DHA)]. Association of AIF1 transcript expression with clinical factors was determined by Spearman’s rank correlation. Bioinformatics analyses were performed to characterize transcripts.
AIF1v1/v3 were mostly expressed in the less severe BC samples, and their expression appeared to originate from the tumor microenvironment. AIF1 isoforms had different expression rates and sources in breast adipose tissue; lymphocytes mostly expressed AIF1v1 while activated macrophages mainly expressed AIF1v3. Bioinformatics analysis revealed major structural differences suggesting distinct functions in BC progression. Lymphocytes were the most infiltrating cells in breast tumors and their number correlated with AIF1v1 adipose expression. Furthermore, DHA supplementation significantly lowered the expression of AIF1 isoforms in BRCAX cell lines. Finally, the expression of AIF1 isoforms in BC and breast adipose tissue correlated with clinical parameters of BC patients.
Results strongly suggest that AIF1v1 as much as AIF1v3 play a major role in the crosstalk between BC and infiltrating immune cells mediating tumor progression, implying their high potential as target molecules for BC diagnostic, prognostication and treatment.
Additional file 1: Table S1. Primer sequence and gene description.
Additional file 2: Figure S1. Estimation of inflammation reaction methods. (A) Delimitation of tumor area and estimation of tumor cell percentage (TCP) and tumor stroma percentage (TSP); (B) Scoring of general inflammatory infiltrate at the invasive margin (Klintrup criteria); (C) Representation of inflammatory cell counting at 20× magnification in one random box in the breast tumor (0.018 mm 2).
Additional file 3. Additional methods.
Additional file 4: Figure S2. Validation of AIF1 expression in BRCAX immortalized lymphoblastoid cells (LCLs) by qRT-PCR in (A) affected sister and (B) non-affected sister. A = affected; NA = non-affected.
Additional file 5: Figure S3. Expression of AIF1 in mammary tissue in isoforms (A) AIF1v1 and (B) AIF1v3. ADH = Atypical ductal hyperplasia; DCIS = Ductal carcinoma in situ; IDC = Invasive ductal carcinoma.
Additional file 6: Figure S4. (A) Analysis of cell viability by crystal violet staining was performed on equal numbers of MCF7 breast cancer cells plated in a 12-well cell culture dish. The cells were transfected with (1) MCF7 alone (2) transfection agent (jetPRIME) 3) empty vector (pcDNA3.1 (+)) and (4) pcDNA3.1 (+)-AIF1v1 and let grown for 4 days. The purple color reflects the number of colonies formed after 4 days. A decrease in the number of colonies indicates decreased proliferation or increased cell death in presence of AIF1. (B) Relative expression levels of AIF1v1 mRNA by real-time PCR. The MCF7 cells seeded in 12-well plates were transfected with (1) MCF7 alone (2) transfection agent (jetPRIME) (3) empty vector (pcDNA3.1(+)) and (4) pcDNA3.1(+)-AIF1v1. HPRT1 was used as an internal control.
Additional file 7: Figure S5. Expression of AIF1v1 (A) and AIF1v3 (B) in cancer cell lines.
Additional file 8: Figure S6. Conversion of E1/E2 at different incubation time periods. E1 = Estrone; E2 = 14C-estradiol.
Additional file 9: Figure S7. AIF1v1 (A) and AIF1v3 (B) expression at varying concentrations of EPA/DHA EPA = Eicosapentaenoic acid; DHA = Docosahexaenoic acid.
Additional file 10: Figure S8. Distribution of breast adipose AIF1v1 expression in BC patients diagnosed with various breast tumors: ductal carcinoma in situ (DCIS), luminal A/B (ER+ and/or PR+), HER2+ (ER−/PR−/HER2+) and triple negative (ER−/PR−/HER2).
