Candidiasis in breast cancer: Tumor progression or not?

Document Type : Review Article

Authors

1 Advanced Therapy Medicinal Product (ATMP) Department, Breast Cancer Research Center, Motamed Cancer Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran

2 Recombinant Vaccine Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

3 Department of Microbiology, Faculty of Advanced Sciences & Technology, Tehran Medical Sciences, Islamic Azad University, (IAUPS), Tehran, Iran

4 Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran

5 Cancer and Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran

6 Department of Biochemistry, Faculty of Basic Sciences, Islamic Azad University, Central Tehran Branch, Tehran, Iran

7 Department of Hematology and Oncology and Stem Cell Transplantation, Firoozgar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

8 Department of Immunology, Shahed University, Tehran, Iran

9 Infectious and Tropical Diseases Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran

10 Biotechnology Research Center, Tehran University of Medical Sciences, Tehran, Iran

11 Immunotherapy Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran

12 Animal Health and Zoonosis PhD Course, Department of Veterinary Medicine, University of Bari, Bari, Italy

10.22038/ijbms.2024.75408.16379

Abstract

Candida albicans is an “opportunistic fungal agent” in cancer patients that can become colonized in both mucosal and deep tissues and cause severe infections. Most evidence has shown that C. albicans can enhance the progress of different cancers by several mechanisms such as generating virulence factors, participation in endogenous production of pro-inflammatory mediators, and stimulating a wide range of immune cells in the host. The main idea of this review is to describe a range of Candida-used mechanisms that are important in candidiasis-associated malignant processes and cancer development, particularly breast cancer. This review intends to provide a detailed discussion on different regulatory mechanisms of C. albicans that undoubtedly help to open new therapeutic horizons of cancer therapy in patients with fungal infection. The current therapeutic approach is not fully effective in immunocompromised and cancer patients, and further studies are required to find new products with effective antifungal properties and minimal side effects to increase the susceptibility of opportunistic fungal infections to conventional antifungal agents. So, in this situation, a special therapy should be considered to control the infection and simultaneously have the most therapeutic index on tumor patients.

