Role of PI3K/AKT/mTOR Signaling Pathways in Breast Cancer

Year : 2025 | Volume : 14 | Issue : 01 | Page : 23 34
    By

    Bhupendra Kumar,

  1. Student, Department of Biotechnology, HELIX BIO GENESIS PVT LTD A-52, Sector-2, Noida, Uttar Pradesh`, India

Abstract

Abstract: Breast cancer is among the most commonly diagnosed cancers and remains a leading cause of mortality among women globally. Although early detection and interventions aimed at curtailing tumor progression have significantly improved breast cancer survival rates, there is an ongoing demand for more potent systemic therapies to effectively prevent metastasis. A central pathway frequently associated with the growth, survival, and motility of breast cancer cells is the PI3K/AKT/mTOR signaling cascade. Over the past three decades, rapid progress has been made in the development of inhibitors targeting these critical signaling components, yielding promising preclinical outcomes for cancer therapeutics. The mTOR pathway regulates essential cellular processes, including cell proliferation, autophagy, and apoptosis, by being activated through multiple pathways within the body. Aberrant activation of mTOR signaling is commonly observed in tumors and is associated with diseases such as cancer, arthritis, insulin resistance, osteoporosis, and other pathological conditions. Recent studies have categorized various inhibitors targeting the PI3K/AKT/mTOR axis, highlighting their therapeutic potential.

Keywords: Breast cancer, PI3K, AKT, mTOR pathways, tumor growth and proliferation

[This article belongs to Research and Reviews: Journal of Oncology and Hematology ]

How to cite this article:
Bhupendra Kumar. Role of PI3K/AKT/mTOR Signaling Pathways in Breast Cancer. Research and Reviews: Journal of Oncology and Hematology. 2025; 14(01):23-34.
How to cite this URL:
Bhupendra Kumar. Role of PI3K/AKT/mTOR Signaling Pathways in Breast Cancer. Research and Reviews: Journal of Oncology and Hematology. 2025; 14(01):23-34. Available from: https://journals.stmjournals.com/rrjooh/article=2025/view=199601


