Author(s):
Hanaa H. Ahmed, Hadeer A. Aglan, Ghada H. Elsayed, Hebatallah G. Hafez, Emad F. Eskander
Email(s):
hanaaomr@yahoo.com , ha_dero@yahoo.com , ghadanrc@yahoo.com , hebagamal70388@gmail.com , gysi_pharma@yahoo.com.
DOI:
10.52711/0974-360X.2021.00499 
Address:
Hanaa H. Ahmed1,2*, Hadeer A. Aglan1,2, Ghada H. Elsayed1,2, Hebatallah G. Hafez1,2, Emad F. Eskander1
1Hormones Department, Medical Research Division, National Research Centre, Giza, Egypt.
2Stem Cells Lab, Center of Excellence for Advanced Sciences, National Research Centre, Giza, Egypt.
*Corresponding Author
Published In:
Volume - 14,
Issue - 5,
Year - 2021
ABSTRACT:
This approach was designed to explore the influence of quercetin on distinct molecular pathways implicated in breast cancer evolution. The cytotoxic impact of quercetin on two breast cancer cell lines, MCF-7 and MDA-MB-231 was quantified via MTT assay. The expression levels of the selected genes involved in apoptosis, proliferation, progression, invasion and metastases of breast cancer were analyzed using RT-PCR. The outcomes of the present study explicated that quercetin exhibited suppression effect on MCF-7 and MDA-MB-231 with IC50 = 151 and 958µM respectively after 48 h incubation time. Furthermore, the molecular genetic analysis revealed that quercetin provoked significant downregulation in the expression level of survivin, STAT3, IL-6, VEGF, Slug and MMP7 genes in both cell lines after hours. Meanwhile, MCF-7 exhibited insignificant downregulation in the expression level of Snail and Notch-4 genes after treatment with quercetin. In MDA-MB-231 cells, quercetin evoked insignificant downregulation in the expression level of Snail gene but significant downregulation in the expression level of Notch-4 gene. Conclusively, this work provides scientific clue that quercetin can combat breast cancer through modulating consequential signal transduction pathways engaged in breast cancer development.
Cite this article:
Hanaa H. Ahmed, Hadeer A. Aglan, Ghada H. Elsayed, Hebatallah G. Hafez, Emad F. Eskander. Quercetin Offers Chemopreventive Potential against Breast Cancer by Targeting a Network of Signalling Pathways. doi: 10.52711/0974-360X.2021.00499
Cite(Electronic):
Hanaa H. Ahmed, Hadeer A. Aglan, Ghada H. Elsayed, Hebatallah G. Hafez, Emad F. Eskander. Quercetin Offers Chemopreventive Potential against Breast Cancer by Targeting a Network of Signalling Pathways. doi: 10.52711/0974-360X.2021.00499 Available on: https://www.rjptonline.org/AbstractView.aspx?PID=2021-14-5-83
REFERENCES:
1. Habeela JN, Mohan MRMK. In Silico Molecular Docking Studies on the Chemical Constituents of Clerodendrum phlomidis for its Cytotoxic Potential against Breast Cancer Markers. Research Journal of Pharmacy and Technology. 2018; 11(4): 1612-1618.
2. Kashyap D, Garg VK, Tuli HS, et al. Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential. Biomolecules. 2019; 9(5): 174–195.
3. Soto AM, Sonnenschein C. Environmental causes of cancer: endocrine disruptors as carcinogens. Nature reviews. Endocrinology. 2010; 6(7): 363–370.
4. Dange VN, Shid SJ, Magdum CS, et al. A Review on Breast cancer: An Overview. Asian Journal of Pharmaceutical Research. 2017; 7(1): 49-51.
5. Jayashree V, Velraj M. Breast Cancer and various Prognostic Biomarkers for the diagnosis of the disease: A Review. Research Journal of Pharmacy and Technology. 2017; 10(9): 3211-3216.