Keywords

Main Subjects


1. Rohan TE, Xue X, Lin H-M, D’Alfonso TM, Ginter PS, Oktay MH, et al. Tumor microenvironment of metastasis and risk of distant metastasis of breast cancer. J Natl Cancer Inst 2014;106:1-11.
2. Islami F, Miller KD, Siegel RL, Zheng Z, Zhao J, Han X, et al. National and state estimates of lost earnings from cancer deaths in the United States. JAMA oncology 2019;5:e191460.
3. Taheri FH, Seyedolmohadesin M, Bayat M, Mahdavi M, Yazdi MH, Eslamifar A, et al. The effect of Candida albicans systemic infection on matrix metalloproteinases in breast cancer bearing BALB/c mice. Iran J Allergy Asthma Immunol 2013;12:81-85.
4. Sobel JD. Vulvovaginal candidosis. The Lancet 2007;369:1961-1971.
5. Chung L-M, Liang J-A, Lin C-L, Sun L-M, Kao C-H. Cancer risk in patients with candidiasis: a nationwide population-based cohort study. Oncotarget 2017;8:63562-63573.
6. Klimesova K, Jiraskova Zakostelska Z, Tlaskalova-Hogenova H. Oral bacterial and fungal microbiome impacts colorectal carcinogenesis. Front Microbiol 2018;9:774.
7. Coker OO, Nakatsu G, Dai RZ, Wu WKK, Wong SH, Ng SC, et al. Enteric fungal microbiota dysbiosis and ecological alterations in colorectal cancer Gut 2019;68:654-662.
8. Jacobsen ID, Wilson D, Wächtler B, Brunke S, Naglik JR, Hube B. Candida albicans dimorphism as a therapeutic target. Expert Rev Anti Infect Ther 2012;10:85-93.
9. Dühring S, Germerodt S, Skerka C, Zipfel PF, Dandekar T, Schuster S. Host-pathogen interactions between the human innate immune system and Candida albicans—understanding and modeling defense and evasion strategies. Front Microbiol 2015; 6:625.
10. Qin Y, Zhang L, Xu Z, Zhang J, Jiang Y-y, Cao Y, Yan T. Innate immune cell response upon Candida albicans infection. Virulence 2016;7:512-526.
11. Takeuchi O, Akira S. Pattern recognition receptors and inflammation Cell 2010;140:805-820.
12. Taghavi M, Khosravi A, Mortaz E, Nikaein D, Athari SS. Role of pathogen-associated molecular patterns (PAMPS) in immune responses to fungal infections. Eur J Pharmacol 2017;808:8-13. 
13. Mech F, Wilson D, Lehnert T, Hube B, Thilo Figge M. Epithelial invasion outcompetes hypha development during Candida albicans infection as revealed by an image‐based systems biology approach. Cytometry Part A 2014;85:126-139.
14. Naglik JR, König A, Hube B, Gaffen SL. Candida albicans–epithelial interactions and induction of mucosal innate immunity. Curr Opin Microbiol 2017 ;40:104-112.
15. Mayer FL, Wilson D, Hube B. Candida albicans pathogenicity mechanisms. Virulence 2013;4:119-128.
16. Wilson D, Thewes S, Zakikhany K, Fradin C, Albrecht A, Almeida R, et al. Identifying infection-associated genes of Candida albicans in the postgenomic era. FEMS Yeast Res 2009;9:688-700.
17. Li M, Chen Q, Tang R, Shen Y, Da Liu W. The expression of β-defensin-2, 3 and LL-37 induced by Candida albicans phospholipomannan in human keratinocytes. J Dermatol Sci 2011;61:72-75.
18. Vautier S, da Glória Sousa M, Brown GD. C-type lectins, fungi and Th17 responses. Cytokine Growth Factor Rev 2010;21:405-412.
19. Paulone S, Ardizzoni A, Tavanti A, Piccinelli S, Rizzato C, Lupetti A, et al. The synthetic killer peptide KP impairs Candida albicans biofilm in vitro. PLoS One 2017;12:e0181278.
20. Rodríguez-Cerdeira C, Gregorio MC, Molares-Vila A, López-Barcenas A, Fabbrocini G, Bardhi B, et al. Biofilms and vulvovaginal candidiasis. Colloids and Surfaces B: Biointerfaces 2019;174:110-125.
21. Moyes DL, Naglik JR. Mucosal immunity and Candida albicans infection. Clin Dev Immunol 2011;2011:346307. 
22. De Luca A, Zelante T, D’angelo C, Zagarella S, Fallarino F, Spreca A, et al. IL-22 defines a novel immune pathway of antifungal resistance. Mucosal Immunol 2010;3:361-373.
