Autophagy-related gene 12 (ATG12) is a novel determinant of primary resistance to HER2-targeted therapies: Utility of transcriptome analysis of the autophagy interactome to guide breast cancer treatment

Oncotarget

Volumn 3, Issue 12, 2012, Pages 1600-1614

  Cufí, Sílvia ^a,b   Vazquez Martin, Alejandro ^a,b   Oliveras Ferraros, Cristina ^a,b   Corominas Faja, Bruna ^a,b   Urruticoechea, Ander ^c   Martin Castillo, Begoña ^a,b   Menendez, Javier A ^a,b  

^a Catalan Institute of Oncology Girona (ICO Girona)   (Spain)

^b GIRONA BIOMEDICAL RESEARCH INSTITUTE IDIBGI   (Spain)

^c HOSPITAL UNIVERSITARI DE BELLVITGE   (Spain)

Author keywords

ATG genes; Autophagy; HER2; Lapatinib; Trastuzumab

Indexed keywords

CISPLATIN; DOXORUBICIN; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 1; EPIDERMAL GROWTH FACTOR RECEPTOR 2; ERLOTINIB; FLUOROURACIL; GEFITINIB; LAPATINIB; LENTIVIRUS VECTOR; NAVELBINE; PACLITAXEL; TRANSCRIPTOME; TRASTUZUMAB; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; AUTOPHAGY; AUTOPHAGY INTERACTOME; AUTOPHAGY RELATED GENE 12; BREAST CANCER; CANCER CELL; CANCER GROWTH; CANCER RESISTANCE; CANCER THERAPY; CELL STRAIN; CELL STRAIN JIMT1; CELL STRAIN SKBR3; CELL VACUOLE; CONTROLLED STUDY; DRUG TARGETING; GENE; GENE CONTROL; GENE SILENCING; GENETIC TRANSCRIPTION; HUMAN; HUMAN CELL; IN VITRO STUDY; MOUSE; NONHUMAN; PROTEIN EXPRESSION; PROTEIN TARGETING; QUANTITATIVE ANALYSIS; REAL TIME POLYMERASE CHAIN REACTION; UPREGULATION;

EID: 84874712300     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.742     Document Type: Article

References (114)