6. Duo J, Ying G-G, Wang G-W, et al. Quercetin inhibits human breast cancer cell proliferation and induces apoptosis via Bcl-2 and Bax regulation. Molecular Medicine Reports. 2012; 5(6): 1453–1456.
7. Hariramani N, Jayanthi S. A Systematic Review of Intrinsic Factors and its Influence in Breast Cancer. Research Journal of Pharmacy and Technology. 2018; 11(8): 3543-3546.
8. Karale PA, Karale MA, Utikar MC. Advanced Molecular Targeted Therapy in Breast Cancer. Research Journal of Pharmacology and Pharmacodynamics.2018; 10(1): 29-37.
9. Chandrasekar R, Sivagami B, Niranjan Babu M. A Pharmacoeconomic Focus on Medicinal Plants with Anticancer Activity. Research Journal of Pharmacognosy and Phytochemistry. 2018; 10(1): 91-100.
10. Hemalatha CN, Anbarasu K, Vijey Aanandhi M. Evaluation of Anti-Cancer and Anti-Oxidant Activity of Cissus quandrangularis Extracts in DMBA induced Mammary Carcinomas. Research Journal of Pharmacy and Technology. 2017; 10(1): 293-300.
11. Thennarasu A. Quercetin in Health and Disease. Research Journal of Pharmacy and Technology. 2013; 6(12): 1397-1399.
12. Marais JPJ, Deavours B, Dixon RA, et al. The stereochemistry of flavonoids. In The Science of Flavonoids. Springer New York, 2006; pp. 1–46.
13. Okamoto T. Safety of quercetin for clinical application (Review). International Journal of Molecular Medicine. 2005; 16(2): 275–278.
14. Kashyap D, Tuli HS, Garg VK, et al. Oncogenic and Tumor-Suppressive Roles of MicroRNAs with Special Reference to Apoptosis: Molecular Mechanisms and Therapeutic Potential. Molecular Diagnosis and Therapy. 2018; 22(2): 179–201.
15. Shanmugam MK, Lee JH, Chai EZP, et al. Cancer prevention and therapy through the modulation of transcription factors by bioactive natural compounds. Seminars in Cancer Biology. 2016; 40–41: 35–47.
16. Van Meerloo J, Kaspers GJ, Cloos J. Cell sensitivity assays: The MTT assay. Methods in Molecular Biology. 2011; 731: 237-245.
17. Speth PA, Linssen PC, Boezeman JB, et al. Cellular and plasma adriamycin concentrations in long-term infusion therapy of leukemia patients. Cancer Chemotherapy and Pharmacology. 1987; 20: 305–310.
18. Gyamfi J, Lee Y-H, Eom M, et al. Interleukin-6/STAT3 signalling regulates adipocyte induced epithelial-mesenchymal transition in breast cancer cells. Scientific Reports. 2018; 8: 8859.
19. Lee K, Nam M, Lee H, et al. Protective effects of chebulic acid on alveolar epithelial damage induced by urban particulate matter. BMC Complementary and Alternative Medicine. 2017; 17: 373.
20. Liu L-Z, Jiang Y, Carpenter RL, et al. Role and Mechanism of Arsenic in Regulating Angiogenesis. PLoS ONE. 2011; 6: e20858.
21. Han Y-H, Kee J-Y, Hong S-H. Rosmarinic Acid Activates AMPK to Inhibit Metastasis of Colorectal Cancer. Frontiers in Pharmacol. 2018; 9: 68.
22. Gong C, Shen J, Fang Z, et al. Abnormally expressed JunB transactivated by IL-6/STAT3 signaling promotes uveal melanoma aggressiveness via epithelial-mesenchymal transition. Bioscience Reports. 2018; 38: BSR20180532.
23. Di D, Chen L, Guo Y, et al. BCSC-1 suppresses human breast cancer metastasis by inhibiting NF-κB signaling. International Journal of Oncology. 2018; 52: 1674-1684.