References

  1. Breast Cancer in Men—CDC Report. Centers for Disease Control and Prevention; 2020 Aug 11 [cited 2020 Oct 6]. Available from: https://www.cdc.gov/cancer/men
  2. Sancho-Garnier H, Colonna M. Épidémiologie des cancers du sein: Breast cancer epidemiology. Presse Med. 2019;48(10):1076–84. doi:10.1016/j.lpm.2019.09.017
  3. Graham AC. Breast Cancer Epidemiology and Risk Factors. Medscape; 2019 Dec 26. Available from: https://emedicine.medscape.com/article/1697353-overview
  4. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S. Cancer Incidence and Mortality Worldwide: IARC; 2013.
  5. National Cancer Institute Surveillance, Epidemiology, and End Results Programme (SEER)—Cancer Stat Facts: Female Breast Cancer. 2020 [cited 2020 Oct 7]. Available from: http://seer.cancer.gov/statfacts/html/breast.html
  6. Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Mortality-All COD, Aggregated with State, Total US (1990–2017) . National Cancer Institute, Division of Cancer Control and Population Sciences, Surveillance Research Program; 2019.
  7. DeSantis CE, Ma J, Goding SA, Newman LA, Jemal A. Breast cancer statistics, 2017: Racial disparity in mortality by state. CA Cancer J Clin. 2017;67(6):439–48. doi:10.3322/caac.21412
  8. Bernstein L, Ross RK. Endogenous hormones and breast cancer risk. Epidemiol Rev. 1993;15(1):48–65. doi:10.1093/oxfordjournals.epirev.a036112
  9. Colditz GA, Rosner B. Cumulative risk of breast cancer to age 70 years according to risk factor status: Data from the Nurses’ Health Study. Am J Epidemiol. 2000;152(10):950–64. doi:10.1093/aje/152.10.950
  10. Giordano SH, Buzdar AU, Hortobagyi GN. Breast cancer in men. Ann Intern Med. 2002;137(8):678–87. doi:10.7326/0003-4819-137-8-200210150-00014
  11. Meo SA, Suraya F, Jamil B, Al Rouq F, Meo AS, Sattar K, et al. Association of ABO and Rh blood groups with breast cancer. Saudi J Biol Sci. 2017;24(7):1609–13. doi:10.1016/j.sjbs.2016.10.008
  12. National Center for Health Statistics. SEER Cancer Statistics Review, 1973–1999. Bethesda, MD: National Cancer Institute; 1998.
  13. Lilienfeld AM. The relationship of cancer of the female breast to artificial menopause and marital status. Cancer. 1956;9(5):927–34. doi:10.1002/1097-0142(195609)9:53.0.co;2-k
  14. Ma H, Henderson KD, Sullivan-Halley J, Duan L, Marshall SF, Ursin G, et al. Pregnancy-related factors and the risk of breast carcinoma in situ and invasive breast cancer among postmenopausal women in the California Teachers Study cohort. Breast Cancer Res. 2010;12(3):R35. doi:10.1186/bcr2576
  15. Balekouzou A, Yin P, Pamatika CM, Bekolo CE, Nambei SW, Djeintote M, et al. Reproductive risk factors associated with breast cancer in women in Bangui: A case-control study. BMC Womens Health. 2017;17(1):14. doi:10.1186/s12905-017-0377-6
  16. Kim Y, Yoo KY, Goodman MT. Differences in incidence, mortality, and survival of breast cancer by regions and countries in Asia and contributing factors. Asian Pac J Cancer Prev. 2015;16(7):2857–70. doi:10.7314/apjcp.2015.16.7.2857
  17. Freund C, Mirabel L, Annane K, Mathelin C. Breastfeeding and breast cancer. Gynecol Obstet Fertil. 2005;33(11):739–44. doi:10.1016/j.gyobfe.2005.09.018
  18. Jeong SH, An YS, Choi JY, Park B, Kang D, Lee MH, et al. Risk reduction of breast cancer by childbirth, breastfeeding, and their interaction in Korean women: Heterogeneous effects across menopausal status, hormone receptor status, and pathological subtypes. J Prev Med Public Health. 2017;50(6):401–10. doi:10.3961/jpmph.17.110