1. 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;3:269-280.
2. Chen FL, Xia W, Spector NL. Acquired resistance to small molecule ErbB2 tyrosine kinase inhibitors. Clin Cancer Res. 2008;14:6730-6734.
3. Spector NL, Blackwell KL.Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2009;27:5838-5847.
4. Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol. 2011;9:16-32.
5. Wong H, Leung R, Kwong A, Chiu J, Liang R, Swanton C, Yau T. Integrating molecular mechanisms and clinical evidence in the management of trastuzumab resistant or refractory HER-2 metastatic breast cancer. Oncologist. 2011;16:1535-1546.
6. Gajria D, Chandarlapaty S. HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies. Expert Rev Anticancer Ther. 2011;11:263-275.
7. Garrett JT, Arteaga CL. Resistance to HER2-directed antibodies and tyrosine kinase inhibitors: mechanisms and clinical implications. Cancer Biol Ther. 2011;11:793-800.
8. Stern HM. Improving treatment of HER2-positive cancers: opportunities and challenges. Sci Transl Med. 2012;4:127rv2.
9. Vazquez-Martin A, Oliveras-Ferraros C, Colomer R, Brunet J, Menendez JA. Low-scale phosphoproteome analyses identify the mTOR effector p70 S6 kinase 1 as a specific biomarker of the dual-HER1/HER2 tyrosine kinase inhibitor lapatinib (Tykerb) in human breast carcinoma cells. Ann Oncol. 2008;19:1097-1109.
10. Vázquez-Martín A, Oliveras-Ferraros C, del Barco S, Martín-Castillo B, Menéndez JA. mTOR inhibitors and the anti-diabetic biguanide metformin: new insights into the molecular management of breast cancer resistance to the HER2 tyrosine kinase inhibitor lapatinib (Tykerb). Clin Transl Oncol. 2009;11:455-459.
11. Martin-Castillo B, Dorca J, Vazquez-Martin A, Oliveras-Ferraros C, Lopez-Bonet E, Garcia M, Del Barco S, Menendez JA. Incorporating the antidiabetic drug metformin in HER2-positive breast cancer treated with neo-adjuvant chemotherapy and trastuzumab: an ongoing clinical-translational research experience at the Catalan Institute of Oncology. Ann Oncol. 2010;21:187-189.
12. Oliveras-Ferraros C, Vazquez-Martin A, Martin-Castillo B, Cufí S, Del Barco S, Lopez-Bonet E, Brunet J, Menendez JA. Dynamic emergence of the mesenchymal CD44(pos)CD24(neg/low) phenotype in HER2-gene amplified breast cancer cells with de novo resistance to trastuzumab (Herceptin). Biochem Biophys Res Commun. 2010;397:27-33.
13. Oliveras-Ferraros C, Vazquez-Martin A, Martin-Castilló B, Pérez-Martínez MC, Cufí S, Del Barco S, Bernado L, Brunet J, López-Bonet E, Menendez JA. Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: new insights into de novo resistance to trastuzumab (Herceptin). Int J Oncol. 2010;37:669-678.
14. Steelman LS, Chappell WH, Abrams SL, Kempf RC, Long J, Laidler P, Mijatovic S, Maksimovic-Ivanic D, Stivala F, Mazzarino MC, Donia M, Fagone P, Malaponte G, Nicoletti F, Libra M, Milella M, Tafuri A, Bonati A, Bäsecke J, Cocco L, Evangelisti C, Martelli AM, Montalto G, Cervello M, McCubrey JA. Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Aging (Albany NY). 2011;3:192-222.
15. Davies AH, Dunn SE. YB-1 drives preneoplastic progression: Insight into opportunities for cancer prevention. Oncotarget. 2011;2:401-406.
16. Oliveras-Ferraros C, Fernández-Arroyo S, Vazquez-Martin A, Lozano-Sánchez J, Cufí S, Joven J, Micol V, Fernández-Gutiérrez A, Segura-Carretero A, Menendez JA. Crude phenolic extracts from extra virgin olive oil circumvent de novo breast cancer resistance to HER1/HER2-targeting drugs by inducing GADD45-sensed cellular stress, G2/M arrest and hyperacetylation of Histone H3. Int J Oncol. 2011;38:1533-1547.
17. Oliveras-Ferraros C, Vazquez-Martin A, Cufí S, Torres-Garcia VZ, Sauri-Nadal T, Barco SD, Lopez-Bonet E, Brunet J, Martin-Castillo B, Menendez JA. Inhibitor of Apoptosis (IAP) survivin is indispensable for survival of HER2 gene-amplified breast cancer cells with primary resistance to HER1/2-targeted therapies. Biochem Biophys Res Commun. 2011;407:412-419.
18. Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, Martin-Castillo B, Menendez JA. The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer Res Treat. 2011;126:355-364.
