REFERENCES
2. Kohler BA, Sherman RL, Howlader N, et al. Annual report to the nation on the status of cancer, 1975-2011, featuring incidence of breast cancer subtypes by race/ethnicity, poverty, and state. J Natl Cancer Inst 2015;107:djv048.
3. WHO. Breast cancer. Available from: https://www.who.int/news-room/fact-sheets/detail/breast-cancer [Last accessed on 2 Apr 2022].
4. Kalimutho M, Parsons K, Mittal D, et al. Targeted therapies for triple-negative breast cancer: combating a stubborn disease. Trends Pharmacol Sci 2015;36:822-46.
5. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127-37.
6. Lax I, Burgess WH, Bellot F, et al. Localization of a major receptor-binding domain for epidermal growth factor by affinity labeling. Mol Cell Biol 1988;8:1831-4.
7. Hsu JL, Hung MC. The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer. Cancer Metastasis Rev 2016;35:575-88.
8. Olayioye MA. Update on HER-2 as a target for cancer therapy: intracellular signaling pathways of ErbB2/HER-2 and family members. Breast Cancer Res 2001;3:385-9.
9. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 2006;7:505-16.
10. Moasser MM. The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 2007;26:6469-87.
11. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177-82.
12. Lyerly HK. The breast: comprehensive management of benign and malignant diseases. Ann Surg 1992;215:192.
13. Dawood S, Broglio K, Buzdar AU, Hortobagyi GN, Giordano SH. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol 2010;28:92-8.
14. Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. JCO 2014;32:3744-52.
15. Slamon DJ, Leyland-jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783-92.
16. Baselga J, Cortés J, Kim SB, et al. CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366:109-19.
17. Nielsen DL, Andersson M, Kamby C. HER2-targeted therapy in breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors. Cancer Treat Rev 2009;35:121-36.
18. Wong AL, Lee SC. Mechanisms of resistance to trastuzumab and novel therapeutic strategies in HER2-positive breast cancer. Int J Breast Cancer 2012;2012:415170.
19. Hurvitz SA, Hu Y, O'Brien N, Finn RS. Current approaches and future directions in the treatment of HER2-positive breast cancer. Cancer Treat Rev 2013;39:219-29.
20. Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007;12:395-402.
21. Eichhorn PJ, Gili M, Scaltriti M, et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 2008;68:9221-30.
22. Margariti N, Fox SB, Bottini A, Generali D. “Overcoming breast cancer drug resistance with mTOR inhibitors”. Could it be a myth or a real possibility in the short-term future? Breast Cancer Res Treat 2011;128:599-606.
23. Yuan R, Kay A, Berg WJ, Lebwohl D. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. J Hematol Oncol 2009;2:45.
24. Martino MC, van Koetsveld PM, Pivonello R, Hofland LJ. Role of the mTOR pathway in normal and tumoral adrenal cells. Neuroendocrinology 2010;92 Suppl 1:28-34.
25. Keck S, Glencer AC, Rugo HS. Everolimus and its role in hormone-resistant and trastuzumab-resistant metastatic breast cancer. Future Oncol 2012;8:1383-96.
26. Mayer I. Role of mTOR inhibition in preventing resistance and restoring sensitivity to hormone-targeted and HER2-targeted therapies in breast cancer. Clin Adv Hematol Oncol 2013;11:217-24.
27. Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61-70.
28. Esteva FJ, Guo H, Zhang S, et al. PTEN, PIK3CA, p-AKT, and p-p70S6K status: association with trastuzumab response and survival in patients with HER2-positive metastatic breast cancer. Am J Pathol 2010;177:1647-56.
29. Nagata Y, Lan KH, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004;6:117-27.
30. O'Brien NA, Browne BC, Chow L, et al. Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. Mol Cancer Ther 2010;9:1489-502.