  19. Deng Y, Xu H, Zeng X. Induced abortion and breast cancer: An updated meta-analysis. Medicine (Baltimore). 2018;97(13):e9613. doi:10.1097/md.0000000000009613
  20. Key T, Appleby P, Barnes I, Reeves G. Endogenous sex hormones and breast cancer in postmenopausal women: Reanalysis of nine prospective studies. J Natl Cancer Inst. 2002;94(8):606–16. doi:10.1093/jnci/94.8.606
  21. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90(18):1371–88. doi:10.1093/jnci/90.18.1371
  22. Tworoger SS, Eliassen AH, Rosner B, Sluss P, Hankinson SE. Plasma prolactin concentrations and risk of postmenopausal breast cancer. Cancer Res. 2004;64(18):6814–9. doi:10.1158/0008-5472.can-04-1870
  23. Collaborative Group of Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: Collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet. 1996;347(9017):1713–27. doi:10.1016/s0140-6736(96)90806-5
  24. Beral V, Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362(9382):419–27. doi:10.1016/s0140-6736(03)14065-2
  25. Beral V, Bull D, Doll R, Key T, Peto R, Reeves G. Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet. 1997;350(9084):1047–59. doi:10.1016/s0140-6736(97)08233-0
  26. Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: Estrogen versus estrogen plus progestin. J Natl Cancer Inst. 2000;92(4):328–32. [CrossRef]
  27. Colditz GA. Estrogen, estrogen plus progestin therapy, and risk of breast cancer. Clin Cancer Res. 2005;11(2 Suppl):909s–917s.
  28. Rojas K, Stuckey A. Breast cancer epidemiology and risk factors. Clin Obstet Gynecol. 2016;59(4):651–72. [CrossRef] [PubMed]
  29. Yari K, Rahimi Z, Moradi MT, Rahimi Z. The MMP-2-735 C allele is a risk factor for susceptibility to breast cancer. Asian Pac J Cancer Prev. 2014;15(15):6199–203. [CrossRef]
  30. O’Brien KM, Sandler DP, Taylor JA, Weinberg CR. Serum vitamin D and risk of breast cancer within five years. Environ Health Perspect. 2017;125(7):077004. [CrossRef]
  31. Hamajima N, Hirose K, Tajima K, Rohan T, Calle EE, Heath CW Jr, et al. Alcohol, tobacco and breast cancer—Collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer. 2002;87(11):1234–45. [PubMed]
  32. Romieu I, Scoccianti C, Chajès V, de Batlle J, Biessy C, Dossus L, et al. Alcohol intake and breast cancer in the European prospective investigation into cancer and nutrition. Int J Cancer. 2015;137(8):1921–30. [CrossRef] [PubMed]
  33. Luo J, Margolis KL, Wactawski-Wende J, Horn K, Messina C, Stefanick ML, et al. Association of active and passive smoking with risk of breast cancer among postmenopausal women: A prospective cohort study. BMJ. 2011;342:d1016. [CrossRef] [PubMed]
  34. Tong JH, Li Z, Shi J, Li HM, Wang Y, Fu LY, et al. Passive smoking exposure from partners as a risk factor for ER+/PR+ double positive breast cancer in never-smoking Chinese urban women: A hospital-based matched case control study. PLoS ONE. 2014;9(6):e97498. [CrossRef] [PubMed]
  35. S. Surgeon General. The health consequences of involuntary exposure to tobacco smoke: A report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services; 2006 [cited 2020 Oct 11]. Available from: www.surgeongeneral.gov/library/secondhandsmoke/report/index.html
  36. Mctiernan A, Kooperberg C, White E, Wilcox S, Coates R, Adams-Campbell LL, et al. Recreational physical activity and the risk of breast cancer in postmenopausal women: The women’s health initiative cohort study. JAMA. 2003;290(10):1331–6. [CrossRef] [PubMed]
  37. Lee JA. Meta-analysis of the association between physical activity and breast cancer mortality. Cancer Nurs. 2019;42(4):271–85. [CrossRef] [PubMed]