23. Eyerich S, Wagener J, Wenzel V, Scarponi C, Pennino D, Albanesi C, et al. IL‐22 and TNF‐α represent a key cytokine combination for epidermal integrity during infection with Candida albicans. Eur J Immunol 2011;41:1894-1901.
24. Luo S, Skerka C, Kurzai O, Zipfel PF. Complement and innate immune evasion strategies of the human pathogenic fungus Candida albicans. Mol Immunol 2013;56:161-169.
25. Miramón P, Dunker C, Windecker H, Bohovych IM, Brown AJ, Kurzai O, Hube B. Cellular responses of Candida albicans to phagocytosis and the extracellular activities of neutrophils are critical to counteract carbohydrate starvation, oxidative and nitrosative stress. PLoS One 2012;7:e52850.
26. Lefkowitz SS, Gelderman MP, Lefkowitz DL, Moguilevsky N, Bollen A. Phagocytosis and intracellular killing of Candida albicans by macrophages exposed to myeloperoxidase. J Infect Dis 1996;173:1202-1207.
27. Urban CF, Reichard U, Brinkmann V, Zychlinsky A. Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cellul Microbiol 2006;8:668-676.
28. Jimenez-Lopez C, Lorenz MC. Fungal immune evasion in a model host–pathogen interaction: Candida albicans versus macrophages. PLoS Pathog 2013;9:e1003741.
29. Krysan DJ, Sutterwala FS, Wellington M. Catching fire: Candida albicans, macrophages, and pyroptosis. PLoS Pathog 2014;10:e1004139.
30. Takao S, Smith EH, Wang D, Chan C, Bulkley GB, Klein AS. Role of reactive oxygen metabolites in murine peritoneal macrophage phagocytosis and phagocytic killing. Am J Physiol 1996;271(4 Pt 1):C1278-84. 
31. Liu P, Wu X, Liao C, Liu X, Du J, Shi H, et al. Escherichia coli and Candida albicans induced macrophage extracellular trap-like structures with limited microbicidal activity. PLoS One 2014;9:e90042.
32. Cheng S-C, Joosten LA, Kullberg B-J, Netea MG. Interplay between Candida albicans and the mammalian innate host defense. Infect Immun 2012;80:1304-1313.
33. Ramirez-Ortiz ZG, Means TK. The role of dendritic cells in the innate recognition of pathogenic fungi (A. fumigatus, C. neoformans and C. albicans). Virulence 2012;3:635-646.
34. d’Ostiani CF, Del Sero G, Bacci A, Montagnoli C, Spreca A, Mencacci A, et al. Dendritic cells discriminate between yeasts and hyphae of the fungus Candida albicans: Implications for initiation of T helper cell immunity in vitro and in vivo. J Exp Med 2000;191:1661-1674.
35. Kashem SW, Igyártó BZ, Gerami-Nejad M, Kumamoto Y, Mohammed J, Jarrett E, et al. Candida albicans morphology and dendritic cell subsets determine T helper cell differentiation. Immunity 2015;42:356-366.
36. Roudbary M, Roudbar Mohammadi S, Bozorgmehr M, Moazzeni SM. The effects of Candida albicans cell wall protein fraction on dendritic cell maturation. Iran J Immunol 2009;6:67-74.
37. van de Veerdonk FL, Marijnissen RJ, Kullberg BJ, Koenen HJ, Cheng S-C, Joosten I, et al. The macrophage mannose receptor induces IL-17 in response to Candida albicans. Cell Host Microbe 2009;5:329-340.
38. Lin L, Ibrahim AS, Xu X, Farber JM, Avanesian V, Baquir B, et al. Th1-Th17 cells mediate protective adaptive immunity against Staphylococcus aureus and Candida albicans infection in mice. PLoS pathog 2009;5:e1000703.
39. Wood SM, Ljunggren H-G, Bryceson YT. Insights into NK cell biology from human genetics and disease associations. Cell Mol Life Sci 2011;68:3479-3493. 
40. Voigt J, Hünniger K, Bouzani M, Jacobsen ID, Barz D, Hube B, et al. Human natural killer cells acting as phagocytes against Candida albicans and mounting an inflammatory response that modulates neutrophil antifungal activity. J Infect Dis 2014;209:616-626.
41. Martín-Antonio B, Suñe G, Perez-Amill L, Castella M, Urbano-Ispizua A. Natural killer cells: Angels and devils for immunotherapy. Int J Mol Sci 2017;18:1868.
42. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol 2008;9:503-510.
43. Quintin J, Voigt J, van der Voort R, Jacobsen ID, Verschueren I, Hube B, et al. Differential role of NK cells against Candida albicans infection in immunocompetent or immunocompromised mice. Eur J Immunol 2014;44:2405-2414.
