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Volume 7, Issue 4 (July - August 2022)                   J Obstet Gynecol Cancer Res 2022, 7(4): 258-271 | Back to browse issues page

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Rahimi M, Talebi Kakroodi S, Tajvidi M. The Importance of RTK Signaling Genes and their Inhibitors in Breast Cancer. J Obstet Gynecol Cancer Res. 2022; 7 (4) :258-271
URL: http://jogcr.com/article-1-414-en.html
1- Department of Microbiology, Karaj Branch, Islamic Azad University, Karaj, Iran , mar.rahimi20@gmail.com
2- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
3- Clinical care and Health Promotion Research Center, Karaj Branch, Islamic Azad University, Karaj, Iran
Abstract:   (888 Views)

Receptor tyrosine kinase (RTK) signaling is a crucial pathway in the development of many cancers. KIT, PI3K, and AKT are the major genes in this pathway. KIT RTK functions in cell signal transduction in various cell types, such as cancer cells. A central element of RTK signaling is phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit A (PIK3CA), involved in cell proliferation, survival, and growth. AKT is a serine/threonine-specific protein kinase that has an important role in several processes, such as apoptosis and cell proliferation. The importance of mutations and overexpression of KIT, PI3K, and AKT genes in breast cancer has been previously demonstrated. This review investigated the relationship between gene mutations and overexpression and clinicopathological variable of KIT, PI3K, and AKT in breast cancer. Finally, the role of inhibitor drugs of these genes in breast cancer treatment. These data were collected from PubMed and Google Scholar databases from 2000 to 2021. The expression of KIT, PI3K, and AKT genes in normal breast tissues has been observed. However, mutations and overexpression of these genes are associated with malignancies. The mutations in KIT, PI3K, and AKT genes are different from those found in other malignancies. Also, most of the drugs that inhibit the RTK signaling are being tested in clinical trials for the treatment of breast cancer. Monitoring and timely management of adverse effects are critical to minimize toxicities and optimize the efficacy of this targeted therapy. Therefore, further development of predictive biomarkers can better select patients who will benefit from RTK inhibitors.

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Systematic Review: Review | Subject: Gynecology Oncology
Received: 2021/06/6 | Accepted: 2021/07/24 | Published: 2022/03/14

1. Breast Cancer". NCI. Archived from the original on 25 June 2014. Retrieved 29 June 2014.
2. Breast Cancer Treatment. NCI. 23 May 2014. Archived from the original on 5 July 2014. Retrieved 29 June 2014.
3. World Cancer Report 2014. World Health Organization. 2014. pp. Chapter 5.2.
4. Patani, N.,Martin, L.A.&Dowsett, M. Biomarkers for the clinical management of breast cancer: international perspective. Int J Cancer.2013; 133: 1-13. [DOI:10.1002/ijc.27997] [PMID]
5. Sever R, Brugge S. Signal Transduction in Cancer. Cold Spring Harbor Laboratory Press. 2017; 5(4): a006098. [DOI:10.1101/cshperspect.a006098] [PMID] [PMCID]
6. Shimizu K, Oku N. Cancer anti-angiogenic therapy. Biol Pharm Bull. 2004; 27: 599-605. [DOI:10.1248/bpb.27.599] [PMID]
7. Boris Pasche (2010). Cancer Genetics (Cancer Treatment and Research). Berlin: Springer. pp. 19-20. [DOI:10.1007/978-1-4419-6033-7] [PMID]
8. Gage M, Wattendorf D, Henry LR. Translational advances regarding hereditary breast cancer syndromes. Journal of surgical oncology.2012; 105 (5): 444-51. [DOI:10.1002/jso.21856] [PMID]
9. Kolata, Gina (23 September 2012). "Genetic Study Finds 4 Distinct Variations of Breast Cancer". The New York Times. Archived from the original on 24 September 2012. Retrieved 23 September 2012.
10. Adrian Lee; Carlos Arteaga (14 December 2009). "32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium". Sunday Morning Year-End Review. Archived from the original (PDF) on 13 August 2013.