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86. CrossRef
Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30(7):1073–81. CrossRef
Jiang X, Shapiro DJ. The immune system and inflammation in breast cancer. Mol Cell Endocrinol. 2014;382(1):673–82. CrossRef
Freeman MR, Li Q, Chung LW. Can stroma reaction predict cancer lethality? Clin Cancer Res. 2013;19(18):4905–7. CrossRef
Klintrup K, Makinen JM, Kauppila S, Vare PO, Melkko J, Tuominen H, et al. Inflammation and prognosis in colorectal cancer. Eur J Cancer. 2005;41(17):2645–54. CrossRef
Mohammed ZM, Going JJ, Edwards J, Elsberger B, McMillan DC. The relationship between lymphocyte subsets and clinico-pathological determinants of survival in patients with primary operable invasive ductal breast cancer. Br J Cancer. 2013;109(6):1676–84. CrossRef
Richards CH, Flegg KM, Roxburgh CS, Going JJ, Mohammed Z, Horgan PG, et al. The relationships between cellular components of the peritumoural inflammatory response, clinicopathological characteristics and survival in patients with primary operable colorectal cancer. Br J Cancer. 2012;106(12):2010–5. CrossRef
Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26(2):259–71. CrossRef
Tang X. Tumor-associated macrophages as potential diagnostic and prognostic biomarkers in breast cancer. Cancer Lett. 2013;332(1):3–10. CrossRef
Tricot G. New insights into role of microenvironment in multiple myeloma. Lancet. 2000;355(9200):248–50. CrossRef
Utans U, Arceci RJ, Yamashita Y, Russell ME. Cloning and characterization of allograft inflammatory factor-1: a novel macrophage factor identified in rat cardiac allografts with chronic rejection. J Clin Invest. 1995;95(6):2954–62. CrossRef
Deininger MH, Meyermann R, Schluesener HJ. The allograft inflammatory factor-1 family of proteins. FEBS Lett. 2002;514(2–3):115–21. CrossRef
Zhao YY, Yan DJ, Chen ZW. Role of AIF-1 in the regulation of inflammatory activation and diverse disease processes. Cell Immunol. 2013;284(1–2):75–83. CrossRef
Fukui M, Tanaka M, Toda H, Asano M, Yamazaki M, Hasegawa G, et al. The serum concentration of allograft inflammatory factor-1 is correlated with metabolic parameters in healthy subjects. Metabolism. 2012;61(7):1021–5. CrossRef
Lorente-Cebrian S, Decaunes P, Dungner E, Bouloumie A, Arner P, Dahlman I. Allograft inflammatory factor 1 (AIF-1) is a new human adipokine involved in adipose inflammation in obese women. BMC Endocr Disord. 2013;13:54. CrossRef
Fukui M, Tanaka M, Asano M, Yamazaki M, Hasegawa G, Imai S, et al. Serum allograft inflammatory factor-1 is a novel marker for diabetic nephropathy. Diabetes Res Clin Pract. 2012;97(1):146–50. CrossRef
Huang X, Zhao Y, Jia S, Yan D, Chen Z. Effects of daintain/AIF-1 on beta cell dysfunction in INS-1 cells. Biosci Biotechnol Biochem. 2011;75(9):1842–4. CrossRef
Zhao YY, Huang XY, Chen ZW. Daintain/AIF-1 (allograft inflammatory factor-1) accelerates type 1 diabetes in NOD mice. Biochem Biophys Res Commun. 2012;427(3):513–7. CrossRef
Deininger MH, Seid K, Engel S, Meyermann R, Schluesener HJ. Allograft inflammatory factor-1 defines a distinct subset of infiltrating macrophages/microglial cells in rat and human gliomas. Acta Neuropathol. 2000;100(6):673–80. CrossRef
Jia J, Bai Y, Fu K, Sun ZJ, Chen XM, Zhao YF. Expression of allograft inflammatory factor-1 and CD68 in haemangioma: implication in the progression of haemangioma. Br J Dermatol. 2008;159(4):811–9. CrossRef
Tian Y, Kelemen SE, Autieri MV. Inhibition of AIF-1 expression by constitutive siRNA expression reduces macrophage migration, proliferation, and signal transduction initiated by atherogenic stimuli. Am J Physiol Cell Physiol. 2006;290(4):C1083–91. CrossRef
Watano K, Iwabuchi K, Fujii S, Ishimori N, Mitsuhashi S, Ato M, et al. Allograft inflammatory factor-1 augments production of interleukin-6, -10 and -12 by a mouse macrophage line. Immunology. 2001;104(3):307–16. CrossRef