44. Bonifazi P, Zelante T, D’angelo C, De Luca A, Moretti S, Bozza S, et al. Balancing inflammation and tolerance in vivo through dendritic cells by the commensal Candida albicans. Mucosal Immunol 2009;2:362-374.
45. Huang H, Ostroff GR, Lee CK, Wang JP, Specht CA, Levitz SM. Distinct patterns of dendritic cell cytokine release stimulated by fungal β-glucans and toll-like receptor agonists. Infect immun 2009;77:1774-1781.
46. Naglik JR. Candida immunity. New J Sci 2014;2014:390241.
47. Romani L. Immunity to fungal infections. Nat Rev Immunol 2004;4:1-23.
48. LeibundGut-Landmann S, Groß O, Robinson MJ, Osorio F, Slack EC, Tsoni SV, et al. Syk-and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol 2007;8:630-638.
49. Cenci E, Mencacci A, Spaccapelo R, Tonnetti L, Mosci P, Enssle K-H, et al. T helper cell type 1 (Th1)-and Th2-like responses are present in mice with gastric candidiasis but protective immunity is associated with Th1 development. J Infec Dis 1995;171:1279-1288.
50. Fidel Jr PL. History and update on host defense against vaginal candidiasis. Am J Reprod Immunol 2007;57:2-12.
51. Gringhuis SI, Wevers BA, Kaptein TM, Van Capel TM, Theelen B, Boekhout T, et al. Selective C-Rel activation via Malt1 controls anti-fungal TH-17 immunity by dectin-1 and dectin-2. PLoS Pathog 2011;7:e1001259.
52. Pietrella D, Rachini A, Pines M, Pandey N, Mosci P, Bistoni F, et al. Th17 cells and IL-17 in protective immunity to vaginal candidiasis. PLoS One 2011;6:e22770.
53. Xu X, Wang R, Su Q, Huang H, Zhou P, Luan J, et al. Expression of Th1-Th2-and Th17-associated cytokines in laryngeal carcinoma Oncol lett 2016;12:1941-1948.
54. Bober LA, Grace MJ, Pugliese-Sivo C, Rojas-Triana A, Waters T, Sullivan LM, et al. The effect of GM-CSF and G-CSF on human neutrophil function. Immunopharmacology 1995;29:111-119.
55. Weisbart RH, Kwan L, Golde DW, Gasson JC. Human GM-CSF primes neutrophils for enhanced oxidative metabolism in response to the major physiological chemoattractants. Blood 1987;69:18-21.
56. Dale DC, Liles WC, Llewellyn C, Price TH. Effects of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) on neutrophil kinetics and function in normal human volunteers. Am J Hematol 1998;57:7-15.
57. Kasahara S, Jhingran A, Dhingra S, Salem A, Cramer RA, Hohl TM. Role of granulocyte-macrophage colony-stimulating factor signaling in regulating neutrophil antifungal activity and the oxidative burst during respiratory fungal challenge. J Infect Dis 2016;213:1289-1298.
58. Pandiyan P, Conti HR, Zheng L, Peterson AC, Mathern DR, Hernández-Santos N, et al. CD4+ CD25+ Foxp3+ regulatory T cells promote Th17 cells in vitro and enhance host resistance in mouse Candida albicans Th17 cell infection model. Immunity 2011;34:422-434.
59. Josefowicz SZ, Lu L-F, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 2012;30:531-564.
60. Kekäläinen E, Tuovinen H, Joensuu J, Gylling M, Franssila R, Pöntynen N, et al. A defect of regulatory T cells in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Immunol 2007;178:1208-1215.
61. Kirchner FR, Littringer K, Altmeier S, Tran VDT, Schönherr F, Lemberg C, et al. Persistence of Candida albicans in the oral mucosa induces a curbed inflammatory host response that is independent of immunosuppression. 
Front Immunol 2019;10:330.
62. Whibley N, MacCallum DM, Vickers MA, Zafreen S, Waldmann H, Hori S, et al. Expansion of Foxp3+ T‐cell populations by Candida albicans enhances both Th17‐cell responses and fungal dissemination after intravenous challenge. Eur J Immunol 2014;44:1069-1083.
63. Ahmadi N, Ahmadi A, Kheirali E, Yadegari MH, Bayat M, Shajiei A, et al. Systemic infection with Candida albicans in breast tumor bearing mice: Cytokines dysregulation and induction of regulatory T cells. J Mycol Med 2019;29:49-55.
