MATRIX METALLOPROTEINASES-2 AND -9 AS REDOX-DEPENDENT MARKERS OF BREAST CANCER METASTASIS
DOI:
https://doi.org/10.32471/oncology.2663-7928.t-23-3-2021-g.9732Keywords:
adipose tissue, breast cancer, gelatinases, markers of progression, superoxide radicalsAbstract
Determining prognostic factors is a key point for assessing the aggressiveness of breast cancer (BC), individual prognosis and probable response to treatment. MMP-2 and -9 (gelatinases) are redox-dependent molecules that provide proteolytic degradation of the intercellular matrix and signaling at each stage of the metastatic cascade. Aim: to investigate the relationship between redox-dependent activation of gelatinases and metastasis, levels of MMP-2 and -9 activity in the adipose tissue (AT) of obese breast cancer patients and in the serum of breast cancer patients with a different hormone receptor status. Object and methods: blood, tumor and adipose tissues of 116 patients with stage I-IV breast cancer were studied. Methods of zymography in polyacrylamide gel, electron-paramagnetic resonance, statistical were used. Results: superoxide radicals (SR), which control the activity of gelatinases, are involved in the destruction regulation of the intercellular matrix during the progression of breast cancer. The levels of the SR generation rate and the activity of MMP-2 and -9 in the tumor correlate with each other, as well as with the stages and regional metastasis of breast cancer. The levels of gelatinase activity in the breast AT in patients with breast cancer of the basal molecular subtype with obesity depend on its volume and distance from the tumor. We detected violations of the redox state of neutrophils and the functioning of gelatinases in the serum of patients with breast cancer of reproductive age, which depend on the hormonal status of women, are manifested by increased levels of SR and MMP-9 activity in ER (-)/PR (-) tumor status and may affect the course of the disease and the survival of patients. Conclusions: indicators of gelatinase activity, determined in tumor and blood, are promising markers of breast cancer progression, in particular for overweight patients and/or for patients of reproductive age with a certain hormonal status.
References
Rositch AF, Unger-Saldana K, DeBoer RJ, et al. The role of dissemination and implementation science in global breast cancer control programs: Frameworks, methods, and examples. Cancer 2020; 126 (Suppl 10): 2394–404.
Wild CP, Weiderpass E, Stewart BW, editors. World Cancer Report: Cancer Research for Cancer Prevention. Lyon, France: International Agency for Research on Cancer 2020. Available from: http://publications.iarc.fr/586.
Ginsburg O, Yip CH, Brooks A, et al. Breast cancer early detection: A phased approach to implementation. Cancer 2020; 126 (Suppl 10): 2379–93.
Mutebi M, Anderson BO, Duggan C, et al. Breast cancer treatment: A phased approach to implementation. Cancer 2020; 126 (Suppl 10): 2365–78.
Goossens GH, Blaak EE. Adipose tissue dysfunction and impaired metabolic health in human obesity: a matter of oxygen. Front endocrinol (lausanne) 2015; 6 (55): 1–5.
Colditz G, Peterson L. Obesity and Cancer: Evidence, Impact, and Future Directions.Clinical Chemistry 2018; 64 (1): 154–62.
Reaves DK, Ginsburg E, Bang JJ, et al. Persistent organic pollutants & obesity: potential mechanisms for breast cancer promotion? Endocr relat cancer 2015; 22 (2): 69–86.
Choi TG, Kim SS. Physiological functions of Mitochondrial Reactive Oxygen Species. Free Radical Medicine and Biology 2019; DOI: 10.5772/intechopen.88386.
Mohammadian H, Sharifi R, Rezanezhad Amirdehi S, et al. Matrix metalloproteinase MMP1 and MMP9 genes expression in breast cancer tissue. Gene Reports 2020; DOI: 10.1016/j.genrep.2020.100906.
Martins LM, de Melo Escorcio Dourado CS, Campos-Verdes LM, et al. Expression of matrix metalloproteinase 2 and 9 in breast cancer and breast fibroadenoma: a randomized, double-blind study. Oncotarget 2019; 10 (64): 6879–84.
Perillo B, Di Donato M, Pezone A, et al. ROS in cancer therapy: the bright side of the moon. Exp Mol Med 2020; 52: 192–203.
Burlaka AP, Sidorik EP, Ganusevich II, et al. High formation of superoxide anion and nitric oxide, and matrix metalloproteinases activity in vascular wall of rectal carcinoma vessels. Exp Oncol 2006; 28: 323–5.
De Clerk YA, Perez N, Shimada H, et al. Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer research 1992; 52: 701–8.
Nuttall FQ. Body Mass Index Obesity, BMI, and Health. Nutrition Research, 2015; 50 (3): 117–28.
Ghouse SM, Vadrevu SK, Manne S, et al. Therapeutic targeting of vasculature in the premetastatic and metastatic niches reduces lung metastasis. J Immunol 2020; DOI: 10.4049/jimmunol.1901208.
Wang Y, Ding Y, Guo N, Wang S. MDSCs: key criminals of tumor pre-metastatic niche formation. Front Immunol 2019; 10: 172.
Wu H, Ballantyne CM. Metabolic Inflammation and Insulin Resistance in Obesity. Circulation Research 2020; 126: 1549–64.
Nurul M, Hussain AS, Sarwar S, et al. How the association between obesity and inflammation may lead to insulin resistance and cancer. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 2019; 13 (2): 1213–24.
Burlaka AP, Ganusevich II, Vovk AV, et al. Prognostic value of blood redox-state indicators in patients with breast cancer. Oncology 2018; 20 (1): 17–22 (in Ukrainian).
Merlo S, Sortino MA. Estrogen activates matrix metalloproteinases-2 and -9 to increase beta amyloid degradation. Mol Cell Neurosci 2012; 49 (4): 423–9.
Morales-Vásquez F, Castillo-Sánchez R, Gómora MJ, et al. Expression of metalloproteinases MMP-2 and MMP-9 is associated to the presence of androgen receptor in epithelial ovarian tumors. J Ovarian Res 2020; DOI: 10.1186/s13048-020-00676-x.
Quintero-Fabián S, Arreola R, Becerril-Villanueva E, et al. Role of matrix metalloproteinases in angiogenesis and cancer. Front Oncol 2019; 9: 1370.
Wu J, Heemskerk JWM, Baaten CCFMJ. Platelet membrane receptor proteolysis: implications for platelet function. Front Cardiovasc Med 2021; DOI: 10.3389/fcvm.2020.608391.
Kuliczkowski W, Radomski M, Gąsior M, et al. MMP-2, MMP-9, and TIMP-4 and response to aspirin in diabetic and nondiabetic patients with stable coronary artery disease: a pilot study. Biomed Res Int 2017; DOI: 10.1155/2017/9352015.
Larkin CM, Hante NK, Breen EP, et al. Role of matrix metalloproteinases 2 and 9, toll-like receptor 4 and platelet-leukocyte aggregate formation in sepsis-associated thrombocytopenia. PLoS One 2018; DOI: 10.1371/journal.pone.0196478.
Ye Y, Kuang X, Xie Z, et al. Small-molecule MMP2/MMP9 inhibitor SB-3CT modulates tumor immune surveillance by regulating PD-L1. Genome Med 2020; 12 (1): 83.
Samavat H, Kurzer MS. Estrogen metabolism and breast cancer. Cancer Lett 2015; 356 (2 Pt A): 231–43.