24. Upadhyay P, Sudhir N, Kaur E, et al. Notch pathway activation is essential for maintenance of stem-like cells in early tongue cancer. Oncotarget. 2016; 7: 50437–50449.
25. Wang M-C, Wu A-G, Huang Y-Z, et al. Autophagic regulation of cell growth by altered expression of Beclin 1 in triple-negative breast cancer. International Journal of Clinical and Experimental Medicine. 2015; 8: 7049–7058.
26. Parameswari P, Devika. R. In silico Molecular Docking Studies of Quercetin Compound against Anti-inflammatory and Anticancer Proteins. Research Journal of Pharmacy and Technology. 2019; 12(11): 5305-5309.
27. Kim GT, Lee SH, Kim JI, et al. Quercetin regulates the sestrin 2-AMPK-p38 MAPK signalling pathway and induces apoptosis by increasing the generation of intracellular ROS in a p53-independent manner. International Journal of Molecular Medicine. 2014; 33(4): 863–869.
28. Arivukkarasu R, Rajasekaran A, Kankaria V, et al. In Vitro Anti Cancer Activity and detection of Quercetin, Apigenin in Methanol extract of Euphorbia nivulia Buch.-Ham. By HPTLC Technique. Research Journal of Pharmacy and Technology. 2017; 10(8): 2637-2640.
29. Chien S-Y, Wu Y-C, Chung J-G, et al. Quercetin-induced apoptosis acts through mitochondrial- and caspase-3-dependent pathways in human breast cancer MDA-MB-231 cells. Human and Experimental Toxicology. 2009; 28(8): 493–503.
30. Deng X-H, Song H-Y, Zhou Y-F, et al. Effects of quercetin on the proliferation of breast cancer cells and expression of survivin in vitro. Experimental and Therapeutic Medicine. 2013; 6(5): 1155–1158.
31. Tran J, Master Z, Yu JL, et al. A role for survivin in chemoresistance of endothelial cells mediated by VEGF. Proceedings of the National Academy of Sciences of the United States of America. 2002; 99(7): 4349–4354.
32. Kawasaki H, Altieri DC, Lu C De, et al. Inhibition of apoptosis by survivin predicts shorter survival rates in colorectal cancer. Cancer Research. 1998; 58(22): 5071–5074.
33. Altieri DC. Targeting survivin in cancer. Cancer Letters. 2013; 332(2): 225–228.
34. Swana HS, Grossman D, Anthony JN, et al. Tumor Content of the Antiapoptosis Molecule Survivin and Recurrence of Bladder Cancer. New England Journal of Medicine. 1999; 341(6): 452–453.
35. Li F, Yang J, Ramnath N, et al. Nuclear or cytoplasmic expression of survivin: what is the significance? International Journal of Cancer. 2005; 114(4): 509–512.
36. Ryan BM, O’Donovan N, Duffy MJ. Survivin: a new target for anti-cancer therapy. Cancer Treatment Reviews. 2009; 35(7): 553–562.
37. Fukuda S, Pelus LM. Survivin, a cancer target with an emerging role in normal adult tissues. Molecular Cancer Therapeutics. 2006; 5(5): 1087–1098.
38. Wall NR, O’Connor DS, Plescia J, et al. Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis. Cancer Research. 2003; 63(1): 230–235.
39. Zhao J, Tenev T, Martins LM, et al. The ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner. Journal of Cell Science. 2000; 113 Pt 23(23): 4363–4371.
40. Yang Y, Fang S, Jensen JP, et al. Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli. Science. 2000; 288(5467): 874–877.
41. Grossman D, Kim PJ, Schechner JS, et al. Inhibition of melanoma tumor growth in vivo by survivin targeting. Proceedings of the National Academy of Sciences of the United States of America. 2001; 98(2): 635–640.
42. Blanc-Brude OP, Mesri M, Wall NR, et al. Therapeutic targeting of the survivin pathway in cancer: initiation of mitochondrial apoptosis and suppression of tumor-associated angiogenesis. Clinical Cancer Research. 2003; 9(7): 2683–2692.