19. Adams JR, Schachter NF, Liu JC, Zacksenhaus E, Egan SE. Elevated PI3K signaling drives multiple breast cancer subtypes. Oncotarget. 2011;2:435-447.
20. Chappell WH, Steelman LS, Long JM, Kempf RC, Abrams SL, Franklin RA, Bäsecke J, Stivala F, Donia M, Fagone P, Malaponte G, Mazzarino MC, Nicoletti F, Libra M, Maksimovic-Ivanic D, Mijatovic S, Montalto G, Cervello M, Laidler P, Milella M, Tafuri A, Bonati A, Evangelisti C, Cocco L, Martelli AM, McCubrey JA. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget. 2011;2:135-164.
21. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Montalto G, Cervello M, Nicoletti F, Fagone P, Malaponte G, Mazzarino MC, Candido S, Libra M, Bäsecke J, Mijatovic S, Maksimovic-Ivanic D, Milella M, Tafuri A, Cocco L, Evangelisti C, Chiarini F, Martelli AM. Mutations and Deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascades. Oncotarget. 2012;3:954-987.
22. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Franklin RA, Montalto G, Cervello M, Libra M, Candido S, Malaponte G, Mazzarino MC, Fagone P, Nicoleti F, Bäsecke J, Mijatovic S, Maksimovic-Ivanic D, Milella M, Tafuri A, Chiarini F, Evangelisti C, Cocco L, Martelli AM. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascade Inhibitors: How Mutations Can Result in Therapy Resistance and How to Overcome Resistance. Oncotarget. 2012 Oct 20. [Epub ahead of print]
23. Aurisicchio L, Marra E, Roscilli G, Mancini R, Ciliberto G. The promise of anti-ErbB3 monoclonals as new cancer therapeutics. Oncotarget. 2012;3:744-758.
24. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009; 43:67-93.
25. Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science 2000; 290:1717-1721.
26. Lum JJ, DeBerardinis RJ, Thompson CB. Autophagy in metazoans: cell survival in the land of plenty. Nat Rev Mol Cell Biol 2005; 6:439-448.
27. Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. Autophagy facilitates the development of breast cancer resistance to the anti-HER2 monoclonal antibody trastuzumab. PLoS One. 2009;4:e6251.
28. Vazquez-Martin A, Cufí S, Oliveras-Ferraros C, Martin-Castillo B, Del Barco S, López-Bonet E, Menendez JA. Expression status of the autophagy-regulatory gene ATG6/BECN1 in ERBB2-positive breast carcinomas: bypassing ERBB2-induced oncogenic senescence to regulate the efficacy of ERBB2-targeted therapies. Genes Chromosomes Cancer. 2011;50:284-290.
29. 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. 2012 May 31. [Epub ahead of print]
30. Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer. 2007;7:961-967.
31. White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer. 2012;12:401-410.
32. Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther. 2011;10:1533-1541.
33. Janku F, McConkey DJ, Hong DS, Kurzrock R. Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol. 2011;8:528-539.
34. Eng CH, Abraham RT. The autophagy conundrum in cancer: influence of tumorigenic metabolic reprogramming. Oncogene. 2011; 30:4687-4696.
35. Zhou S, Zhao L, Kuang M, Zhang B, Liang Z, Yi T, Wei Y, Zhao X. Autophagy in tumorigenesis and cancer therapy: Dr. Jekyll or Mr. Hyde? Cancer Lett. 2012;323:115-127.
36. Jin S, White E. Role of autophagy in cancer: management of metabolic stress. Autophagy 2007; 3:28-31.
37. Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S, White E. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 2007;21:1621-1635.
38. Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, Chen G, Jin S, White E. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev. 2007;21:1367-1381.
39. Mathew R, White E. Why sick cells produce tumors: the protective role of autophagy. Autophagy 2007; 3:502-505.
40. Negri T, Tarantino E, Orsenigo M, Reid JF, Gariboldi M, Zambetti M, Pierotti MA, Pilotti S. Chromosome band 17q21 in breast cancer: significant association between beclin 1 loss and HER2/NEU amplification. Genes Chromosomes Cancer. 2010;49:901-909.
41. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ, Bernards R. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395-402.
42. Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W, Beijersbergen RL, Valero V, Seoane J, Bernards R, Baselga J. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. 2008;68:9221-9230.