64. Conche C, Greten FR. Fungi enter the stage of colon carcinogenesis. Immunity. 2018;49:384-386.
65. Yu D, Liu Z. The research progress in the interaction between Candida albicans and cancers. Frontiers in Microbiology. 2022;13:988734.
66. Ramirez-Garcia A, Rementeria A, Aguirre-Urizar JM, Moragues MD, Antoran A, Pellon A, et al. Candida albicans and cancer: Can this yeast induce cancer development or progression? Crit Rev Microbiol 2016;42:181-193.
67. Swann P, Magee P. Nitrosamine-induced carcinogenesis. The alkylation of nucleic acids of the rat by N-methyl-N-nitrosourea, dimethylnitrosamine, dimethyl sulphate and methyl methanesulphonate. Biochem J 1968;110:39-47.
68. Archer M. Mechanisms of action of N-nitroso compounds. Cancer Surv 1989;8:241-250.
69. Larsson SC, Bergkvist L, Wolk A. Processed meat consumption, dietary nitrosamines and stomach cancer risk in a cohort of Swedish women. Int J Cancer 2006;119:915-919.
70. Song P, Wu L, Guan W. Dietary nitrates, nitrites, and nitrosamines intake and the risk of gastric cancer: A meta-analysis. Nutrients 2015;7:9872-9895.
71. Chu F, Li G. Simultaneous occurrence of fumonisin B1 and other mycotoxins in moldy corn collected from the People’s Republic of China in regions with high incidences of esophageal cancer. Appl Environ Microbiol 1994;60:847-852.
72. Gankhuyag N, Lee K-H, Cho J-Y. The role of nitrosamine (NNK) in breast cancer carcinogenesis. J Mammary Gland Biol Neoplasia 2017;22:159-170.
73. Krogh P. The role of yeasts in oral cancer by means of endogenous nitrosation. Acta Odontol Scand 1990;48:85-88.
74. Nagy K, Sonkodi I, Szöke I, Nagy E, Newman H. The microflora associated with human oral carcinomas. Oral oncol 1998;34:304-308.
75. Jayachandran AL, Katragadda R, Thyagarajan R, Vajravelu L, Manikesi S, Kaliappan S, Jayachandran B. Oral Candidiasis among cancer patients attending a tertiary Care Hospital in Chennai, South India: an evaluation of Clinicomycological association and antifungal susceptibility pattern. Can J Infect Dis Med Microbiol 2016;2016:8758461.
76. Tamgadge S, Tamgadge A, Pillai A. Association of Candida sp. with the Degrees of Dysplasia and Oral Cancer: A study by calcofluor white under fluorescent microscopy. Iran J Pathol 2017;12:348-355.
77. Gupta V, Abhisheik K, Balasundari S, Devendra NK, Shadab K, Anupama M. Identification of Candida albicans using different culture media and its association in leukoplakia and oral squamous cell carcinoma. J Oral Maxillofac Pathol 2024;28:23-28.
78. Holt JT, Thompson ME, Szabo C, Robinson-Benion C, Arteaga CL, King M-C, Jensen RA. Growth retardation and tumour inhibition by BRCA1. Nat Genet 1996;12:298-302.
79. Humphrey JS, Salim A, Erdos MR, Collins FS, Brody LC, Klausner RD. Human BRCA1 inhibits growth in yeast: Potential use in diagnostic testing. Proc Natl Acad Sci U S A 1997;94:5820-5825.
80. Lin NU, Claus E, Sohl J, Razzak AR, Arnaout A, Winer EP. Sites of distant recurrence and clinical outcomes in patients with metastatic triple‐negative breast cancer: High incidence of central nervous system metastases. Cancer.2008;113:2638-2645.
81. Gainza‐Cirauqui ML, Nieminen MT, Novak Frazer L, Aguirre‐Urizar JM, Moragues MD, Rautemaa R. Production of carcinogenic acetaldehyde by Candida albicans from patients with potentially malignant oral mucosal disorders. J Oral Pathol Med 2013;42:243-249.
82. Seitz HK, Stickel F. Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism. Genes Nutr 2010;5:121-128.
83. Manzo-Avalos S, Saavedra-Molina A. Cellular and mitochondrial effects of alcohol consumption. Int J Environ Res Public Health 2010;7:4281-304.
84. Humans IWGotEoCRt, Cancer IAfRo, Organization WH. Re-evaluation of Some Organic Chemicals, Hydrazine and Hydrogen Peroxide: Other compounds reviewed in plenary sessions. IARC Monogr Eval Carcinog Risks Hum. 1999;71:1-1554.