11. King, D; Yeomanson, D; Bryant, HE. PI3King the Lock: Targeting the PI3K/Akt/mTOR Pathway as a Novel Therapeutic Strategy in Neuroblastoma. J Pediatr Hematol/Oncol. 2015;37(4): 245-51. [DOI:10.1097/MPH.0000000000000329] [PMID]
12. Peltier, J; O'Neill, A; Schaffer, D. V. PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation. Dev Neurobiol. 2007; 67(10): 1348-61 [DOI:10.1002/dneu.20506] [PMID]
13. Miettinen M, Lasota J. KIT (CD117): A Review on Expression in Normal and Neoplastic Tissues, and Mutations and Their Clinicopathologic Correlation. Appl Immunohistochem Mol Morphol. 2005; 13: 205-20. [DOI:10.1097/01.pai.0000173054.83414.22] [PMID]
14. Kitamura Y, Hirota S. Kit as a human oncogenic tyrosine kinase. Cell Mol Life Sci. 2004; 61:2924-31. [DOI:10.1007/s00018-004-4273-y] [PMID]
15. Yarden Y, Kuang WJ, Yang‐Feng T, Coussens L, Munemitsu S, Dull TJ, et al. Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand.EMBO J. 1987;6:3341-51. [DOI:10.1002/j.1460-2075.1987.tb02655.x] [PMID] [PMCID]
16. Spritz RA, Strunk KM, Lee ST, Lu-Kuo JM, Ward DC, Le Paslier D, et al. A YAC contig spanning a cluster of human type III receptor protein tyrosine kinase genes (PDGFRA-KIT-KDR) in chromosome segment 4q12. Genomics. 1994;22(2):431-6. [DOI:10.1006/geno.1994.1405] [PMID]
17. Tuveson D, Willis N, Jacks T, Gri J, Singer S. STI571 inactivation of the gastrointestinal stromal tumor c-KIToncoprotein: biological and clinical implications. Oncogene. 2001; 20:5054-8. [DOI:10.1038/sj.onc.1204704] [PMID]
18. Orsenigo M, Brich S, Riva C, Conca E, Bertulli R, Dileo P, et al. Fluorescence in situ hybridization analysis and immunophenotyping ofc-Kit/PDGFRA and Bcl-2 expression in gastrointestinal stromal tumors. Anal Quant CytolHistol. 2010; 32 (4):225-33.
19. Antonescu C, Romeo S, Zhang L, Nafa K, Hornick J, Nielsen G, et al. Dedifferentiation in Gastrointestinal Stromal Tumor to an Anaplastic KIT Negative Phenotype - a Diagnostic Pitfall. Morphologic and Molecular Characterization of 8 Cases Occurring either de-novo or after Imatinib Therapy. Am J Surg Pathol. 2013; 37(3): 385-92. [DOI:10.1097/PAS.0b013e31826c1761] [PMID] [PMCID]
20. Malaise M, Steinbach D, Corbacioglu S. Clinical implications of c-Kit mutations in acute myelogenous leukemia. Find out how to access preview-only content. Curr Hematol Malig Rep. 2009; 4(2): 77-82. [DOI:10.1007/s11899-009-0011-8] [PMID]
21. Renneville A, Roumier C, Biggio V, Nibourel O, Boissel N, Fenaux P, Preudhomme C. Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia. 2008; 22:915-31. [DOI:10.1038/leu.2008.19] [PMID]
22. Beadling C, Jacobson-Dunlop E, Hodi FS, Le C, Warrick A, Patterson J, Town A, Harlow A. KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res. 2008;14 (21):6821-8. [DOI:10.1158/1078-0432.CCR-08-0575] [PMID]
23. Entrez Gene: PIK3CA
24. Samuels Y, Waldman T. Rommel C, Vanhaesebroeck B, Vogt PK, eds. Oncogenic mutations of PIK3CA in human cancers. Current Topics in Microbiology and Immunology. Springer Berlin Heidelberg. 2010; 347: 21-41. [DOI:10.1007/82_2010_68] [PMID] [PMCID]
25. Ogino S, Lochhead P, Giovannucci E, Meyerhardt JA, Fuchs CS, Chan AT. Discovery of colorectal cancer PIK3CA mutation as a potential predictive biomarker: power and promise of molecular pathological epidemiology. Oncogene. 2013; 33: 2949-55. [DOI:10.1038/onc.2013.244] [PMID] [PMCID]
26. Tumor Genetics; AKT Function and Oncogenic Activity" (PDF). Scientific Report. Fox Chase Cancer Center. 2005. Archived from the original (PDF) on 2010-06-04. Retrieved 2013-01-23.
27. Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med. 2011; 365 (7): 611-9 [DOI:10.1056/NEJMoa1104017] [PMID] [PMCID]
28. Chen J, Somanath PR, Razorenova O, Chen WS, Hay N, Bornstein P, et al. Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo. Nature Med.2005; 11 (11): 1188-96. [DOI:10.1038/nm1307] [PMID] [PMCID]
29. Somanath PR, Razorenova OV, Chen J, Byzova TV. Akt1 in endothelial cell and angiogenesis. Cell Cycle.2006; 5 (5): 512-8. [DOI:10.4161/cc.5.5.2538] [PMID] [PMCID]
30. Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, Peterson TR, Choi Y, Gray NS, Yaffe MB, Marto JA. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science. 2011;332(6035):1317-22. [DOI:10.1126/science.1199498] [PMID] [PMCID]
31. Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N. Engl. J. Med. 2011; 365(7): 611-9.
32. Vandenbark GR, DeCastro CM, Taylor H, Kaufman E. Cloning and structural analysis of the human c-kit gene. Oncogene. 1992;7:1259-66.
33. Giebel LB, Strunk KM, Holmes SA, Spritz RA. Organization and nucleotide sequence of the human KIT (mast/stem cell growth factor receptor) proto-oncogene. Oncogene. 1992;7(11):2207-17.
34. Longley BJ, Reguera MJ, Ma Y. Classes of c-KIT activating mutations: proposed mechanisms of action and implications for disease classification and therapy. Leuk Res. 2001;25(7):571-6. [DOI:10.1016/S0145-2126(01)00028-5]
35. [35] Kitamura Y, Hirota S. Kit as a human oncogenic tyrosine kinase. Cell Mol Life Sci. 2004; 61:2924-31. [DOI:10.1007/s00018-004-4273-y] [PMID]
36. Miettinen M, Lasota J. Gastrointestinal stromal tumors: definition, occurrence, pathology, differential diagnosis, and molecular genetics. Pol J Pathol. 2003; 54:3-24.
37. Miettinen, Markku MD; Lasota, Jerzy MD. KIT (CD117): A Review on Expression in Normal and Neoplastic Tissues, and Mutations and Their Clinicopathologic Correlation. Appl Immunohistochem Molecular Morphol. 2005;13 (3): 205-20. [DOI:10.1097/01.pai.0000173054.83414.22] [PMID]
38. Natali PG, Nicotra MR, Sures I, Mottolese M, Botti C, Ullrich A. Breast cancer is associated with loss of the c-kit oncogene product. Int J Cancer.1992; 52:713-7. [DOI:10.1002/ijc.2910520508] [PMID]
39. Chui X, Egami H, Yamashita J, Kurizaki T, Ohmachi H, Yamamoto S, Ogawa M. Immunohistochemical expression of the c-kit proto-oncogene product in human malignant and non-malignant breast tissues. Br J Cancer. 1996;73(10):1233-6. [DOI:10.1038/bjc.1996.236] [PMID] [PMCID]
40. M, Behjati F, Khorram Khorshid HR, Karimlou M, Keyhani E. The Relationship between KIT Copy Number Variation, Protein Expression, and Angiogenesis in Sporadic Breast Cancer. Rep Biochem Mol Biol. 2020; 9(1): 40-9. [DOI:10.29252/rbmb.9.1.40] [PMID] [PMCID]
41. Hill PA. c-kit expression in adenoid cystic carcinoma of the breast. Pathology. 2004; 36:362-4. [DOI:10.1080/00313020410001721537] [PMID]
42. Natali PG, Nicotra MR, Sures I, Santoro E, Bigotti A, Ullrich A. Expression of c-kit receptor in normal and transformed human nonlymphoid tissues. Cancer Res. 1992;52(22):6139-43.
43. Matsuda R, Takahashi T, Nakamura S, Sekido Y, Nishida K, Seto M, Seito T, Sugiura T, Ariyoshi Y, Takahashi T, Ueda R. Expression of the c-kit protein in human solid tumors and in corresponding fetal and adult normal tissues. Am J Pathol. 1993;142(1):339.