43. Dave B, Migliaccio I, Gutierrez MC, Wu MF, Chamness GC, Wong H, Narasanna A, Chakrabarty A, Hilsenbeck SG, Huang J, Rimawi M, Schiff R, Arteaga C, Osborne CK, Chang JC. Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2-overexpressing locally advanced breast cancers. J Clin Oncol. 2011;29:166-173.
44. Razis E, Bobos M, Kotoula V, Eleftheraki AG, Kalofonos HP, Pavlakis K, Papakostas P, Aravantinos G, Rigakos G, Efstratiou I, Petraki K, Bafaloukos D, Kostopoulos I, Pectasides D, Kalogeras KT, Skarlos D, Fountzilas G. Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer. Breast Cancer Res Treat. 2011;128:447-456.
45. Tsujimoto Y, Shimizu S. Another way to die: autophagic programmed cell death. Cell Death Differ. 2005;12 Suppl 2:1528-1534.
46. Bialik S, Kimchi A. Autophagy and tumor suppression: recent advances in understanding the link between autophagic cell death pathways and tumor development. Adv Exp Med Biol. 2008;615:177-200.
47. Shen S, Kepp O, Kroemer G. The end of autophagic cell death? Autophagy. 2012;8:1-3.
48. Cheng Y, Li H, Ren X, Niu T, Hait WN, Yang J. Cytoprotective effect of the elongation factor-2 kinase-mediated autophagy in breast cancer cells subjected to growth factor inhibition. PLoS One. 2010;5:e9715.
49. Han W, Pan H, Chen Y, Sun J, Wang Y, Li J, Ge W, Feng L, Lin X, Wang X, Wang X, Jin H. EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells. PLoS One. 2011;6:e18691.
50. Li X, Fan Z. The epidermal growth factor receptor antibody cetuximab induces autophagy in cancer cells by downregulating HIF-1alpha and Bcl-2 and activating the beclin 1/hVps34 complex. Cancer Res. 2010;70:5942-5952.
51. Li X, Lu Y, Pan T, Fan Z. Roles of autophagy in cetuximab-mediated cancer therapy against EGFR. Autophagy. 2010;6:1066-1077.
52. Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2012;8:445-544.
53. Tanner M, Kapanen AI, Junttila T, Raheem O, Grenman S, Elo J, et al. Characterization of a novel cell line established from a patient with Herceptin-resistant breast cancer. Mol Cancer Ther 2004; 3:1585-1592.
54. Nagy P, Friedländer E, Tanner M, Kapanen AI, Carraway KL, Isola J, et al. Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing breast cancer cell line. Cancer Res 2005; 65:473-482.
55. Jönsson G, Staaf J, Olsson E, Heidenblad M, Vallon-Christersson J, Osoegawa K, et al. High-resolution genomic profiles of breast cancer cell lines assessed by tiling BAC array comparative genomic hybridization. Genes Chromosomes Cancer. 2007; 46:543-558.
56. Lenferink AE, Busse D, Flanagan WM, Yakes FM, Arteaga CL. ErbB2/neu kinase modulates cellular p27(Kip1) and cyclin D1 through multiple signaling pathways. Cancer Res. 2001;61:6583-6591.
57. 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;31:769-776.
58. Sims D, Bursteinas B, Gao Q, Jain E, MacKay A, Mitsopoulos C, Zvelebil M. ROCK: a breast cancer functional genomics resource. Breast Cancer Res Treat. 2010;124:567-572.
59. Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, Clark L, Bayani N, Coppe JP, Tong F, Speed T, Spellman PT, DeVries S, Lapuk A, Wang NJ, Kuo WL, Stilwell JL, Pinkel D, Albertson DG, Waldman FM, McCormick F, Dickson RB, Johnson MD, Lippman M, Ethier S, Gazdar A, Gray JW. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 2006;10:515-527.
60. Cufí S, Vazquez-Martin A, Oliveras-Ferraros C, Martin-Castillo B, Vellon L, Menendez JA. Autophagy positively regulates the CD44(+) CD24(-/low) breast cancer stem-like phenotype. Cell Cycle. 2011;10:3871-3885.
61. Geng J, Klionsky DJ. The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. 'Protein modifications: beyond the usual suspects' review series. EMBO Rep. 2008;9:859-864.
62. Tanida I. Autophagosome formation and molecular mechanism of autophagy. Antioxid Redox Signal. 2011;14:2201-2214.
63. Pyo JO, Nah J, Jung YK. Molecules and their functions in autophagy. Exp Mol Med. 2012;44:73-80.
64. Hanada T, Ohsumi Y. Structure-function relationship of Atg12, a ubiquitin-like modifier essential for autophagy. Autophagy. 2005;1:110-118.
65. Hanada T, Noda NN, Satomi Y, Ichimura Y, Fujioka Y, Takao T, Inagaki F, Ohsumi Y. The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J Biol Chem. 2007;282:37298-37302.