31. Rexer BN, Chanthaphaychith S, Dahlman K, Arteaga CL. Direct inhibition of PI3K in combination with dual HER2 inhibitors is required for optimal antitumor activity in HER2+ breast cancer cells. Breast Cancer Res 2014;16:R9.
32. Baselga J, Cortés J, Im SA, et al. Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. J Clin Oncol 2014;32:3753-61.
33. Baselga J, Lewis Phillips GD, Verma S, et al. Relationship between tumor biomarkers and efficacy in EMILIA, a phase III study of trastuzumab emtansine in HER2-positive metastatic breast cancer. Clin Cancer Res 2016;22:3755-63.
34. Salgia R. MET in Lung cancer: biomarker selection based on scientific rationale. Mol Cancer Ther 2017;16:555-65.
35. Fu YT, Zheng HB, Zhou L, et al. Valproic acid, targets papillary thyroid cancer through inhibition of c-Met signalling pathway. Am J Transl Res 2017;9:3138-47.
36. Bottaro DP, Rubin JS, Faletto DL, et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 1991;251:802-4.
37. Organ SL, Tsao MS. An overview of the c-MET signaling pathway. Ther Adv Med Oncol 2011;3:S7-S19.
38. Boccaccio C, Comoglio PM. Invasive growth: a MET-driven genetic programme for cancer and stem cells. Nat Rev Cancer 2006;6:637-45.
39. Blumenschein GR Jr, Mills GB, Gonzalez-Angulo AM. Targeting the hepatocyte growth factor-cMET axis in cancer therapy. J Clin Oncol 2012;30:3287-96.
40. Pilotto S, Carbognin L, Karachaliou N, et al. Tracking MET de-addiction in lung cancer: a road towards the oncogenic target. Cancer Treat Rev 2017;60:1-11.
41. Zhang Y, Xia M, Jin K, et al. Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol Cancer 2018;17:45.
42. Shattuck DL, Miller JK, Carraway KL 3rd, Sweeney C. Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells. Cancer Res 2008;68:1471-7.
43. Gastaldi S, Comoglio PM, Trusolino L. The Met oncogene and basal-like breast cancer: another culprit to watch out for? Breast Cancer Res 2010;12:208.
44. Beviglia L, Matsumoto K, Lin C, Ziober BL, Kramer RH. Expression of the C-Met/HGF receptor in human breast carcinoma: correlation with tumor progression. Int J Cancer 1997;74:301-9.
45. Raghav KP, Wang W, Liu S, et al. cMET and phospho-cMET protein levels in breast cancers and survival outcomes. Clin Cancer Res 2012;18:2269-77.
46. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007;316:1039-43.
47. Pohlmann PR, Mayer IA, Mernaugh R. Resistance to trastuzumab in breast cancer. Clin Cancer Res 2009;15:7479-91.
48. Yue D, Qin X. miR-182 regulates trastuzumab resistance by targeting Met in breast cancer cells. Cancer Gene Ther 2019;26:1-10.
49. Liu L, Shi H, Liu Y, et al. Synergistic effects of foretinib with HER-targeted agents in MET and HER1- or HER2-coactivated tumor cells. Mol Cancer Ther 2011;10:518-30.
50. Melo Gagliato D, Jardim DL, Marchesi MS, Hortobagyi GN. Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer. Oncotarget 2016;7:64431-46.
51. Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M. Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 2001;93:1852-7.
52. Wang Y, Hailey J, Williams D, et al. Inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling and tumor cell growth by a fully human neutralizing anti-IGF-IR antibody. Mol Cancer Ther 2005;4:1214-21.
53. Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ. Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res 2005;65:11118-28.
54. Lu Y, Zi X, Pollak M. Molecular mechanisms underlying IGF-I-induced attenuation of the growth-inhibitory activity of trastuzumab (Herceptin) on SKBR3 breast cancer cells. Int J Cancer 2004;108:334-41.
