Activating transcription factor 4 modulates TGFb-induced aggressiveness in triple-negative breast cancer via SMad2/3/4 and mTORC2 signaling

Clinical Cancer Research

Volumn 24, Issue 22, 2018, Pages 5697-5709

  Gonzalez González, Adrián ^a,b   Muñoz Muela, Esperanza ^a,b   Marchal, Juan A ^c   Cara, Francisca E ^a,b   Molina, Maria P ^a,b   Cruz Lozano, Marina ^a,b   Jiménez, Gema ^c   Verma, Akanksha ^d   Ramírez, Alberto ^e   Qian, Wei ^d   Chen, Wen ^e   Kozielski, Anthony J ^e   Elemento, Olivier ^d   Martín Salvago, María D ^a   Luque, Rafael J ^a   Rosa Garrido, Carmen ^a   Landeira, David ^b,f   Quintana Romero, María ^b,f   Rosato, Roberto R ^e   García, Maria A ^g   Ramirez Tortosa, Cesar L ^a   Kim, Hanna ^h   Rodriguez Aguayo, Cristian ⁱ   Lopez Berestein, Gabriel ⁱ   Sood, Anil K ⁱ   Lorente, Jose A ^b   Sánchez Rovira, Pedro ^a,b   Chang, Jenny C ^e   Granados Principal, Sergio ^a,b   more..

^a Servicio Andaluz de Salud   (Spain)

^b PTS Granada   (Spain)

^c UNIVERSITY OF GRANADA   (Spain)

^d WEILL CORNELL MEDICAL COLLEGE   (United States)

^e HOUSTON METHODIST HOSPITAL   (United States)

^f UNIVERSITY OF GRANADA   (Spain)

^g HOSPITAL UNIVERSITARIO VIRGEN DE LAS NIEVES   (Spain)

^h TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER   (United States)

ⁱ UNIVERSITY OF TEXAS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVATING TRANSCRIPTION FACTOR 4; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; RAC1 PROTEIN; SMAD2 PROTEIN; SMAD3 PROTEIN; SMAD4 PROTEIN; TRANSFORMING GROWTH FACTOR BETA; ATF4 PROTEIN, HUMAN; SMAD PROTEIN; SMALL INTERFERING RNA; TRANSCRIPTOME;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CANCER GROWTH; CANCER PROGNOSIS; CANCER RECURRENCE; CELL PROLIFERATION; CONTROLLED STUDY; ENZYME INHIBITION; ENZYME REGULATION; EPITHELIAL MESENCHYMAL TRANSITION; HUMAN; HUMAN TISSUE; IN VIVO STUDY; MAJOR CLINICAL STUDY; MOUSE; MTOR SIGNALING; NONHUMAN; OVERALL SURVIVAL; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; RECURRENCE FREE SURVIVAL; TRIPLE NEGATIVE BREAST CANCER; TUMOR VOLUME; ANIMAL; BIOLOGICAL MODEL; BIOLOGY; CELL MOTION; DISEASE MODEL; FEMALE; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GENETICS; IMMUNOHISTOCHEMISTRY; METABOLISM; MORTALITY; PATHOLOGY; PROCEDURES; PROGNOSIS; SIGNAL TRANSDUCTION; TUMOR CELL LINE; XENOGRAFT;

ACTIVATING TRANSCRIPTION FACTOR 4; ANIMALS; CELL LINE, TUMOR; CELL MOVEMENT; CELL PROLIFERATION; COMPUTATIONAL BIOLOGY; DISEASE MODELS, ANIMAL; FEMALE; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION, NEOPLASTIC; HETEROGRAFTS; HUMANS; IMMUNOHISTOCHEMISTRY; MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 2; MICE; MODELS, BIOLOGICAL; PROGNOSIS; RNA, SMALL INTERFERING; SIGNAL TRANSDUCTION; SMAD PROTEINS; TRANSCRIPTOME; TRANSFORMING GROWTH FACTOR BETA; TRIPLE NEGATIVE BREAST NEOPLASMS;

EID: 85056597278     PISSN: 10780432     EISSN: 15573265     Source Type: Journal    
DOI: 10.1158/1078-0432.CCR-17-3125     Document Type: Article

References (49)