  38. Orsini M, Trétarre B, Daurès JP, Bessaoud F. Individual socioeconomic status and breast cancer diagnostic stages: A French case-control study. Eur J Public Health. 2016;26(3):445–50. [CrossRef]
  39. Lundqvist A, Andersson E, Ahlberg I, Nilbert M, Gerdtham U. Socioeconomic inequalities in breast cancer incidence and mortality in Europe—a systematic review and meta-analysis. Eur J Public Health. 2016;26(5):804–13. [CrossRef] [PubMed]
  40. Hartmann LC, Sellers TA, Frost MH, Lingle WL, Degnim AC, Ghosh K, et al. Benign breast disease and the risk of breast cancer. N Engl J Med. 2005;353(3):229–37. [CrossRef] [PubMed]
  41. Brinton LA, Lubin JH, Murray MC, Colton T, Hoover RN. Mortality rates among augmentation mammoplasty patients: An update. Epidemiology. 2006;17(2):162–9. [CrossRef]
  42. Lim W, Mayer B, Pawson T. Cell Signaling: Principles and Mechanisms. New York, NY: Garland Science; 2015.
  43. Paduch M, Jelen F, Otlewski J. Structure of small G proteins and their regulators. Acta Biochim Pol. 2001;48(4):829–50. [CrossRef]
  44. Hancock JF. Ras proteins: Different signals from different locations. Nat Rev Mol Cell Biol. 2003;4(5):373–84. [CrossRef]
  45. Yudushkin I. Getting the Akt together: Guiding intracellular Akt activity by PI3K. Biomolecules. 2019;9(2):67. [CrossRef]
  46. Yu X, Long YC, Shen HM. Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy. Autophagy. 2015;11(10):1711–28. [CrossRef]
  47. Balla T. Phosphoinositides: Tiny lipids with giant impact on cell regulation. Physiol Rev. 2013;93(3):1019–37. [CrossRef] [PubMed]
  48. Braccini L, Ciraolo E, Campa CC, Perino A, Longo DL, Tibolla G, et al. PI3K-C2 is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signaling. Nat Commun. 2015; 6:7400. [CrossRef] [PubMed]
  49. Falasca M, Hughes WE, Dominguez V, Sala G, Fostira F, Fang MQ, et al. The role of phosphoinositide 3-kinase C2_ in insulin signaling. J Biol Chem. 2007;282(39):28226–36. [CrossRef] [PubMed]
  50. Backer J. The intricate regulation and complex functions of the Class III phosphoinositide 3-kinase Vps34. Biochem J. 2016;473(17):2251–71. [CrossRef]
  51. Hanker AB, Pfefferle AD, Balko JM, Kuba MG, Young CD, Sánchez V, et al. Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies. Proc Natl Acad Sci U S A. 2013;110(37):14372–7. [CrossRef] [PubMed]
  52. Loibl S, Majewski I, Guarneri V, Nekljudova V, Holmes E, Bria E, et al. Corrections to “PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: Pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab.” Ann Oncol. 2019;30(8):1180. [CrossRef] [PubMed]
  53. Guerin M, Rezai K, Isambert N, Campone M, Autret A, Pakradouni J, et al. PIKHER2: A phase IB study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer. Eur J Cancer. 2017;86:28–36. [CrossRef] [PubMed]
  54. Pistilli B, Pluard T, Urruticoechea A, Farci D, Kong A, Bachelot T, et al. Phase II study of buparlisib (BKM120) and trastuzumab in patients with HER2+ locally advanced or metastatic breast cancer resistant to trastuzumab-based therapy. Breast Cancer Res Treat. 2018;168(2):357–64. [CrossRef]
  55. Loibl S, de la Pena L, Nekljudova V, Zardavas D, Michiels S, Denkert C, et al. Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+ primary breast cancer: A randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE). Eur J Cancer. 2017;85:133–45. [CrossRef]