55. Agnantis N, Goussia A, Zagorianakou P, Bai M. Alterations of the cell cycle regulating proteins in invasive breast cancer. Molecular Genetics; Lung and Breast Carcinomas 2002;1:425-38.
56. Nahta R, Takahashi T, Ueno NT, Hung MC, Esteva FJ. P27(kip1) down-regulation is associated with trastuzumab resistance in breast cancer cells. Cancer Res 2004;64:3981-6.
57. Hubalek M, Brunner C, Matthä K, Marth C. Resistance to HER2-targeted therapy: mechanisms of trastuzumab resistance and possible strategies to overcome unresponsiveness to treatment. Wien Med Wochenschr 2010;160:506-12.
58. Lloyd RV, Erickson LA, Jin L, et al. p27kip1: a multifunctional cyclin-dependent kinase inhibitor with prognostic significance in human cancers. The American Journal of Pathology 1999;154:313-23.
59. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999;13:1501-12.
60. Guan X, Wang Y, Xie R, et al. p27(Kip1) as a prognostic factor in breast cancer: a systematic review and meta-analysis. J Cell Mol Med 2010;14:944-53.
61. Nakayama KI, Nakayama K. Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer 2006;6:369-81.
62. Lane HA, Motoyama AB, Beuvink I, Hynes NE. Modulation of p27/Cdk2 complex formation through 4D5-mediated inhibition of HER2 receptor signaling. Ann Oncol 2001;12 Suppl 1:S21-2.
63. Le XF, Claret FX, Lammayot A, et al. The role of cyclin-dependent kinase inhibitor p27Kip1 in anti-HER2 antibody-induced G1 cell cycle arrest and tumor growth inhibition. J Biol Chem 2003;278:23441-50.
64. Yakes FM, Chinratanalab W, Ritter CA, et al. Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res 2002;62:4132-41.
65. Kute T, Lack CM, Willingham M, et al. Development of herceptin resistance in breast cancer cells. Cytometry A 2004;57:86-93.
66. Ishizawar R, Parsons SJ. c-Src and cooperating partners in human cancer. Cancer Cell 2004;6:209-14.
67. Chu I, Sun J, Arnaout A, et al. p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2. Cell 2007;128:281-94.
68. Bloom J, Pagano M. Deregulated degradation of the cdk inhibitor p27 and malignant transformation. Seminars in Cancer Biology 2003;13:41-7.
70. Galardi S, Mercatelli N, Giorda E, et al. miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. J Biol Chem 2007;282:23716-24.
71. Fornari F, Gramantieri L, Ferracin M, et al. MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene 2008;27:5651-61.
72. Huynh TK, Huang CH, Chen JY, et al. miR-221 confers lapatinib resistance by negatively regulating p27kip1 in HER2-positive breast cancer. Cancer Sci 2021;112:4234-45.
74. Thomas SM, Brugge JS. Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol 1997;13:513-609.
75. Kim LC, Song L, Haura EB. Src kinases as therapeutic targets for cancer. Nat Rev Clin Oncol 2009;6:587-95.
76. Ralston R, Bishop JM. The product of the protooncogene c-Src is modified during the cellular response to platelet-derived growth factor. Proc Natl Acad Sci U S A 1985;82:7845-9.
77. Weernink PA, Rijksen G. Activation and translocation of c-Src to the cytoskeleton by both platelet-derived growth factor and epidermal growth factor. J Biol Chem 1995;270:2264-7.
78. Zhang S, Huang WC, Li P, et al. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med 2011;17:461-9.
79. Peiró G, Ortiz-Martínez F, Gallardo A, et al. Src, a potential target for overcoming trastuzumab resistance in HER2-positive breast carcinoma. Br J Cancer 2014;111:689-95.
80. Ocana A, Gil-Martin M, Antolín S, et al. Efficacy and safety of dasatinib with trastuzumab and paclitaxel in first line HER2-positive metastatic breast cancer: results from the phase II GEICAM/2010-04 study. Breast Cancer Res Treat 2019;174:693-701.