1. Jhan J-R, Andrechek ER. Effective personalized therapy for breast cancer based on predictions of cell signaling pathway activation from gene expression analysis. Oncogene 2017;36:3553-61.
2. Jitariu A, Cîmpean AM, Ribatti D, Raica M. Triple negative breast cancer: the kiss of death. Oncotarget 2017;8:46652-62.
3. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011;121:2750-67.
4. Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM. The integrated stress response. EMBO Rep 2016;17:1374-95.
5. Park Y, Reyna-Neyra A, Philippe L, Thoreen CC. mTORC1 balances cellular amino acid supply with demand for protein synthesis through post-transcriptional control of ATF4. Cell Rep 2017;19:1083-90.
6. Singleton DC, Harris AL. Targeting the ATF4 pathway in cancer therapy. Expert Opin Ther Targets 2012;16:1189-202.
7. Fan C-F, Mao X-Y, Wang E-H. Elevated p-CREB-2 (ser 245) expression is potentially associated with carcinogenesis and development of breast carcinoma. Mol Med Rep 2012;5:357-62.
8. van Geldermalsen M, Wang Q, Nagarajah R, Marshall AD, Thoeng A, Gao D, et al. ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer. Oncogene 2016;35: 3201-8.
9. Bobrovnikova-Marjon E, Grigoriadou C, Pytel D, Zhang F, Ye J, Koumenis C, et al. PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene 2010;29: 3881-95.
10. Nagelkerke A, Bussink J, Mujcic H, Wouters BG, Lehmann S, Sweep FCGJ, et al. Hypoxia stimulates migration of breast cancer cells via the PERK/ ATF4/LAMP3-arm of the unfolded protein response. Breast Cancer Res 2013;15:R2.
11. Feng Y-X, Sokol ES, Del Vecchio CA, Sanduja S, Claessen JHL, Proia TA, et al. Epithelial-to-mesenchymal transition activates PERK-eIF2a and sensitizes cells to endoplasmic reticulum stress. Cancer Discov 2014;4:702-15.
12. Demay Y, Perochon J, Szuplewski S, Mignotte B, Gaumer S. The PERK pathway independently triggers apoptosis and a Rac1/Slpr/JNK/Dilp8 signaling favoring tissue homeostasis in a chronic ER stress Drosophila model. Cell Death Dis 2014;5:e1452.
13. Dey S, Sayers CM, Verginadis II, Lehman SL, Cheng Y, Cerniglia GJ, et al. ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis. J Clin Invest 2015;125:2592-608.
14. Wu H, Wei L, Fan F, Ji S, Zhang S, Geng J, et al. Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis. Nat Commun 2015;6:6239-53.
15. Liu X, Lv Z, Zou J, Liu X, Ma J, Wang J, et al. Afatinib down-regulates MCL-1 expression through the PERK-eIF2a-ATF4 axis and leads to apoptosis in head and neck squamous cell carcinoma. Am J Cancer Res 2016;6: 1708-19.
16. Dekervel J, Bulle A, Windmolders P, Lambrechts D, Van Cutsem E, Verslype C, et al. Acriflavine inhibits acquired drug resistance by blocking the epithelial-to-mesenchymal transition and the unfolded protein response. Transl Oncol 2017;10:59-69.
17. Nagasawa I, Kunimasa K, Tsukahara S, Tomida A. BRAF-mutated cells activate GCN2-mediated integrated stress response as a cytoprotective mechanism in response to vemurafenib. Biochem Biophys Res Commun 2017;482:1491-7.
18. Ben-Sahra I, Hoxhaj G, Ricoult SJH, Asara JM, Manning BD. mTORC1 induces purine synthesis through control of the mitochondrial tetrahy-drofolate cycle. Science 2016;351:728-33.
19. Hao Y, Samuels Y, Li Q, Krokowski D, Guan B-J, Wang C, et al. Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer. Nat Commun 2016;7:11971.
20. Lian N, Lin T, Liu W, Wang W, Li L, Sun S, et al. Transforming growth factor b suppresses osteoblast differentiation via the vimentin activating transcription factor 4 (ATF4) axis. J Biol Chem 2012;287:35975-84.
21. Zhu H, Xia L, Zhang Y, Wang H, Xu W, Hu H, et al. Activating transcription factor 4 confers a multidrug resistance phenotype to gastric cancer cells through transactivation of SIRT1 expression. PLoS One 2012;7:e31431.
22. Zhu H, Chen X, Chen B, Chen B, Song W, Sun D, et al. Activating transcription factor 4 promotes esophageal squamous cell carcinoma invasion and metastasis in mice and is associated with poor prognosis in human patients. PLoS One 2014;9:e103882.
23. Granados-Principal S, Liu Y, Guevara ML, Blanco E, Choi DS, Qian W, et al. Inhibition of iNOS as a novel effective targeted therapy against triple-negative breast cancer. Breast Cancer Res 2015;17:25.
24. Györffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat 2010;123:725-31.
25. Pereira B, Chin S-F, Rueda OM, Vollan H-KM, Provenzano E, Bardwell HA, et al. The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat Commun 2016;7:11479.
26. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2012;2:401-4.
27. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013;6:pl1.
28. Dave B, Granados-Principal S, Zhu R, Benz S, Rabizadeh S, Soon-Shiong P, et al. Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling. Proc Natl Acad Sci U S A 2014;111:8838-43.
29. Zhang X, Claerhout S, Prat A, Dobrolecki LE, Petrovic I, Lai Q, et al. A renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models. Cancer Res 2013;73:4885-97.
30. Choi DS, Blanco E, Kim Y-S, Rodriguez AA, Zhao H, Huang TH-M, et al. Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1. Stem Cells 2014;32:2309-23.
31. Bhola NE, Balko JM, Dugger TC, Kuba MG, Sánchez V, Sanders M, et al. TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Invest 2013;123:1348-58.
32. Martin-Malpartida P, Batet M, Kaczmarska Z, Freier R, Gomes T, Aragón E, et al. Structural basis for genome wide recognition of 5-bp GC motifs by SMAD transcription factors. Nat Commun 2017;8:2070.
33. Sundqvist A, Morikawa M, Ren J, Vasilaki E, Kawasaki N, Kobayashi M, et al. JUNB governs a feed-forward network of TGFβ signaling that aggravates breast cancer invasion. Nucleic Acids Res 2018;46:1180-95.
34. Bierie B, Moses HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 2006;6:506-20.
35. Efeyan A, Sabatini DM. mTOR and cancer: many loops in one pathway. Curr Opin Cell Biol 2010;22:169-76.
36. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009;119:1420-8.
37. Idowu MO, Kmieciak M, Dumur C, Burton RS, Grimes MM, Powers CN, et al. CD44(+)/CD24(-/low) cancer stem/progenitor cells are more abundant in triple-negative invasive breast carcinoma phenotype and are associated with poor outcome. Hum Pathol 2012;43:364-73.
38. Jovanović B, Beeler JS, Pickup MW, Chytil A, Gorska AE, Ashby WJ, et al. Transforming growth factor beta receptor type III is a tumor promoter in mesenchymal-stem like triple negative breast cancer. Breast Cancer Res 2014;16:R69.
39. Liu Z, Gu H, Gan L, Xu Y, Feng F, Saeed M, et al. Reducing Smad3/ATF4 was essential for Sirt1 inhibiting ER stress-induced apoptosis in mice brown adipose tissue. Oncotarget 2017;8:9267-79.
40. Karner CM, Lee S-Y, Long F. Bmp Induces Osteoblast Differentiation through both Smad4 and mTORC1 Signaling. Mol Cell Biol 2017;37: 1-12.
41. Yin X, Wolford CC, Chang Y-S, McConoughey SJ, Ramsey S a, Aderem A, et al. ATF3, an adaptive-response gene, enhances TGF{beta} signaling and cancer-initiating cell features in breast cancer cells. J Cell Sci 2010;123: 3558-65.
42. Lamouille S, Connolly E, Smyth JW, Akhurst RJ, Derynck R. TGF-β-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. J Cell Sci 2012;125:1259-73.
43. Oh WJ, Wu C, Kim SJ, Facchinetti V, Julien L-A, Finlan M, et al. mTORC2 can associate with ribosomes to promote cotranslational phosphorylation and stability of nascent Akt polypeptide. EMBO J 2010;29:3939-51.
44. Pugazhenthi S, Nesterova A, Sable C, Heidenreich KA, Boxer LM, Heasley LE, et al. Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem 2000; 275:10761-6.
45. Saci A, Cantley LC, Carpenter CL. Rac1 regulates the activity of mTORC1 and mTORC2 and controls cellular size. Mol Cell 2011;42:50-61.
46. Das R, Xu S, Nguyen TT, Quan X, Choi S-K, Kim S-J, et al. Transforming growth factor b1-induced apoptosis in podocytes via the extracellular signal-regulated kinase-mammalian target of rapamycin complex 1-NADPH oxidase 4 axis. J Biol Chem 2015;290: 30830-42.
47. Das F, Ghosh-Choudhury N, Bera A, Dey N, Abboud HE, Kasinath BS, et al. Transforming growth factor b integrates Smad 3 to mechanistic target of rapamycin complexes to arrest deptor abundance for glomerular mesangial cell hypertrophy. J Biol Chem 2013;288:7756-68.
48. Gulhati P, Bowen KA, Liu J, Stevens PD, Rychahou PG, Chen M, et al. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res 2011;71:3246-56.
49. Yu JSL, Cui W. Proliferation, survival and metabolism: the role of PI3K/ AKT/mTOR signalling in pluripotency and cell fate determination. Development 2016;143:3050-60.