43. Mu C, Jia P, Yan Z, et al. Quercetin induces cell-cycle G1 arrest through elevating Cdk inhibitors p21 and p27 in human hepatoma cell line (HepG2). Methods and Findings in Experimental and Clinical Pharmacology. 2007; 29(3): 179.
44. Hoffman WH, Biade S, Zilfou JT, et al. Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. The Journal of Biological Chemistry. 2002; 277(5): 3247–3257.
45. Mirza A, McGuirk M, Hockenberry TN, et al. Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene. 2002; 21(17): 2613–2622.
46. Ulasov IV, Tyler MA, Zhu ZB, et al. Oncolytic adenoviral vectors which employ the survivin promoter induce glioma oncolysis via a process of beclin-dependent autophagy. International Journal of Oncology. 2009; 34(3): 729–742.
47. Benekli M, Baer MR, Baumann H, et al. Signal transducer and activator of transcription proteins in leukemias. Blood. 2003; 101(8): 2940–2954.
48. Carpenter RL, Lo H-W. STAT3 Target Genes Relevant to Human Cancers. Cancers. 2014; 6(2): 897–925.
49. Aoki Y, Feldman GM, Tosato G. Inhibition of STAT3 signalling induces apoptosis and decreases survivin expression in primary effusion lymphoma. Blood. 2003; 101(4): 1535–1542.
50. Pandey A, Vishnoi K, Mahata S, et al. Berberine and Curcumin Target Survivin and STAT3 in Gastric Cancer Cells and Synergize Actions of Standard Chemotherapeutic 5-Fluorouracil. Nutrition and Cancer. 2015; 67(8): 1293–1304.
51. Yu H, Lee H, Herrmann A, et al. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nature Reviews Cancer. 2014; 14(11): 736–746.
52. Lim SJ, Li WX. Encyclopedia of Signalling Molecules. Phospho-and Unphospho-STATs in Signal Transduction and Gene Regulation (STAT). Springer; New York. 2012; pp. 1377–1380.
53. Yu H, Jove R. The STATs of cancer — new molecular targets come of age. Nature Reviews Cancer. 2004; 4(2): 97–105.
54. Song L, Turkson J, Karras JG, et al. Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene. 2003; 22(27): 4150–4165.
55. Heinrich PC, Behrmann I, Haan S, et al. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. The Biochemical Journal. 2003; 374(Pt 1): 1–20.
56. Wu YS, Chung I, Wong WF, et al. Paracrine IL-6 signalling mediates the effects of pancreatic stellate cells on epithelial-mesenchymal transition via Stat3/Nrf2 pathway in pancreatic cancer cells. Biochimica et Biophysica Acta. 2017; 1861(2): 296–306.
57. Badve S, Nakshatri H. Breast-cancer stem cells-beyond semantics. The Lancet Oncology. 2012; 13(1): e43-48.
58. Pattabiraman DR, Weinberg RA. Tackling the cancer stem cells - what challenges do they pose? Nature Reviews Drug Discovery. 2014; 13(7): 497–512.
59. Mukherjee A, Khuda-Bukhsh AR. Quercetin Down-regulates IL-6/STAT-3 Signals to Induce Mitochondrial-mediated Apoptosis in a Nonsmall- cell Lung-cancer Cell Line, A549. Journal of Pharmacopuncture. 2015; 18(1): 19–26.
60. Yu D, Ye T, Xiang Y, et al. Quercetin inhibits epithelial-mesenchymal transition, decreases invasiveness and metastasis, and reverses IL-6 induced epithelial-mesenchymal transition, expression of MMP by inhibiting STAT3 signalling in pancreatic cancer cells. OncoTargets and Therapy. 2017; 10: 4719–4729.
61. Kishimoto T. IL-6: from its discovery to clinical applications. International Immunology. 2010; 22(5): 347–52.
62. Hong DS, Angelo LS, Kurzrock R. Interleukin-6 and its receptor in cancer. Cancer. 2007; 110(9): 1911–1928.
63. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002; 420(6917): 860–867.
64. Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Clinical Oncology. 2018; 15(4): 234–248.
65. Nazari F, Pearson AT, Nör JE, Jackson TL. A mathematical model for IL-6-mediated, stem cell driven tumor growth and targeted treatment. PLoS Computational Biology. 2018; 14(1): e1005920.
66. Middleton K, Jones J, Lwin Z, et al. Interleukin-6: An angiogenic target in solid tumors. Critical Reviews in Oncology/Hematology. 2014; 89(1): 129–139.
67. Iwase S, Murakami T, Saito Y, et al. Steep elevation of blood interleukin-6 (IL-6) associated only with late stages of cachexia in cancer patients. European Cytokine Network. 2004; 15(4): 312–316.
68. Eichten A, Su J, Adler AP, et al. Resistance to Anti-VEGF Therapy Mediated by Autocrine IL6/STAT3 Signalling and Overcome by IL6 Blockade. Cancer Research. 2016; 76(8): 2327–2339.
69. Chang Q, Bournazou E, Sansone P, et al. The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. Neoplasia. 2013; 15(7): 848–862.
70. Sansone P, Storci G, Tavolari S, et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. The Journal of Clinical Investigation. 2007; 117(12): 3988–4002.
71. Sullivan NJ, Sasser AK, Axel AE, et al. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene. 2009; 28(33): 2940–2947.
72. Youn H, Jeong J-C, Jeong YS, et al. Quercetin potentiates apoptosis by inhibiting nuclear factor-kappaB signalling in H460 lung cancer cells. Biological and Pharmaceutical Bulletin. 2013; 36(6): 944–951.
73. Granado-Serrano AB, Martín MA, Bravo L, et al. Quercetin modulates NF-kappa B and AP-1/JNK pathways to induce cell death in human hepatoma cells. Nutrition and Cancer. 2010; 62(3): 390–401.
74. Zhang X-A, Zhang S, Yin Q, et al. Quercetin induces human colon cancer cells apoptosis by inhibiting the nuclear factor-kappa B Pathway. Pharmacognosy. 2015; 11(42): 404–409.
75. Libermann TA, Baltimore D. Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Molecular and Cellular Biology. 1990; 10(5): 2327–2334.
76. Leung DW, Cachianes G, Kuang WJ, et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989; 246(4935): 1306–1309.
77. Zhao X, Wang Q, Yang S, et al. Quercetin inhibits angiogenesis by targeting calcineurin in the xenograft model of human breast cancer. European Journal of Pharmacology. 2016; 781: 60–68.
78. Chirumbolo S. Quercetin in Cancer Prevention and Therapy. Integrative Cancer Therapies. 2013; 12(2): 97–102.
79. Ravishankar D, Watson KA, Boateng SY, et al. Exploring quercetin and luteolin derivatives as antiangiogenic agents. European Journal of Medicinal Chemistry. 2015; 97: 259–274.
80. Pratheeshkumar P, Budhraja A, Son Y-O, et al. Quercetin inhibits angiogenesis mediated human prostate tumor growth by targeting VEGFR- 2 regulated AKT/mTOR/P70S6K signalling pathways. PloS One. 2012; 7(10): e47516.
81. Rivera Rivera A, Castillo-Pichardo L, et al. Anti-Breast Cancer Potential of Quercetin via the Akt/AMPK/Mammalian Target of Rapamycin (mTOR) Signalling Cascade. PloS One. 2016; 11(6): e0157251.
82. Jia L, Huang S, Yin X, et al. Quercetin suppresses the mobility of breast cancer by suppressing glycolysis through Akt-mTOR pathway mediated autophagy induction. Life Sciences. 2018; 208: 123–130.
83. Kujawski M, Kortylewski M, Lee H, et al. Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. The Journal of Clinical Investigation. 2008; 118(10): 3367–3377.