85. McCullough M, Jaber M, Barrett A, Bain L, Speight P, Porter S. Oral yeast carriage correlates with presence of oral epithelial dysplasia. Oral Oncol 2002;38:391-393.
86. Nieminen MT, Novak-Frazer L, Rautemaa V, Rajendran R, Sorsa T, Ramage G, et al. A novel antifungal is active against Candida albicans biofilms and inhibits mutagenic acetaldehyde production in vitro. PLos One 2014;9:e97864.
87. Abraham J, Balbo S, Crabb D, Brooks PJ. Alcohol metabolism in human cells causes DNA damage and activates the fanconi anemia–breast cancer susceptibility (FA‐BRCA) DNA damage response network. Alcoholism: Alcohol Clin Exp Res 2011;35:2113-2120.
88. Kim D, Yukl ET, Moënne-Loccoz P, Ortiz de Montellano PR. Fungal heme oxygenases: functional expression and characterization of Hmx1 from Saccharomyces cerevisiae and CaHmx1 from Candida albicans. Biochemistry. 2006;45:14772-14780.
89. Santos R, Buisson N, Knight S, Dancis A, Camadro J-M, Lesuisse E. Haemin uptake and use as an iron source by Candida albicans: Role of CaHMX1-encoded haem oxygenase. Microbiology 2003;149:579-588.
90. Overhaus M, Moore BA, Barbato JE, Behrendt FF, Doering JG, Bauer AJ. Biliverdin protects against polymicrobial sepsis by modulating inflammatory mediators. Am J Physiol Gastrointest Liver Physiol 2006;290:G695-703.
91. Manns JM, Mosser DM, Buckley HR. Production of a hemolytic factor by Candida albicans. Infect Immun 1994;62:5154-156.
92. Weissman Z, Kornitzer D. A family of Candida cell surface haem‐binding proteins involved in haemin and haemoglobin‐iron utilization. Mol Microbiol 2004;53:1209-1220.
93. Okamoto-Shibayama K, Kikuchi Y, Kokubu E, Sato Y, Ishihara K. Csa2, a member of the Rbt5 protein family, is involved in the utilization of iron from human hemoglobin during Candida albicans hyphal growth. FEMS Yeast Res 2014;14:674-767.
94. Coburn R, Williams W, Kahn S. Endogenous carbon monoxide production in patients with hemolytic anemia. J Clin Invest 1966;45:460-468.
95. Lin C-W, Shen S-C, Hou W-C, Yang L-Y, Chen Y-C. Heme oxygenase-1 inhibits breast cancer invasion via suppressing the expression of matrix metalloproteinase-9. Mol Cancer Ther 2008;7:1195-1206.
96. Gandini NA, Alonso EN, Fermento ME, Mascaró M, Abba MC, Coló GP, et al. Heme oxygenase-1 has an antitumor role in breast cancer. Antioxid Redox Signal 2019;30:2030-2049.
97. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006;124:783-801.
98. Mogensen TH. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 2009;22:240-273.
99. Böhringer M, Pohlers S, Schulze S, Albrecht‐Eckardt D, Piegsa J, Weber M, et al. Candida albicans infection leads to barrier breakdown and a MAPK/NF‐κB mediated stress response in the intestinal epithelial cell line C2BBe1. Cell Microbiol 2016;18:889-904.
100. D’Souza WN, Chang C-F, Fischer AM, Li M, Hedrick SM. The Erk2 MAPK regulates CD8 T cell proliferation and survival. J Immunol 2008;181:7617-7629.
101. Oh H, Ghosh S. NF‐κB: Roles and regulation in different CD 4+ T‐cell subsets. Immunol Rev 2013;252:41-51.
102. Gerondakis S, Siebenlist U. Roles of the NF-κB pathway in lymphocyte development and function. Cold Spring Harb Perspect Biol 2010 May;2:a000182.
103. Gratacap RL, Rawls JF, Wheeler RT. Mucosal candidiasis elicits NF-κB activation, proinflammatory gene expression and localized neutrophilia in zebrafish. Dis Model Mech 2013;6:1260-1270.
104. Ali S, Lazennec G. Chemokines: novel targets for breast cancer metastasis. Cancer Metastasis Rev 2007;26:401-420.
105. Esquivel-Velázquez M, Ostoa-Saloma P, Palacios-Arreola MI, Nava-Castro KE, Castro JI, Morales-Montor J. The role of cytokines in breast cancer development and progression. J Interferon Cytokine Res 2015;35:1-16.