  56. Jain S, Shah AN, Santa-Maria CA, Siziopikou K, Rademaker A, Helenowski I, et al. Phase I study of alpelisib (BYL-719) and trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC) after trastuzumab and taxane therapy. Breast Cancer Res Treat. 2018;171(2):371–81. [CrossRef]
  57. Barok M, Tanner M, Köninki K, Isola J. Trastuzumab-DM1 causes tumour growth inhibition by mitotic catastrophe in trastuzumab-resistant breast cancer cells in vivo. Breast Cancer Res. 2011;13(3):R46. [CrossRef]
  58. Zhang M, Jang H, Nussinov R. PI3K inhibitors: Review and new strategies. Chem Sci. 2020;11(21):5855–65. [CrossRef]
  59. Hong R, Edgar K, Song K, Steven S, Young A, Hamilton P, et al. Abstract PD4-14: GDC-0077 is a selective PI3Kalpha inhibitor that demonstrates robust efficacy in PIK3CA mutant breast cancer models as a single agent and in combination with standard of care therapies. Poster Discuss Abstr. 2018;78. [CrossRef]
  60. Turner N, Dent R, O’Shaughnessy J, Kim S-B, Isakoff S, Barrios C, et al. 283MO Ipatasertib (IPAT) + paclitaxel (PAC) for PIK3CA/AKT1/PTEN-altered hormone receptor-positive (HR+) HER2-negative advanced breast cancer (aBC): Primary results from Cohort B of the IPATunity130 randomised phase III trial. Ann Oncol. 2020;31:S354–5. [CrossRef]
  61. Manning BD, Toker A. AKT/PKB signaling: Navigating the network. Cell. 2017;169(3):381–405. [CrossRef]
  62. Dummler B, Hemmings BA. Physiological roles of PKB/Akt isoforms in development and disease. Biochem Soc Trans. 2007;35(Pt 2):231–5. [CrossRef]
  63. Szymonowicz K, Oeck S, Malewicz NM, Jendrossek V. New insights into protein kinase B/Akt signaling: Role of localized Akt activation and compartment-specific target proteins for the cellular radiation response. Cancers (Basel). 2018;10(3):78. [CrossRef]
  64. Revathidevi S, Munirajan AK. Akt in cancer: Mediator and more. Semin Cancer Biol. 2019;59:80–91. [CrossRef]
  65. Risso G, Blaustein M, Pozzi B, Mammi P, Srebrow A. Akt/PKB: One kinase, many modifications. Biochem J. 2015;468(2):99–214. [CrossRef]
  66. Manning BD, Toker A. AKT/PKB signaling: Navigating the network. Cell. 2017;169(3):381–405. [CrossRef]
  67. Luo CT, Li M. Foxo transcription factors in T cell biology and tumor immunity. Semin Cancer Biol. 2018;50:13–20. [CrossRef]
  68. Arcaro A, Guerreiro AS. The phosphoinositide 3-kinase pathway in human cancer: Genetic alterations and therapeutic implications. Curr Genomics. 2007;8(5):271–86. [CrossRef] [PubMed]
  69. Patel P, Woodgett JR. Glycogen Synthase Kinase 3: A Kinase for All Pathways? Curr Top Dev Biol. 2017;123:277–302. [PubMed]
  70. Dokken BB, Sloniger JA, Henriksen EJ. Acute selective glycogen synthase kinase-3 inhibition enhances insulin signaling in prediabetic insulin-resistant rat skeletal muscle. Am J Physiol Endocrinol Metab. 2005;288(6):E1188–94. [CrossRef] [PubMed]
  71. Patel P, Woodgett JR. Glycogen Synthase Kinase 3: A Kinase for All Pathways? Curr Top Dev Biol. 2017;123:277–302. [PubMed]
  72. Lochhead PA, Coghlan M, Rice SQ, Sutherland C. Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphoenolypyruvate carboxykinase gene expression. Diabetes. 2001;50(5):937–46. [CrossRef]
  73. Wei X, Luo L, Chen J. Roles of mTOR signaling in tissue regeneration. Cells. 2019;8(9):1075. [CrossRef]
  74. Kakumoto K, Ikeda J, Okada M, Morii E, Oneyama C. mLST8 promotes mTOR-mediated tumor progression. PLoS One. 2015;10(3):e0119015. [CrossRef]
  75. Mahoney RE, Azpurua J, Eaton BA. Insulin signaling controls neurotransmission via the 4eBP-dependent modification of the exocytotic machinery. eLife. 2016;5:e16807. [CrossRef]