66. Bass A, Sauer D, Klionsky DJ.A PCR analysis of the ubiquitin-like conjugation systems in macroautophagy. Autophagy. 2011;7:1410-1414.
67. Wong AS, Cheung ZH, Ip NY. Molecular machinery of macroautophagy and its deregulation in diseases. Biochim Biophys Acta. 2011;1812:1490-1497.
68. Yang Z, Klionsky DJ. Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol. 2010;22:124-131.
69. Xie Z, Klionsky DJ. Autophagosome formation: core machinery and adaptations. Nat Cell Biol. 2007;9:1102-1109.
70. Mariño G, López-Otín C. Autophagy: molecular mechanisms, physiological functions and relevance in human pathology. Cell Mol Life Sci. 2004;61:1439-54.
71. Maiuri MC, Tasdemir E, Criollo A, Morselli E, Vicencio JM, Carnuccio R, Kroemer G. Control of autophagy by oncogenes and tumor suppressor genes. Cell Death Differ. 2009;16:87-93.
72. Harrison B, Kraus M, Burch L, Stevens C, Craig A, Gordon-Weeks P, Hupp TR. DAPK-1 binding to a linear peptide motif in MAP1B stimulates autophagy and membrane blebbing. J Biol Chem. 2008;283:999-10014.
73. Gozuacik D, Kimchi A. DAPk protein family and cancer. Autophagy. 2006;2:74-79.
74. Kiyono K, Suzuki HI, Matsuyama H, Morishita Y, Komuro A, Kano MR, Sugimoto K, Miyazono K. Autophagy is activated by TGF-beta and potentiates TGF-beta-mediated growth inhibition in human hepatocellular carcinoma cells. Cancer Res. 2009;69:8844-8852.
75. Suzuki HI, Kiyono K, Miyazono K. Regulation of autophagy by transforming growth factor-β (TGF-ß) signaling. Autophagy. 2010;6:645-647.
76. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100:3983-3988.
77. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704-715.
78. Morel AP, Liévre M, Thomas C, Hinkal G, Ansieau S, Puisieux A. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS ONE 2008; 3:2888.
79. Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A, Rimm DL, Wong H, Rodriguez A, Herschkowitz JI, Fan C, Zhang X, He X, Pavlick A, Gutierrez MC, Renshaw L, Larionov AA, Faratian D, Hilsenbeck SG, Perou CM, Lewis MT, Rosen JM, Chang JC. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci U S A. 2009;106:13820-13825.
80. Creighton CJ, Chang JC, Rosen JM. Epithelialmesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer. J Mammary Gland Biol Neoplasia 2010; 15:253-260.
81. Ouyang G, Wang Z, Fang X, Liu J, Yang CJ. Molecular signaling of the epithelial to mesenchymal transition in generating and maintaining cancer stem cells. Cell Mol Life Sci 2010; 67:2605-2618.
82. Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010; 29:4741-4751.
83. Oliveras-Ferraros C, Corominas-Faja B, Cufí S, Vazquez-Martin A, Martin-Castillo B, Iglesias JM, López-Bonet E, Martin AG, Menendez JA. Epithelial-to-mesenchymal transition (EMT) confers primary resistance to trastuzumab (Herceptin). Cell Cycle. 2012;11:4020-4032.
84. Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005;1:15-25.
85. Hardie DG. Sensing of energy and nutrients by AMP-activated protein kinase. Am J Clin Nutr. 2011;93:891S-896S.
86. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13:251-262.
87. Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB. Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev. 2008;18:54-61.
88. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;7:11-20.
89. Jones RG, Thompson CB. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. 2009;23:537-548.
90. Romero-Garcia S, Lopez-Gonzalez JS, Báez-Viveros JL, Aguilar-Cazares D, Prado-Garcia H. Tumor cell metabolism: an integral view. Cancer Biol Ther. 2011;12:939-948.
91. Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell. 2012;21:297-308.
92. Spector NL, Yarden Y, Smith B, Lyass L, Trusk P, Pry K, Hill JE, Xia W, Seger R, Bacus SS. Activation of AMP-activated protein kinase by human EGF receptor 2/EGF receptor tyrosine kinase inhibitor protects cardiac cells. Proc Natl Acad Sci U S A. 2007;104:10607-10612.
93. Shell SA, Lyass L, Trusk PB, Pry KJ, Wappel RL, Bacus SS. Activation of AMPK is necessary for killing cancer cells and sparing cardiac cells. Cell Cycle. 2008;7:1769-1775.
94. Meley D, Bauvy C, Houben-Weerts JH, Dubbelhuis PF, Helmond MT, Codogno P, Meijer AJ. AMP-activated protein kinase and the regulation of autophagic proteolysis. J Biol Chem. 2006;281:34870-34879.