Khirade MF, Lal G, Bapat SA. Derivation of a fifteen gene prognostic panel for six cancers. Sci Rep. 2015;5:13248. CrossRef
Jia J, Cai Y, Wang R, Fu K, Zhao YF. Overexpression of allograft inflammatory factor-1 promotes the proliferation and migration of human endothelial cells (HUV-EC-C) probably by up-regulation of basic fibroblast growth factor. Pediatr Res. 2010;67(1):29–34. CrossRef
Liu S, Tan WY, Chen QR, Chen XP, Fu K, Zhao YY, et al. Daintain/AIF-1 promotes breast cancer proliferation via activation of the NF-kappaB/cyclin D1 pathway and facilitates tumor growth. Cancer Sci. 2008;99(5):952–7. CrossRef
Li T, Feng Z, Jia S, Wang W, Du Z, Chen N, et al. Daintain/AIF-1 promotes breast cancer cell migration by up-regulated TNF-alpha via activate p38 MAPK signaling pathway. Breast Cancer Res Treat. 2012;131(3):891–8. CrossRef
Jia S, Chaibou MA, Chen Z. Daintain/AIF-1 reinforces the resistance of breast cancer cells to cisplatin. Biosci Biotechnol Biochem. 2012;76(12):2338–41. CrossRef
Pouliot MC, Kothari C, Joly-Beauparlant C, Labrie Y, Ouellette G, Simard J, et al. Transcriptional signature of lymphoblastoid cell lines of BRCA1, BRCA2 and non-BRCA1/2 high risk breast cancer families. Oncotarget. 2017;8(45):78691–712. CrossRef
Ennour-Idrissi K, Tetu B, Maunsell E, Poirier B, Montoni A, Rochette PJ, et al. Association of telomere length with breast cancer prognostic factors. PLoS ONE. 2016;11(8):e0161903. CrossRef
Genin M, Clement F, Fattaccioli A, Raes M, Michiels C. M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide. BMC Cancer. 2015;15:577. CrossRef
Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29(9):e45. CrossRef
Warrington JA, Nair A, Mahadevappa M, Tsyganskaya M. Comparison of human adult and fetal expression and identification of 535 housekeeping/maintenance genes. Physiol Genomics. 2000;2(3):143–7. CrossRef
Bustin SA, Beaulieu JF, Huggett J, Jaggi R, Kibenge FS, Olsvik PA, et al. MIQE precis: practical implementation of minimum standard guidelines for fluorescence-based quantitative real-time PCR experiments. BMC Mol Biol. 2010;11:74. CrossRef
Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem. 2009;55(4):611–22. CrossRef
Park JH, McMillan DC, Edwards J, Horgan PG, Roxburgh CS. Comparison of the prognostic value of measures of the tumor inflammatory cell infiltrate and tumor-associated stroma in patients with primary operable colorectal cancer. Oncoimmunology. 2016;5(3):e1098801. CrossRef
Soguel L, Diorio C. Anthropometric factors, adult weight gain, and mammographic features. Cancer Causes Control. 2016;27(3):333–40. CrossRef
Markham NR, Zuker M. DINAMelt web server for nucleic acid melting prediction. Nucleic Acids Res. 2005;33(Web Server issue):W577–81. CrossRef
Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, et al. Clustal W and Clustal X version 2.0. Bioinformatics. 2007;23(21):2947–8. CrossRef
Fidler TP, Campbell RA, Funari T, Dunne N, Balderas Angeles E, Middleton EA, et al. Deletion of GLUT1 and GLUT3 reveals multiple roles for glucose metabolism in platelet and megakaryocyte function. Cell Rep. 2017;20(4):881–94. CrossRef
Lal I, Dittus K, Holmes CE. Platelets, coagulation and fibrinolysis in breast cancer progression. Breast Cancer Res. 2013;15(4):207. CrossRef
Calder PC. Omega-3 fatty acids and inflammatory processes. Nutrients. 2010;2(3):355–74. CrossRef
Autieri MV. cDNA cloning of human allograft inflammatory factor-1: tissue distribution, cytokine induction, and mRNA expression in injured rat carotid arteries. Biochem Biophys Res Commun. 1996;228(1):29–37. CrossRef
Del Galdo F, Jimenez SA. T cells expressing allograft inflammatory factor 1 display increased chemotaxis and induce a profibrotic phenotype in normal fibroblasts in vitro. Arthritis Rheum. 2007;56(10):3478–88. CrossRef