44. Tsuura Y, Hiraki H, Watanabe K, Suzuki T, Igarashi S, Shimamura K, et al. Preferential localization of c-kit product in tissue mast cells, basal cells of skin, epithelial cells of breast, small cell lung carcinoma and seminoma/dysgerminoma in human: immunohistochemical study on formalin-fixed, paraffin-embedded tissues. Virchows Archiv. 1994;424(2):135-41. [DOI:10.1007/BF00193492] [PMID]
45. Lammie A, Drobnjak M, Gerald W, Saad A, Cote R, Cordon-Cardo C. Expression of c-kit and kit ligand proteins in normal human tissues. J Histochem Cytochem. 1994;42(11):1417-25. [DOI:10.1177/42.11.7523489] [PMID]
46. Maeda HI, Yamagata A, Nishikawa S, Yoshinaga KA, Kobayashi SH, Nishi KA, Nishikawa S. Requirement of c-kit for development of intestinal pacemaker system. Development. 1992;116(2):369-75. [DOI:10.1242/dev.116.2.369] [PMID]
47. Hulzinga JD, Thuneberg L, Klüppel M, Malysz J, Mikkelsen HB, Bernstein A. W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature. 1995;373(6512):347-9. [DOI:10.1038/373347a0] [PMID]
48. Liu J, Liu X, Feng X, Liu J, Lv S, Zhang W, Niu Y. C-kit overexpression correlates with KIT gene copy numbers increases in phyllodes tumors of the breast. Breast Cancer Res Treat. 2015;149(2):395-401. [DOI:10.1007/s10549-014-3214-1] [PMID]
49. Zhu Y, Wang Y, Guan B, Rao Q, Wang J, Ma H, et al. C-kit and PDGFRA gene mutations in triple negative breast cancer. Int J Clin Exp Pathol. 2014;7(7):4280..
50. Carvalho S, e Silva AO, Milanezi F, Ricardo S, Leitão D, Amendoeira I, Schmitt FC. c-KIT and PDGFRA in breast phyllodes tumours: overexpression without mutations?. J Clin Pathol. 2004;57(10):1075-9. [DOI:10.1136/jcp.2004.016378] [PMID] [PMCID]
51. Johansson I, Aaltonen KE, Ebbesson A, Grabau D, Wigerup C, Hedenfalk I, Rydén L. Increased gene copy number of KIT and VEGFR2 at 4q12 in primary breast cancer is related to an aggressive phenotype and impaired prognosis. Genes, Chromosomes Cancer. 2012;51(4):375-83. [DOI:10.1002/gcc.21922] [PMID]
52. Rahimi M, Behjat F, Taheri N, Hosseini S, Khorshid HR, Moghaddam FA, et al. Correlation between important genes of mTOR pathway (PI3K and KIT) in Iranian women with sporadic breast cancer. Med J I R Iran. 2018;32:135.. [DOI:10.14196/mjiri.32.135] [PMID] [PMCID]
53. Rahimi M, Keyhani E, Behjati F. The Relation between Exon Variations of KIT Gene and Clinical Pathological Factors of Breast Cancer. J Obstet Gynecol Cancer Res. 2020;5(4):137-48. [DOI:10.30699/jogcr.5.4.137]
54. Hussain SR, Naqvi H, Ahmed F, Babu SG, Bansal C, Mahdi F. Identification of the c-kit gene mutations in biopsy tissues of mammary gland carcinoma tumor. J Egypt Natl Canc Inst. 2012;24(2):97-103.. [DOI:10.1016/j.jnci.2011.10.003] [PMID]
55. Atay S, Banskota S, Crow J, Sethi G, Rink L, Godwin AK. Oncogenic KIT-containing exosomes increase gastrointestinal stromal tumor cell invasion. Proceedings of the National Academy of Sciences. 2014;111(2):711-6. [DOI:10.1073/pnas.1310501111] [PMID] [PMCID]
56. Kondi-Pafiti A, Arkadopoulos N, Gennatas C, Michalaki V, Frangou-Plegmenou M, Chatzipantelis P. Expression of c-kit in common benign and malignant breast lesions. Tumori J. 2010;96(6):978-84. [DOI:10.1177/548.6519] [PMID]
57. McIntyre A, Summersgill B, Grygalewicz B, Gillis AJ, Stoop J, van Gurp RJ, Dennis N, Fisher C, Huddart R, Cooper C, Clark J, Oosterhuis JW, Looijenga LH, Shipley J. Amplification and overexpression of the KIT gene is associated with progression in the seminoma subtype of testicular germ cell tumors of adolescents and adults. Cancer Res. 2005; 65 (18): 8085-9. [DOI:10.1158/0008-5472.CAN-05-0471] [PMID]
58. R Diallo, E Ting, O Gluz, A Herr, G Schütt, H Geddert, S Mohrmann, C-kit expression in high-risk breast cancer subgroup treated with high-dose or conventional dose-dense chemotherapy. Verh Dtsch Ges Pathol. 2006; 90:177-85.