84. Niu G, Wright KL, Huang M, et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene. 2002; 21(13): 2000–2008.
85. Olmeda D, Moreno-Bueno G, Flores JM, et al. SNAI1 is required for tumor growth and lymph node metastasis of human breast carcinoma MDA-MB-231 cells. Cancer Research. 2007; 67(24): 11721–11731.
86. Son H, Moon A. Epithelial-mesenchymal Transition and Cell Invasion. Toxicological Research. 2010; 26(4): 245–252.
87. Thuault S, Valcourt U, Petersen M, et al. Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition. The Journal of Cell Biology. 2006; 174(2): 175–183.
88. Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3’ kinase/AKT pathways. Oncogene. 2005; 24(50): 7443–7454.
89. Baruah Meghna M, Khandwekar AP, Sharma N. Quercetin modulates Wnt signalling components in prostate cancer cell line by inhibiting cell viability, migration, and metastases. Tumor Biology. 2016; 37(10): 14025–14034.
90. Uygur B, Wu W-S. SLUG promotes prostate cancer cell migration and invasion via CXCR4/CXCL12 axis. Molecular Cancer. 2011; 10: 139.
91. Zhang K, Chen D, Jiao X, et al. Slug enhances invasion ability of pancreatic cancer cells through upregulation of matrix metalloproteinase-9 and actin cytoskeleton remodeling. Laboratory Investigation. 2011; 91(3): 426–438.
92. Yang J, Weinberg RA. Epithelial-Mesenchymal Transition: At the Crossroads of Development and Tumor Metastasis. Developmental Cell. 2008; 14(6): 818–829.
93. Firdous AB, Sharmila G, Balakrishnan S, et al. Quercetin, a natural dietary flavonoid, acts as a chemopreventive agent against prostate cancer in an in vivo model by inhibiting the EGFR signalling pathway. Food and Function. 2014; 5(10): 2632–2645.
94. Xu Z, Jiang Y, Steed H, et al. TGFβ and EGF synergistically induce a more invasive phenotype of epithelial ovarian cancer cells. Biochemical and Biophysical Research Communications. 2010; 401(3): 376–381.
95. Franke WW, Grund C, Kuhn C, et al. Formation of Cytoskeletal Elements During Mouse Embryogenesis. Differentiation. 1982; 23(1–3): 43–59.
96. Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development. 2005; 132(14): 3151–3161.
97. Kurrey NK, Bapat SA. Snail and Slug are major determinants of ovarian cancer invasiveness at the transcription level. Gynecologic Oncology. 2005; 97(1): 155–165.
98. Kee J-Y, Han Y-H, Kim D-S, et al. Inhibitory effect of quercetin on colorectal lung metastasis through inducing apoptosis, and suppression of metastatic ability. Phytomedicine. 2016; 23(13): 1680–1690.
99. Roy R, Yang J, Moses MA. Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. Journal of Clinical Oncology. 2009; 27(31): 5287–5297.
100. Liu Y, Tang Z, Lin Y, et al. Effects of quercetin on proliferation and migration of human glioblastoma U251 cells. Biomedicine and Pharmacotherapy. 2017; 92: 33–38.
101. Miyazaki K, Hattori Y, Umenishi F, et al. Purification and characterization of extracellular matrix-degrading metalloproteinase, matrin (pump-1), secreted from human rectal carcinoma cell line. Cancer Research. 1990; 50(24): 7758–7764.
102. Heppner KJ, Matrisian LM, Jensen RA, et al. Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. The American Journal of Pathology. 1996; 149(1): 273–282.
103. Mori M, Barnard GF, Mimori K, et al. Overexpression of matrix metalloproteinase-7 mRNA in human colon carcinomas. Cancer. 1995; 75(6 Suppl): 1516–1519.
104. Guillen-Ahlers H, Buechler SA, Suckow MA, et al. Sulindac treatment alters collagen and matrilysin expression in adenomas of ApcMin/+ mice. Carcinogenesis. 2008; 29(7): 1421–1427.