Schwab JM, Frei E, Klusman I, Schnell L, Schwab ME, Schluesener HJ. AIF-1 expression defines a proliferating and alert microglial/macrophage phenotype following spinal cord injury in rats. J Neuroimmunol. 2001;119(2):214–22. CrossRef
Chanmee T, Ontong P, Konno K, Itano N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers. 2014;6(3):1670–90. CrossRef
Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–99. CrossRef
Cai H, Zhu XD, Ao JY, Ye BG, Zhang YY, Chai ZT, et al. Colony-stimulating factor-1-induced AIF1 expression in tumor-associated macrophages enhances the progression of hepatocellular carcinoma. Oncoimmunology. 2017;6(9):e1333213. CrossRef
Li X, Yao W, Yuan Y, Chen P, Li B, Li J, et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut. 2017;66(1):157–67. CrossRef
Hussein MR, Elsers DA, Fadel SA, Omar AE. Immunohistological characterisation of tumour infiltrating lymphocytes in melanocytic skin lesions. J Clin Pathol. 2006;59(3):316–24. CrossRef
Tan AH, Goh SY, Wong SC, Lam KP. T helper cell-specific regulation of inducible costimulator expression via distinct mechanisms mediated by T-bet and GATA-3. J Biol Chem. 2008;283(1):128–36. CrossRef
Zitvogel L, Galluzzi L, Kepp O, Smyth MJ, Kroemer G. Type I interferons in anticancer immunity. Nat Rev Immunol. 2015;15(7):405–14. CrossRef
Mohammed ZM, Going JJ, Edwards J, McMillan DC. The role of the tumour inflammatory cell infiltrate in predicting recurrence and survival in patients with primary operable breast cancer. Cancer Treat Rev. 2012;38(8):943–55. CrossRef
Bremnes RM, Busund LT, Kilvaer TL, Andersen S, Richardsen E, Paulsen EE, et al. The role of tumor-infiltrating lymphocytes in development, progression, and prognosis of non-small cell lung cancer. J Thorac Oncol. 2016;11(6):789–800. CrossRef
Roxburgh CS, Salmond JM, Horgan PG, Oien KA, McMillan DC. Tumour inflammatory infiltrate predicts survival following curative resection for node-negative colorectal cancer. Eur J Cancer. 2009;45(12):2138–45. CrossRef
Fox HS, Bond BL, Parslow TG. Estrogen regulates the IFN-gamma promoter. J Immunol. 1991;146(12):4362–7. PubMed
Leek RD, Landers RJ, Harris AL, Lewis CE. Necrosis correlates with high vascular density and focal macrophage infiltration in invasive carcinoma of the breast. Br J Cancer. 1999;79(5–6):991–5. CrossRef
Nakaya M, Tachibana H, Yamada K. Effect of estrogens on the interferon-gamma producing cell population of mouse splenocytes. Biosci Biotechnol Biochem. 2006;70(1):47–53. CrossRef
Ruh MF, Bi Y, D’Alonzo R, Bellone CJ. Effect of estrogens on IL-1beta promoter activity. J Steroid Biochem Mol Biol. 1998;66(4):203–10. CrossRef
Yan DJ, Chen ZW. 17beta-Estradiol increased the expression of daintain/AIF-1 in RAW264.7 macrophages. Biosci Biotechnol Biochem. 2010;74(10):2103–5. CrossRef
Schley PD, Jijon HB, Robinson LE, Field CJ. Mechanisms of omega-3 fatty acid-induced growth inhibition in MDA-MB-231 human breast cancer cells. Breast Cancer Res Treat. 2005;92(2):187–95. CrossRef
Liu J, Ma DW. The role of n-3 polyunsaturated fatty acids in the prevention and treatment of breast cancer. Nutrients. 2014;6(11):5184–223. CrossRef
Merendino N, Costantini L, Manzi L, Molinari R, D’Eliseo D, Velotti F. Dietary omega-3 polyunsaturated fatty acid DHA: a potential adjuvant in the treatment of cancer. Biomed Res Int. 2013;2013:310186. CrossRef
Vaughan VC, Hassing MR, Lewandowski PA. Marine polyunsaturated fatty acids and cancer therapy. Br J Cancer. 2013;108(3):486–92. CrossRef
Monk JM, Turk HF, Liddle DM, De Boer AA, Power KA, Ma DW, et al. n-3 polyunsaturated fatty acids and mechanisms to mitigate inflammatory paracrine signaling in obesity-associated breast cancer. Nutrients. 2014;6(11):4760–93. CrossRef
- An isoform of AIF1 involved in breast cancer
Ferial Amira Slim
- BioMed Central
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