59. Diallo R, Rody A, Jackisch C, Ting E, C-KIT expression in ductal carcinoma in situ of the breast: co-expression with HER-2/neu. Hum Pathol. 2006;37(2):205-11. [DOI:10.1016/j.humpath.2005.10.015] [PMID]
60. Tsutsui S, Yasuda K, Suzuki K, Takeuchi H, Nishizaki T, Higashi H, Era S. A loss of c-kit expression is associated with an advanced stage and poor prognosis in breast cancer. Br J Cancer. 2006;94(12):1874-8. [DOI:10.1038/sj.bjc.6603183] [PMID] [PMCID]
61. Hussain SR, G. Babu S, Raza ST, Singh P, Screening of the c-kit gene missense mutation in invasive ductal carcinoma of breast among north Indian population, Mol Biol Rep.2012; 39:9139-44. [DOI:10.1007/s11033-012-1786-6] [PMID]
62. Poveda A, GarcíadelMuro X, Lopez Guerrero J, Martínez V , Romero I, Valverde C, et al. GEIS 2013 guidelines for gastrointestinal sarcomas (GIST).Cancer Chemother Pharmacol.2014; 74:883-98. [DOI:10.1007/s00280-014-2547-0] [PMID] [PMCID]
63. Heinrich MC, Blanke CD, Druker BJ, Corless CL. Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol.2002; 20:1692-703. [DOI:10.1200/JCO.2002.20.6.1692] [PMID]
64. [64] Demetri GD, Von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. New Eng J Med. 2002;347(7):472-80. [DOI:10.1056/NEJMoa020461] [PMID]
65. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22: 3813-25. [DOI:10.1200/JCO.2004.05.140] [PMID]
66. Kitamura Y, Hirota S. Kit as a human oncogenic tyrosine kinase. Cell Mol Life Sci. 2004; 61:2924-31. [DOI:10.1007/s00018-004-4273-y] [PMID]
67. Debiec-Rychter M, Cools J, Dumez H, et al. Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology. 2005; 128:270-9. [DOI:10.1053/j.gastro.2004.11.020] [PMID]
68. C. Heinrich M, Marino-Enriquez A, Presnell A, S. Donsky R, Sorafenib Inhibits Many Kinase Mutations Associated with Drug-Resistant Gastrointestinal Stromal Tumors. Mol Cancer Ther. 2012; 11(8): 1770-80. [DOI:10.1158/1535-7163.MCT-12-0223] [PMID] [PMCID]
69. Bronte G, Andreis D, Bravaccini S, Maltoni R, Sorafenib for the treatment of breast cancer. Expert Opin Pharmacother. 2017;18(6):621-30. [DOI:10.1080/14656566.2017.1309024] [PMID]
70. Huang WS, Metcalf CA, Sundaramoorthi R, Wang Y. Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutan. J Med Chem. 2010; 53 (12): 4701-19. [DOI:10.1021/jm100395q] [PMID]
71. Musumeci F, Greco C, Grossi G, Molinari A, Schenone S. Recent studies on ponatinib in cancers other than chronic myeloid leukemia. Cancers. 2018;10(11):430. [DOI:10.3390/cancers10110430] [PMID] [PMCID]
72. Mehta M, Griffith J, Panneerselvam J, Babu A, Regorafenib sensitizes human breast cancer cells to radiation by inhibiting multiple kinases and inducing DNA damage, Int J Radiat Biol. 2020; 2;1-12.
73. https://innovationessence.com/cancerous-disorders-targeted/ Doctors Treat Deadly Cancerous Disorders with Gene-Guided, Targeted Therapy: Posted on February 16, 2017.
74. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7: 606-19. [DOI:10.1038/nrg1879] [PMID]
75. Samuels Y,Wang Z, Bardelli A, Siliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004; 304:554. [DOI:10.1126/science.1096502] [PMID]
76. Bader AG, Kang S, Zhao L, Vogt PK. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer. 2005;5: 921-9. [DOI:10.1038/nrc1753] [PMID]
77. Klarenbeek S, van Miltenburg MH, Jonkers J. Genetically engineered mouse models of PI3K signaling in breast cancer. Mol Oncol. 2013;7(2):146-64. [DOI:10.1016/j.molonc.2013.02.003] [PMID] [PMCID]
78. Levine DA, Bogomolniy F, Yee CJ, Lash A, Barakat RR, Borgen PI, et al. Frequent mutation of the PIK3CA gene in ovarian and breast cancer. Clin Cancer Res. 2005; 11:2875-8. [DOI:10.1158/1078-0432.CCR-04-2142] [PMID]
79. Isakoff SJ, Engelman JA, Irie HY, Luo J, Brachmann SM, Pearline RV, Cantley LC and Brugge JS: Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res.2005;65:10992-1000. [DOI:10.1158/0008-5472.CAN-05-2612] [PMID]
80. Hosseini S, Behjati F, Rahimi M, Taheri N. The relationship between PIK3CA Amplification and P110α Tissue Expression with CD34 Tissue Expression as an Angiogenesis Marker in Iranian Women with Sporadic Breast Cancer. Iran J Pathol.2018; 13(4):447-453.