81. Formisano L, Nappi L, Rosa R, et al. Epidermal growth factor-receptor activation modulates Src-dependent resistance to lapatinib in breast cancer models. Breast Cancer Res 2014;16:R45.
82. Lu Y, Yu Q, Liu JH, et al. Src family protein-tyrosine kinases alter the function of PTEN to regulate phosphatidylinositol 3-kinase/AKT cascades. J Biol Chem 2003;278:40057-66.
83. O'Connor CM, Perl A, Leonard D, Sangodkar J, Narla G. Therapeutic targeting of PP2A. Int J Biochem Cell Biol 2018;96:182-93.
84. Pallas DC, Shahrik LK, Martin BL, et al. Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A. Cell 1990;60:167-76.
85. Chen W, Possemato R, Campbell K, et al. Identification of specific PP2A complexes involved in human cell transformation. Cancer Cell 2004;5:127-36.
86. Wandzioch E, Pusey M, Werda A, et al. PME-1 modulates protein phosphatase 2A activity to promote the malignant phenotype of endometrial cancer cells. Cancer Res 2014;74:4295-305.
87. Sablina AA, Hector M, Colpaert N, Hahn WC. Identification of PP2A complexes and pathways involved in cell transformation. Cancer Res 2010;70:10474-84.
88. Tan J, Lee PL, Li Z, et al. B55β-associated PP2A complex controls PDK1-directed myc signaling and modulates rapamycin sensitivity in colorectal cancer. Cancer Cell 2010;18:459-71.
89. Virshup DM, Shenolikar S. From promiscuity to precision: protein phosphatases get a makeover. Mol Cell 2009;33:537-45.
90. Schmoldt A, Benthe HF, Haberland G. Digitoxin metabolism by rat liver microsomes. Biochem Pharmacol 1975;24:1639-41.
91. Haesen D, Abbasi Asbagh L, Derua R, et al. Recurrent PPP2R1A mutations in uterine cancer act through a dominant-negative mechanism to promote malignant cell growth. Cancer Res 2016;76:5719-31.
92. Curtis C, Shah SP, Chin SF, et al. METABRIC Group. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 2012;486:346-52.
93. Cheng AS, Lau SS, Chen Y, et al. EZH2-mediated concordant repression of Wnt antagonists promotes β-catenin-dependent hepatocarcinogenesis. Cancer Res 2011;71:4028-39.
95. Fingar DC, Richardson CJ, Tee AR, et al. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol 2004;24:200-16.
96. Rodgers JT, Vogel RO, Puigserver P. Clk2 and B56β mediate insulin-regulated assembly of the PP2A phosphatase holoenzyme complex on Akt. Mol Cell 2011;41:471-9.
97. Hui L, Rodrik V, Pielak RM, et al. mTOR-dependent suppression of protein phosphatase 2A is critical for phospholipase D survival signals in human breast cancer cells. J Biol Chem 2005;280:35829-35.
98. Peterson RT, Desai BN, Hardwick JS, Schreiber SL. Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein. Proc Natl Acad Sci U S A 1999;96:4438-42.
99. Hahn K, Miranda M, Francis VA, et al. PP2A regulatory subunit PP2A-B’ counteracts S6K phosphorylation. Cell Metab 2010;11:438-44.
100. Padmanabhan S, Mukhopadhyay A, Narasimhan SD, et al. A PP2A regulatory subunit regulates C. elegans insulin/IGF-1 signaling by modulating AKT-1 phosphorylation. Cell 2009;136:939-51.
101. Kuo YC, Huang KY, Yang CH, et al. Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt. J Biol Chem 2008;283:1882-92.
102. Bao Y, Oguz G, Lee WC, et al. EZH2-mediated PP2A inactivation confers resistance to HER2-targeted breast cancer therapy. Nat Commun 2020;11:5878.