106. Rodríguez-Cuesta J, Hernando FL, Mendoza L, Gallot N, de Cerio AAD, Martínez-de-Tejada G, Vidal-Vanaclocha F. Candida albicans enhances experimental hepatic melanoma metastasis. Clin Exp Metastasis 2010;27:35-42.
107. Pikman R, Ben-Ami R. Immune modulators as adjuncts for the prevention and treatment of invasive fungal infections. Immunotherapy 2012;4:1869-1882.
108. Zelante T, De Luca A, Bonifazi P, Montagnoli C, Bozza S, Moretti S, et al. IL‐23 and the Th17 pathway promote inflammation and impair antifungal immune resistance. Eur J Immunol 2007;37:2695-2706.
109. Vodovotz Y, Bogdan C, Paik J, Xie Q, Nathan C. Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor beta. J Exp Med 1993;178:605-613.
110. Derynck R, Akhurst RJ, Balmain A. TGF-β signaling in tumor suppression and cancer progression. Nat Genet 2001;29:117-129.
111. Walker RA, Dearing SJ. Transforming growth factor beta1 in ductal carcinoma in situ and invasive carcinomas of the breast. Eur J Cancer 1992;28:641-644.
112. Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, et al. Surface phenotype and antigenic specificity of human interleukin 17–producing T helper memory cells. Nat Immunol 2007;8:639-646.
113. Stockinger B, Omenetti S. The dichotomous nature of T helper 17 cells. Nat Rev Immunol 2017;17:535-544.
114. Yano J, Noverr MC, Fidel Jr PL. Cytokines in the host response to Candida vaginitis: Identifying a role for non-classical immune mediators, S100 alarmins. Cytokine. 2012;58:118-128.
115. Huang W, Na L, Fidel PL, Schwarzenberger P. Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis 2004;190:624-631.
116. Donskov F, von der Maase H. Impact of immune parameters on long-term survival in metastatic renal cell carcinoma. J Clin Oncol 2006;24:1997-2005.
117. Moyes DL, Richardson JP, Naglik JR. Candida albicans-epithelial interactions and pathogenicity mechanisms: scratching the surface. Virulence. 2015;6:338-346.
118. Gustafson K, Vercellotti G, Bendel C, Hostetter M. Molecular mimicry in Candida albicans. Role of an integrin analogue in adhesion of the yeast to human endothelium. J Clin Invest 1991;87:1896-1902.
119. Dana N, Todd Rd, Pitt J, Springer TA, Arnaout MA. Deficiency of a surface membrane glycoprotein (Mo1) in man. J Clin Invest 1984;73:153-159.
120. Gilmore BJ, Retsinas EM, Lorenz JS, Hostetter MK. An iC3b receptor on Candida albicans: structure, function, and correlates for pathogenicity. J Infect Dis 1988;157:38-46.
121. Forche A, Abbey D, Pisithkul T, Weinzierl M, Ringstrom T, Bruck D, et al. Stress alters rates and types of loss of heterozygosity in Candida albicans. MBio 2011;2:e00129-11.
122. Ford CB, Funt JM, Abbey D, Issi L, Guiducci C, Martinez DA, et al. The evolution of drug resistance in clinical isolates of Candida albicans. Elife. 2015;4:e00662.
123. Hirakawa MP, Martinez DA, Sakthikumar S, Anderson MZ, Berlin A, Gujja S, et al. Genetic and phenotypic intra-species variation in Candida albicans. Genome Res 2015;25:413-425.
124. Lephart PR, Magee PT. Effect of the major repeat sequence on mitotic recombination in Candida albicans. Genetics 2006;174:1737-1744.
125. Braun BR, van Het Hoog M, d’Enfert C, Martchenko M, Dungan J, Kuo A, et al. A human-curated annotation of the Candida albicans genome. PLoS Genet 2005;1:e21.
126. Jones T, Federspiel NA, Chibana H, Dungan J, Kalman S, Magee B, et al. The diploid genome sequence of Candida albicans. Proc Natl Acad Sci U S A 2004 ;101:7329-7334.
127. Chibana H, Iwaguchi S, Homma M, Chindamporn A, Nakagawa Y, Tanaka K. Diversity of tandemly repetitive sequences due to short periodic repetitions in the chromosomes of Candida albicans. J Bacteriol1994;176:3851-3858.
128. Goodwin TJ, Poulter RT. The CARE-2 and rel-2 repetitive elements of Candida albicans contain LTR fragments of a new retrotransposon. Gene 1998;218:85-93.