95. Ben Sahra I, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, Le Marchand-Brustel Y, Giorgetti-Peraldi S, Cormont M, Bertolotto C, Deckert M, Auberger P, Tanti JF, Bost F. Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res. 2010;70:2465-2475.
96. Ben Sahra I, Tanti JF, Bost F. The combination of metformin and 2 deoxyglucose inhibits autophagy and induces AMPK-dependent apoptosis in prostate cancer cells. Autophagy. 2010;6:670-671.
97. Vazquez-Martin A, Oliveras-Ferraros C, Cufí S, Del Barco S, Martin-Castillo B, Menendez JA. Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status. Cell Cycle. 2010;9:3807-3814.
98. Cufí S, Vazquez-Martin A, Oliveras-Ferraros C, Martin-Castillo B, Joven J, Menendez JA. Metformin against TGFβ-induced epithelial-to-mesenchymal transition (EMT): from cancer stem cells to aging-associated fibrosis. Cell Cycle. 2010;9:4461-4468.
99. Vazquez-Martin A, López-Bonetc E, Cufí S, Oliveras-Ferraros C, Del Barco S, Martin-Castillo B, Menendez JA. Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions. Drug Resist Updat. 2011;14:212-223.
100. Cufi S, Corominas-Faja B, Vazquez-Martin A, Oliveras-Ferraros C, Dorca J, Bosch-Barrera J, Martin-Castillo B, Menendez JA. Metformin-induced preferential killing of breast cancer initiating CD44+CD24-/low cells is sufficient to overcome primary resistance to trastuzumab in HER2+ human breast cancer xenografts. Oncotarget. 2012;3:395-398.
101. Del Barco S, Vazquez-Martin A, Cufí S, Oliveras-Ferraros C, Bosch-Barrera J, Joven J, Martin-Castillo B, Menendez JA. Metformin: multi-faceted protection against cancer. Oncotarget. 2011;2:896-917.
102. McAfee Q, Zhang Z, Samanta A, Levi SM, Ma XH, Piao S, Lynch JP, Uehara T, Sepulveda AR, Davis LE, Winkler JD, Amaravadi RK. Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency. Proc Natl Acad Sci U S A. 2012;109:8253-8258.
103. Amaravadi RK, Winkler JD. Lys05: A new lysosomal autophagy inhibitor. Autophagy. 2012;8:1383-1384.
104. Liu J, Xia H, Kim M, Xu L, Li Y, Zhang L, Cai Y, Norberg HV, Zhang T, Furuya T, Jin M, Zhu Z, Wang H, Yu J, Li Y, Hao Y, Choi A, Ke H, Ma D, Yuan J. Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell. 2011;147:223-234.
105. Solomon VR, Lee H. Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies. Eur J Pharmacol. 2009; 625:220-233.
106. Carew JS, Kelly KR, Nawrocki ST.Autophagy as a target for cancer therapy: new developments. Cancer Manag Res. 2012;4:357-365.
107. Gorski SM, Ries J, Lum JJ. Targeting autophagy: The Achilles' heel of cancer. Autophagy. 2012;8:1279-1280.
108. Maycotte P, Aryal S, Cummings CT, Thorburn J, Morgan MJ, Thorburn A. Chloroquine sensitizes breast cancer cells to chemotherapy independent of autophagy. Autophagy. 2012;8:200-212.
109. Mancias JD, Kimmelman AC. Targeting autophagy addiction in cancer. Oncotarget. 2011;2:1302-1306.
110. Austin CD, De Maziére AM, Pisacane PI, van Dijk SM, Eigenbrot C, Sliwkowski MX, Klumperman J, Scheller RH. Endocytosis and sorting of ErbB2 and the site of action of cancer therapeutics trastuzumab and geldanamycin. Mol Biol Cell. 2004;15:5268-5282.
111. Austin CD, Wen X, Gazzard L, Nelson C, Scheller RH, Scales SJ. Oxidizing potential of endosomes and lysosomes limits intracellular cleavage of disulfide-based antibody-drug conjugates. Proc Natl Acad Sci U S A. 2005;102:17987-17992.
112. Marx C, Held JM, Gibson BW, Benz CC. ErbB2 trafficking and degradation associated with K48 and K63 polyubiquitination. Cancer Res. 2010;70:3709-3717.
113. Paris L, Cecchetti S, Spadaro F, Abalsamo L, Lugini L, Pisanu ME, Iorio E, Natali PG, Ramoni C, Podo F. Inhibition of phosphatidylcholine-specific phospholipase C downregulates HER2 overexpression on plasma membrane of breast cancer cells. Breast Cancer Res. 2010;12:R27.
114. Moussay E, Kaoma T, Baginska J, Muller A, Van Moer K, Nicot N, Nazarov PV, Vallar L, Chouaib S, Berchem G, Janji B. The acquisition of resistance to TNFa in breast cancer cells is associated with constitutive activation of autophagy as revealed by a transcriptome analysis using a custom microarray. Autophagy. 2011;7:760-770.