81. Dirican E, Akkiprik M, Özer A. Mutation distributions and clinical correlations of PIK3CA gene mutations in breast cancer. Tumor Biol. 2016;37 (6):7033-45. [DOI:10.1007/s13277-016-4924-2] [PMID]
82. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov.2009;8:627-44. [DOI:10.1038/nrd2926] [PMID] [PMCID]
83. Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, et al. PIK3CAmutations correlate with hormone receptors, nodemetastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005; 65:2554-9. [DOI:10.1158/0008-5472-CAN-04-3913] [PMID]
84. Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M, Inbar Y, et al. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science. 2007;317: 239-42. [DOI:10.1126/science.1135394] [PMID]
85. Guo RX, Wei LH, Wang JL, Sun PM, Sun XL. Activation of phosphatidylinositol 3-kinase-protein kinase B (PI3K-PKB) induced by 17beta-estradiol in endometrial carcinoma cell (Ishikawa). Zhonghua fu Chan ke za zhi. 2004;39(7):469-73.
86. Schuur ER, Loktev AV, Sharma M, Sun Z, Roth RA, Weigel RJ.Ligand-dependent interaction of estrogen receptoralpha with members of the forkhead transcription factor family. J Biol Chem. 2001;276(36):33554-60. [DOI:10.1074/jbc.M105555200] [PMID]
87. Generali D, Fox SB, Brizzi MP, Allevi G, Bonardi S, Aguggini S, et al. Down-regulation of phosphatidylinositol 3'-kinase/AKT/molecular target of rapamycin metabolic pathway by primary letrozole-based therapy in human breast cancer. Clin Cancer Res. 2008;14(9):2673-80. [DOI:10.1158/1078-0432.CCR-07-1046] [PMID]
88. Campbell M, Allen WE, Sawyer C, Vanhaesebroeck B, Trimble ER. Glucose-potentiated chemotaxis in human vascular smoothmuscle is dependent on cross-talk between the PI3K and MAPK signaling pathways. Circ Res. 2004;95(4):380-8. [DOI:10.1161/01.RES.0000138019.82184.5d] [PMID]
89. Miricescu D, Totan A, Stanescu-Spinu II, Badoiu SC, Stefani C, Greabu M. PI3K/AKT/mTOR signaling pathway in breast cancer: From molecular landscape to clinical aspects. Int J Mol Sci. 2021;22(1):173. [DOI:10.3390/ijms22010173] [PMID] [PMCID]
90. Cancer Genom Atlas Network. http://cancergenome.nih.gov.Accessed 13 Sep 2012.
91. Martínez-Sáez O, Chic N, Pascual T, Adamo B, Vidal M, Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast Cancer Res. 2020; 22: 45. [DOI:10.1186/s13058-020-01284-9] [PMID] [PMCID]
92. Mosele F, Stefanovska B, Lusque A, et al. Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer. Ann Oncol. 2019;30:iii47.. [DOI:10.1093/annonc/mdz100]
93. Cizkova M,, Susini A, Vacher S, Cizeron-Clairac G, PIK3CAmutation impact on survival in breast cancer patients and in ERα, PR and ERBB2-based subgroups. Breast Cancer Res. 2012;14(1): R28. [DOI:10.1186/bcr3113] [PMID] [PMCID]
94. Lee J, Loh K, Yap Y, PI3K/Akt/mTOR inhibitors in breast cancer, Cancer Biol Med. 2015;12:342-54.
95. Rusquec P, Blonz C, Frenel J, Campone M. Targeting the PI3K/Akt/mTOR pathway in estrogen-receptor positive HER2 negative advanced breast cancer, Therapeutic Advances in Medical Oncology. Ther Adv Med Oncol. 2020;12:1758835920940939. [DOI:10.1177/1758835920940939] [PMID] [PMCID]
96. Hanusch C, Schneeweiss A, Loibl S, Untch M, Paepke S, Kümmel S, et al. Dual blockade with AFatinib and trastuzumab as NEoadjuvant treatment for patients with locally advanced or operable breast cancer receiving taxaneanthracycline containing chemotherapy-DAFNE (GBG-70). Clin Cancer Res. 2015;21(13):2924-31. [DOI:10.1158/1078-0432.CCR-14-2774] [PMID]
97. Druker BJ. Imatinib: a viewpoint by Brian J. Druker Drugs. 2001;61(12):1775-6. [DOI:10.2165/00003495-200161120-00009] [PMID]
98. Arteaga CL, Moulder SL, Yakes FM. HER (erbB) tyrosine kinase inhibitors in the treatment of breast cancer. Semin Oncol. 2002; 3(11):4-10. [DOI:10.1053/sonc.2002.34047] [PMID]
99. Wakeling AE. Epidermal growth factor receptor tyrosine kinase inhibitors. Curr Opin Pharmacol. 2002;2(4):382-7. [DOI:10.1016/S1471-4892(02)00183-2]
100. "FDA Approval for duvelisib (COPIKTRA, Verastem, Inc.) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)". US Food and Drug Administration. September 24, 2018.