105. Zhang C, Guo F, Xu G, et al. STAT3 cooperates with Twist to mediate epithelial-mesenchymal transition in human hepatocellular carcinoma cells. Oncology Reports. 2015; 33(4): 1872–1882.
106. Orgaz JL, Pandya P, Dalmeida R, et al. Diverse matrix metalloproteinase functions regulate cancer amoeboid migration. Nature communications. 2014; 5: 4255.
107. Lesina M, Kurkowski MU, Ludes K, et al. Stat3/Socs3 activation by IL-6 transsignalling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer cell. 2011; 19(4): 456–469.
108. Crawford HC, Fingleton BM, Rudolph-Owen LA, et al. The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors. Oncogene. 1999; 18(18): 2883–2891.
109. Yun J, Pannuti A, Espinoza I, et al. Crosstalk between PKCα and Notch-4 in endocrine-resistant breast cancer cells. Oncogenesis. 2013; 2: e60.
110. Kawahara T, Kawaguchi-Ihara N, Okuhashi Y, et al. Cyclopamine and quercetin suppress the growth of leukemia and lymphoma cells. Anticancer Research. 2009; 29(11): 4629–4632.
111. Bao B, Wang Z, Ali S, et al. Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells. Cancer letters. 2011; 307(1): 26–36.
112. Zhong Y, Shen S, Zhou Y, et al. NOTCH1 is a poor prognostic factor for breast cancer and is associated with breast cancer stem cells. OncoTargets and Therapy. 2016; 9: 6865–6871.
113. Callahan R, Raafat A. Notch signalling in mammary gland tumorigenesis. Journal of Mammary Gland Biology and Neoplasia. 2001; 6(1): 23–36.
114. Farnie G, Clarke RB. Mammary stem cells and breast cancer--role of Notch signalling. Stem Cell Reviews. 2007; 3(2): 169–175.
115. Palomero T, Dominguez M, Ferrando AA. The role of the PTEN/AKT Pathway in NOTCH1-induced leukemia. Cell Cycle. 2008; 7(8): 965–970.
116. Singh JK, Farnie G, Bundred NJ, et al. Targeting CXCR1/2 significantly reduces breast cancer stem cell activity and increases the efficacy of inhibiting HER2 via HER2-dependent and -independent mechanisms. Clinical Cancer Research. 2013; 19(3): 643–656.
117. Hernandez-Aya LF, Gonzalez-Angulo AM. Targeting the phosphatidylinositol 3-kinase signalling pathway in breast cancer. Oncologist. 2011; 16(4): 404–414.
118. Cao L, Yang Y, Ye Z, et al. Quercetin‑3‑methyl ether suppresses human breast cancer stem cell formation by inhibiting the Notch1 and PI3K/Akt signalling pathways. International Journal of Molecular Medicine. 2018; 24: 1625–1636.
119. Zhu H, Bhaijee F, Ishaq N, et al. Correlation of Notch1, pAKT and nuclear NF-κB expression in triple negative breast cancer. American Journal of Cancer Research. 2013; 3(2): 230-239.
120. Li L, Zhao F, Lu J, et al. Notch-1 Signalling Promotes the Malignant Features of Human Breast Cancer through NF-κB Activation M. PLoS ONE. 2014; 9(4): e95912.
121. Xie T-X, Xia Z, Zhang N, et al. Constitutive NF-kappaB activity regulates the expression of VEGF and IL-8 and tumor angiogenesis of human glioblastoma. Oncology Reports. 2010; 23(3): 725–732.
122. Wang Z, Ahmad A, Li Y, et al. Targeting notch to eradicate pancreatic cancer stem cells for cancer therapy. Anticancer Research. 2011; 31(4): 1105–1113.
123. LaFoya B, Munroe JA, Albig AR. A comparison of resveratrol and other polyphenolic compounds on Notch activation and endothelial cell activity. PloS One. 2019; 14(1): e0210607.