103. Tan JZ, Yan Y, Wang XX, Jiang Y, Xu HE. EZH2: biology, disease, and structure-based drug discovery. Acta Pharmacol Sin 2014;35:161-74.
104. Ookhtens M, Kannan R, Lyon I, Baker N. Liver and adipose tissue contributions to newly formed fatty acids in an ascites tumor. Am J Physiol 1984;247:R146-53.
105. Kamphorst JJ, Cross JR, Fan J, et al. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc Natl Acad Sci U S A 2013;110:8882-7.
106. Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 2007;7:763-77.
107. Röhrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer 2016;16:732-49.
108. Su X, Abumrad NA. Cellular fatty acid uptake: a pathway under construction. Trends Endocrinol Metab 2009;20:72-7.
109. Febbraio M, Hajjar DP, Silverstein RL. CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J Clin Invest 2001;108:785-91.
110. Vazquez-Martin A, Colomer R, Brunet J, Menendez JA. Pharmacological blockade of fatty acid synthase (FASN) reverses acquired autoresistance to trastuzumab (Herceptin by transcriptionally inhibiting ‘HER2 super-expression’ occurring in high-dose trastuzumab-conditioned SKBR3/Tzb100 breast cancer cells. Int J Oncol 2007;31:769-76.
111. Feng WW, Bang S, Kurokawa M. CD36: a key mediator of resistance to HER2 inhibitors in breast cancer. Mol Cell Oncol 2020;7:1715766.
112. Silverstein RL, Febbraio M. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior. Sci Signal 2009;2:re3.
114. Syeda Z, Langden SSS, Munkhzul C, Lee M, Song SJ. Regulatory mechanism of MicroRNA expression in cancer. Int J Mol Sci 2020;21:1723.
115. Ahmad A, Aboukameel A, Kong D, et al. Phosphoglucose isomerase/autocrine motility factor mediates epithelial-mesenchymal transition regulated by miR-200 in breast cancer cells. Cancer Res 2011;71:3400-9.
116. Adams BD, Guttilla IK, White BA. Involvement of microRNAs in breast cancer. Semin Reprod Med 2008;26:522-36.
117. Rao X, Di Leva G, Li M, et al. MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways. Oncogene 2011;30:1082-97.
118. Ye X, Bai W, Zhu H, et al. MiR-221 promotes trastuzumab-resistance and metastasis in HER2-positive breast cancers by targeting PTEN. BMB Rep 2014;47:268-73.
119. Tian T, Zhou Y, Feng X, et al. MicroRNA-16 is putatively involved in the NF-κB pathway regulation in ulcerative colitis through adenosine A2a receptor (A2aAR) mRNA targeting. Sci Rep 2016;6:30824.
120. Venturutti L, Cordo Russo RI, Rivas MA, et al. MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1. Oncogene 2016;35:6189-202.
121. Corcoran C, Rani S, Breslin S, et al. miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer. Mol Cancer 2014;13:71.
122. Hunter FW, Barker HR, Lipert B, et al. Mechanisms of resistance to trastuzumab emtansine (T-DM1) in HER2-positive breast cancer. Br J Cancer 2020;122:603-12.
123. Nahta R, Yu D, Hung MC, Hortobagyi GN, Esteva FJ. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol 2006;3:269-80.
124. D'Amato V, Raimondo L, Formisano L, et al. Mechanisms of lapatinib resistance in HER2-driven breast cancer. Cancer Treat Rev 2015;41:877-83.
125. Canfield K, Li J, Wilkins OM, et al. Receptor tyrosine kinase ERBB4 mediates acquired resistance to ERBB2 inhibitors in breast cancer cells. Cell Cycle 2015;14:648-55.
126. Garrett JT, Olivares MG, Rinehart C, et al. Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. Proc Natl Acad Sci U S A 2011;108:5021-6.