129. Goodwin TJ, Poulter RT. Multiple LTR-retrotransposon families in the asexual yeast Candida albicans. Genome Res 2000;10:174-191.
130. Selmecki A, Forche A, Berman J. Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science. 2006;313:367-370.
131. Selmecki A, Forche A, Berman J. Genomic plasticity of the human fungal pathogen Candida albicans. Eukaryot Cell 2010;9:991-1008.
132. Kadosh D. Shaping up for battle: morphological control mechanisms in human fungal pathogens. PLoS Pathog 2013;9:e1003795.
133. Rusche LN, Kirchmaier AL, Rine J. The establishment, inheritance, and function of silenced chromatin in Saccharomyces cerevisiae. Annu Rev Biochem 2003;72:481-516.
134. Sitterlé E, Maufrais C, Sertour N, Palayret M, d’Enfert C, Bougnoux M-E. Within-host genomic diversity of Candida albicans in healthy carriers. Sci Rep 2019 ;9:2563.
135. Thomas M, Lange-Grünweller K, Weirauch U, Gutsch D, Aigner A, Grünweller A, et al. The proto-oncogene Pim-1 is a target of miR-33a. Oncogene 2012;31:918-928.
136. Liang G, Liu Z, Tan L, Su A, Jiang WG, Gong C. HIF1α-associated circDENND4C promotes proliferation of breast cancer cells in hypoxic environment. Anticancer Res 2017;37:4337-4343.
137. He R, Liu P, Xie X, Zhou Y, Liao Q, Xiong W, et al. circGFRA1 and GFRA1 act as ceRNAs in triple negative breast cancer by regulating miR-34a. J Exp Clin Cancer Res 2017;36:145.
138. Guil S, Esteller M. RNA–RNA interactions in gene regulation: the coding and noncoding players. Trends Biochem Sci 2015;40:248-256.
139. Muhammad SA, Fatima N, Syed N-i-H, Wu X, Yang XF, Chen JY. MicroRNA expression profiling of human respiratory epithelium affected by invasive Candida infection. PLoS One 2015;10:e0136454.
140. Monk CE, Hutvagner G, Arthur JSC. Regulation of miRNA transcription in macrophages in response to Candida albicans. PLoS One 2010;5:e13669.
141. Ramirez-Garcia A, Gallot N, Abad A, Mendoza L, Rementeria A, Hernando FL. Molecular fractionation and characterization of a Candida albicans fraction that increases tumor cell adhesion to hepatic endothelium. Appl Microbiol Biotechnol 2011;92:133-145.
142. Onyewu C, Heitman J. Unique applications of novel antifungal drug combinations. Anti-Infective Agents in Medicinal Chemistry. 2007;6:3-15.
143. Wakharde AA, Halbandge SD, Phule DB, Karuppayil SM. Anticancer drugs as antibiofilm agents in candida albicans: Potential targets. Assay Drug Dev Technol 2018;16:232-246.
144. Routh MM, Chauhan NM, Karuppayil SM. Cancer drugs inhibit morphogenesis in the human fungal pathogen, Candida albicans. Braz J Microbiol 2013;44:855-859.
145. Routh MM, Raut JS, Karuppayil SM. Dual properties of anticancer agents: an exploratory study on the in vitro anti-Candida properties of thirty drugs. Chemotherapy 2011;57:372-380.
146. Muthular M, Bálsamo F, Passero P, Jewtuchowicz V, Miozza V, Villalba MB, et al. Effects of tamoxifen on periodontal disease and Candida albicans of patients with breast cancer and other pathologies. Future microbiol 2019;14:129-137.
147. Liu S, Hou Y, Liu W, Lu C, Wang W, Sun S. Components of the calcium-calcineurin signaling pathway in fungal cells and their potential as antifungal targets. Eukaryot Cell 2015;14:324-334.
148. Dolan K, Montgomery S, Buchheit B, DiDone L, Wellington M, Krysan DJ. Antifungal activity of tamoxifen: In vitro and in vivo activities and mechanistic characterization. Antimicrob Agents Chemother 2009;53:3337-3346.
149. Hosseinzadeh A, Stylianou M, Lopes JP, Müller DC, Häggman A, Holmberg S, et al. Stable redox-cycling nitroxide tempol has antifungal and immune-modulatory properties. Front Microbiol 2019;10:1843.
150. Moran GP, Coleman DC, Sullivan DJ. Comparative genomics and the evolution of pathogenicity in human pathogenic fungi. Eukaryot Cell 2011;10:34-42.
151. Taylor JW. Evolutionary perspectives on human fungal pathogens. Cold Spring Harb Perspect Med 2014;5: a019588.