  76. Kakumoto K, Ikeda J, Okada M, Morii E, Oneyama C. mLST8 promotes mTOR-mediated tumor progression. PLoS ONE. 2015;10:e0119015. [CrossRef]
  77. Berchtold D, Walther TC. TORC2 plasma membrane localization is essential for cell viability and restricted to a distinct domain. Mol Biol Cell. 2009;20:1565–1575. [CrossRef]
  78. Liu P, Gan W, Inuzuka H, Lazorchak AS, Gao D, Arojo O, et al. Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signaling to suppress tumorigenesis. Nat Cell Biol. 2013;15:1340–1350. [CrossRef]
  79. Hollenhorst PC, Bose ME, Mielke MR, Müller U, Fox CA. Forkhead genes in transcriptional silencing, cell morphology, and the cell cycle. Overlapping and distinct functions for FKH1 and FKH2 in Saccharomyces cerevisiae. Genetics. 2000;154:1533–1548.
  80. Cabrera-Ortega A, Feinberg D, Liang Y, Rossa JC, Graves DT. The role of Forkhead Box 1 (FOXO1) in the immune system: Dendritic cells, T cells, B cells, and hematopoietic stem cells. Crit Rev Immunol. 2017;37:1–13. [CrossRef] [PubMed]
  81. Ma Z, Xin Z, Hu W, Jiang S, Yang Z, Yan X, et al. Forkhead box O proteins: Crucial regulators of cancer EMT. Semin Cancer Biol. 2018;50:21–31. [CrossRef] [PubMed]
  82. Maiese K. Forkhead transcription factors: Formulating a FOXO target for cognitive loss. Curr Neurovasc Res. 2017;14:415–420. [CrossRef] [PubMed]
  83. Cretella D, Digiacomo G, Giovannetti E, Cavazzoni A. PTEN alterations as a potential mechanism for tumor cell escape from PD-1/PD-L1 inhibition. Cancers. 2019;11:1318. [CrossRef]
  84. Luongo F, Colonna F, Calapà F, Vitale S, Fiori ME, De Maria R. PTEN tumor-suppressor: The dam of stemness in cancer. Cancers. 2019;11:1076. [CrossRef]
  85. Naderali E, Khaki AA, Rad JS, Alihemmati A, Rahmati M, Nozad-Charoudeh H. Regulation and modulation of PTEN activity. Mol Biol Rep. 2018;45:2869–2881. [CrossRef]
  86. Maehama T, Taylor GS, Dixon JE. PTEN and myotubularin: Novel phosphoinositide phosphatases. Annu Rev Biochem. 2001;70:247–279. [CrossRef]
  87. Nguyen KT, Tajmir P, Lin CH, Liadis N, Zhu XD, Eweida M, et al. Essential role of PTEN in body size determination and pancreatic beta-cell homeostasis in vivo. Mol Cell Biol. 2006;26:4511–4518. [CrossRef]
  88. Abraham J. PI3K/AKT/mTOR pathway inhibitors: The ideal combination partners for breast cancer therapies? Expert Rev Anticancer Ther. 2015;15:51–68. [CrossRef]
  89. Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature. 2012;485(7396):55–61. [CrossRef]
  90. Lim HJ, Crowe P, Yang JL. Current clinical regulation of PI3K/PTEN/Akt/mTOR signalling in treatment of human cancer. J Cancer Res Clin Oncol. 2015;141(4):671–689. [CrossRef]
  91. Zhang Y, Zhang J, Xu K, Xiao Z, Sun J, Xu J, et al. PTEN/PI3K/mTOR/B7-H1 signaling pathway regulates cell progression and immunoresistance in pancreatic cancer. Hepatogastroenterology. 2013;60(127):1766–1772.
  92. Chen JS, Wang Q, Fu XH, Huang XH, Chen XL, Cao LQ, et al. Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: Association with MMP-9. Hepatol Res. 2009;39(2):177–186. [CrossRef]
  93. Deng L, Chen L, Zhao L, Xu Y, Peng X, Wang X, et al. Ubiquitination of Rheb governs growth factor-induced mTORC1 activation. Cell Res. 2019;29(2):136–150. [CrossRef]
  94. Wang B, Jie Z, Joo D, Ordureau A, Liu P, Gan W, et al. TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling. Nature. 2017;545(7654):365–369. [CrossRef]
Regular Issue Subscription Review Article
Volume 14
Issue 01
Received 02/01/2025
Accepted 17/01/2025
Published 18/02/2025
Publication Time 47 Days
213

Login


My IP

PlumX Metrics