101. Novel Agents Show Promise Against Endocrine-resistant Breast Cancer. July 2016
102. FDA approves first PI3K inhibitor for breast cancer". 2019-05-24.
103. FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma". U.S. Food and Drug Administration (FDA). 5 February 2021. Retrieved 5 February 2021. This article incorporates text from this source, which is in the public domain.
104. TG Therapeutics Announces FDA Accelerated Approval of Ukoniq (umbralisib)" (Press release). TG Therapeutics. 5 February 2021. Retrieved 5 February 2021 - via GlobeNewswire.
105. Motawi TM, Sadik NA, Fahim SA, Shouman SA. Combination of imatinib and clotrimazole enhances cell growth inhibition in T47D breast cancer cells. Chem Biol Interact. 2015; 233:147-56. [DOI:10.1016/j.cbi.2015.03.028] [PMID]
106. Zardavas D, Phillips WA, Loi S. PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data. Breast Cancer Res. 2014;16(1):201. [DOI:10.1186/bcr3605] [PMID] [PMCID]
107. Coughlin CM, Johnston DS, Strahs A, Burczynski ME, Bacus S, Hill J, et al. Approaches and limitations of phosphatidylinositol-3-kinase pathway activation status as a predictive biomarker in the clinical development of targeted therapy. Breast Cancer Res Treat. 2010; 124:1-11. [DOI:10.1007/s10549-010-1108-4] [PMID]
108. Yang Z, Di M, Yuan J, Shen W, The prognostic value of phosphorylated Akt in breast cancer: a systematic review. Sci Rep.2015;5:7758. [DOI:10.1038/srep07758] [PMID] [PMCID]
109. Hinz N, Jücker M. Distinct functions of AKT isoforms in breast cancer: a comprehensive review. Cell Communication and Signaling. 2019;17(1):154. [DOI:10.1186/s12964-019-0450-3] [PMID] [PMCID]
110. Pérez-Tenorio G, Stål O. Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br J Cancer. 2002;86(4):540-5. [DOI:10.1038/sj.bjc.6600126] [PMID] [PMCID]
111. Liu W, Bagaitkar J, Watabe K, Roles of AKT signal in breast cancer. Front Biosci.2007; 12,4011-9. [DOI:10.2741/2367] [PMID]
112. Tserga A, Chatziandreou I, V. Michalopoulos N, Patsouris E. Mutation of genes of the PI3K/AKT pathway in breast cancer supports their potential importance as biomarker for breast cancer aggressiveness. Virchows Arch. 2016; 469:35-43. [DOI:10.1007/s00428-016-1938-5] [PMID]
113. Yang S, Polley E, Lipkowitzc S, New insights on PI3K/AKT pathway alterations and clinical outcomes in breast cancer. Cancer Treat Rev.2016;45:87-96. [DOI:10.1016/j.ctrv.2016.03.004] [PMID] [PMCID]
114. Stemke-Hale K, Gonzalez-Angulo A, Lluch A, M. Neve R. An Integrative Genomic and Proteomic Analysis of PIK3CA, PTEN, and AKT Mutations in Breast Cancer, Cancer Res.2008;68(15):6084-91. [DOI:10.1158/0008-5472.CAN-07-6854] [PMID] [PMCID]
115. A. Aleskandarany M, A. Rakha E, A. Ahmed M, G. Powe D, Clinicopathologic and molecular significance of phospho-Akt expression in early invasive breast cancer. Breast Cancer Res Treat.2011;127:407-16. [DOI:10.1007/s10549-010-1012-y] [PMID]
116. Altomare D, Testa J, Perturbations of the AKT signaling pathway in human cancer. Oncogene.2005;24: 7455-64. [DOI:10.1038/sj.onc.1209085] [PMID]
117. Stål O, Pérez-Tenorio G, Akerberg L, Olsson B, Nordenskjöld B, Skoog L, et al. Akt kinases in breast cancer and the results of adjuvant therapy. Breast Cancer Res. 2003;5(2): 37-44. [DOI:10.1186/bcr569] [PMID] [PMCID]
118. Florena AM, Tripodo C, Guarnotta C, Ingrao S, Porcasi R, Martorana A, et al. Associations between Notch-2, Akt-1 and HER2/neu expression in invasive human breast cancer: A tissue microarray immunophenotypic analysis on 98 patients. Pathobiology.2007;74(6):317-22. [DOI:10.1159/000110024] [PMID]
119. Bellacosa A. Feo Dd, Godwin AK, Bell DW, Cheng JQ, Altomare DA, et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer. 1995;64(4):280-5. [DOI:10.1002/ijc.2910640412] [PMID]
120. Grell P, Fabian P, Khoylou M, Radova L, Slaby O, Hrstka R, et al. Akt expression and compartmentalization in prediction of clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab. Int J Oncol. 2012;41(4):1204-12 [DOI:10.3892/ijo.2012.1576] [PMID] [PMCID]
121. Hu X, Wang J, He W, Zhao P, Ye C. MicroRNA-433 targets AKT3 and inhibits cell proliferation and viability in breast cancer. Oncol Lett. 2018;15(3):3998-4004. [DOI:10.3892/ol.2018.7803] [PMID] [PMCID]
122. Pérez-Tenorio G, Karlsson E, Stål O. Clinical value of isoform-specific detection and targeting of AKT1, AKT2 and AKT3 in breast cancer. Breast Cancer Man. 2014;3(5):409-21. [DOI:10.2217/bmt.14.35]
123. Zinda MJ, Johnson MA, Paul JD, Horn C, Konicek BW, Lu ZH, et al. AKT-1, −2, and −3 are expressed in both normal and tumor tissues of the lung, breast, prostate, and colon. Clin Cancer Res. 2001;7(8):2475-9.
124. Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70. [DOI:10.1038/nature11412] [PMID] [PMCID]
125. Chin YR, Yoshida T, Marusyk A, Beck AH, Polyak K, Toker A. Targeting Akt3 signaling in triple-negative breast cancer. Cancer Res. 2014;74(3):964-73. [DOI:10.1158/0008-5472.CAN-13-2175] [PMID] [PMCID]
126. O'Hurley G, Daly E, O'Grady A, Cummins R, Quinn C, Flanagan L, et al. Investigation of molecular alterations of AKT-3 in triple-negative breast cancer. Histopathology. 2014;64(5):660-70. [DOI:10.1111/his.12313] [PMID]
127. Vio Quest Pharmaceuticals Announces Phase I/IIa Trial For Akt Inhibitor VQD-002. Apr 2007.
128. NITULESCU GM, MARGINA D, JUZENAS P, PENG Q. Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review). Int J Oncol. 2016; 48(3): 869-85. [DOI:10.3892/ijo.2015.3306] [PMID] [PMCID]
129. Carnero A. The PKB/AKT pathway in cancer. Curr Pharm Des. 2010; 16:34-44. [DOI:10.2174/138161210789941865] [PMID]
130. [130] Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K, et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol.2011; 29(35): 4688-95. [DOI:10.1200/JCO.2011.35.5263] [PMID]
131. MK-2206 phase-2 trials.
132. AKT inhibitor AZD5363 well tolerated, yielded partial response in patients with advanced solid tumors.
133. "PARP/AKT Inhibitor Combination Active in Multiple Tumor Types. April 2016". Archived from the original on 2016-05-07. Retrieved 2016-04-20.
134. Jabbarzadeh Kaboli P, Salimian F, Aghapour S, Xiang S, Zhao Q, Li M, et al. Akt-targeted therapy as a promising strategy to overcome drug resistance in breast cancer - A comprehensive review from chemotherapy to immunotherapy". Pharmacol Res.2020;156:104806. [DOI:10.1016/j.phrs.2020.104806] [PMID]
135. Berndt N, Yang H, Trinczek B, Betzi S, Zhang Z, Wu B, Lawrence NJ, Pellecchia M, Schönbrunn E, Cheng JQ, et al. The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane. Cell Death Differ. 2010; 17:1795-804. [DOI:10.1038/cdd.2010.63] [PMID] [PMCID]
136. Song M, M. Bode A, Dong Z, Lee M. AKT as a Therapeutic Target for Cancer. Cancer Res.2019; ;79(6):1019-31. [DOI:10.1158/0008-5472.CAN-18-2738] [PMID]

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