Heregulin/ErbB3 signaling enhances CXCR4-driven Rac1 activation and breast cancer cell motility via hypoxia-inducible factor 1α

Molecular and Cellular Biology

Volumn 36, Issue 15, 2016, Pages 2011-2026

  Lopez Haber, Cynthia ^a   Barrio Real, Laura ^a   Casado Medrano, Victoria ^a   Kazanietz, Marcelo G ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHEMOKINE RECEPTOR CXCR4; EPIDERMAL GROWTH FACTOR RECEPTOR 3; GUANINE NUCLEOTIDE EXCHANGE FACTOR; HYPOXIA INDUCIBLE FACTOR 1ALPHA; NEU DIFFERENTIATION FACTOR; RAC PROTEIN; RAC1 PROTEIN; REX PROTEIN; CXCR4 PROTEIN, HUMAN; ERBB3 PROTEIN, HUMAN; HIF1A PROTEIN, HUMAN; RAC1 PROTEIN, HUMAN;

ARTICLE; BREAST CANCER CELL LINE; CELL MIGRATION; CELL MOTILITY; CHROMATIN IMMUNOPRECIPITATION; HUMAN; HUMAN CELL; MUTAGENESIS; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; TRANSCRIPTION INITIATION; UPREGULATION; BREAST TUMOR; CELL MOTION; FEMALE; GENE EXPRESSION REGULATION; GENETICS; MCF-7 CELL LINE; METABOLISM; METASTASIS; PATHOLOGY; PROGNOSIS; TUMOR CELL LINE;

BREAST NEOPLASMS; CELL LINE, TUMOR; CELL MOVEMENT; FEMALE; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT; MCF-7 CELLS; NEOPLASM METASTASIS; PROGNOSIS; RAC1 GTP-BINDING PROTEIN; RECEPTOR, ERBB-3; RECEPTORS, CXCR4; SIGNAL TRANSDUCTION; TRANSCRIPTIONAL ACTIVATION;

EID: 85011992202     PISSN: 02707306     EISSN: 10985549     Source Type: Journal    
DOI: 10.1128/mcb.00180-16     Document Type: Article

References (87)

1. Olayioye MA, Neve RM, Lane HA, Hynes NE. 2000. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 19:3159-3167. http://dx.doi.org/10.1093/emboj/19.13.3159
2. Citri A, Skaria KB, Yarden Y. 2003. The deaf and the dumb: the biology of ErbB-2 and ErbB-3. Exp Cell Res 284:54-65. http://dx.doi.org/10.1016/S0014-4827(02)00101-5
3. Citri A, Yarden Y. 2006. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7:505-516
4. Wilson KJ, Gilmore JL, Foley J, Lemmon MA, Riese DJ II. 2009. Functional selectivity of EGF family peptide growth factors: implications for cancer. Pharmacol Ther 122:1-8. http://dx.doi.org/10.1016/j.pharmthera.2008.11.008
5. Suo Z, Risberg B, Karlsson MG, Villman K, Skovlund E, Nesland JM. 2002. The expression of EGFR family ligands in breast carcinomas. Int J Surg Pathol 10:91-99. http://dx.doi.org/10.1177/106689690201000202
6. Revillion F, Lhotellier V, Hornez L, Bonneterre J, Peyrat JP. 2008. ErbB/HER ligands in human breast cancer, and relationships with their receptors, the bio-pathological features and prognosis. Ann Oncol 19:73-80
7. Stern DF. 2008. ERBB3/HER3 and ERBB2/HER2 duet in mammary development and breast cancer. J Mammary Gland Biol Neoplasia 13:215-223. http://dx.doi.org/10.1007/s10911-008-9083-7
8. Hynes NE, MacDonald G. 2009. ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol 21:177-184. http://dx.doi.org/10.1016/j.ceb.2008.12.010
9. Arteaga CL, Engelman JA. 2014. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25:282-303. http://dx.doi.org/10.1016/j.ccr.2014.02.025
10. Momeny M, Saunus JM, Marturana F, McCart Reed AE, Black D, Sala G, Iacobelli S, Holland JD, Yu D, Da Silva L, Simpson PT, Khanna KK, Chenevix-Trench G, Lakhani SR. 2015. Heregulin-HER3-HER2 signaling promotes matrix metalloproteinase-dependent blood-brain-barrier transendothelial migration of human breast cancer cell lines. Oncotarget 6:3932-3946. http://dx.doi.org/10.18632/oncotarget.2846
11. Hellyer NJ. 2001. Heregulin-dependent activation of phosphoinositide 3-kinase and Akt via the ErbB2/ErbB3 co-receptor. J Biol Chem 276: 42153-42161. http://dx.doi.org/10.1074/jbc. M102079200
12. Campbell MR, Moasser MM. 2015. HER targeting in HER2-negative breast cancers: looking for the HER3 positive. Clin Cancer Res 21:2886-2888. http://dx.doi.org/10.1158/1078-0432.CCR-14-3012
13. Chiu CG, Masoudi H, Leung S, Voduc DK, Gilks B, Huntsman DG, Wiseman SM. 2010. HER-3 overexpression is prognostic of reduced breast cancer survival: a study of 4046 patients. Ann Surg 251:1107-1116. http://dx.doi.org/10.1097/SLA.0b013e3181dbb77e
14. Suo Z, Risberg B, Kalsson MG, Willman K, Tierens A, Skovlund E, Nesland JM. 2002. EGFR family expression in breast carcinomas. cerbB-and c-erbB-4 receptors have different effects on survival. J Pathol 196:17-25. http://dx.doi.org/10.1002/path.1003
15. Ritter CA, Perez-Torres M, Rinehart C, Guix M, Dugger T, Engelman JA, Arteaga CL. 2007. Human breast cancer cells selected for resistance to trastuzumab in Vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res 13:4909-4919. http://dx.doi.org/10.1158/1078-0432.CCR-07-0701
16. Chakrabarty A, Rexer BN, Wang SE, Cook RS, Engelman JA, Arteaga CL. 2010. H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3. Oncogene 29:5193-5203. http://dx.doi.org/10.1038/onc.2010.257
17. Lee CY, Lin Y, Bratman SV, Feng W, Kuo AH, Scheeren FA, Engreitz JM, Varma S, West RB, Diehn M. 2014. Neuregulin autocrine signaling promotes self-renewal of breast tumor-initiating cells by triggering HER2/HER3 activation. Cancer Res 74:341-352. http://dx.doi.org/10.1158/0008-5472.CAN-13-1055
18. Weinstein EJ, Kitsberg DI, Leder P. 2000. A mouse model for breast cancer induced by amplification and overexpression of the neu promoter and transgene. Mol Med 6:4-16
19. Atlas E, Cardillo M, Mehmi I, Zahedkargaran H, Tang C, Lupu R. 2003. Heregulin is sufficient for the promotion of tumorigenicity and metastasis of breast cancer cells in vivo. Mol Cancer Res 1:165-175
20. Kim J, Jeong H, Lee Y, Kim C, Kim H, Kim A. 2013. HRG-beta1-driven ErbB3 signaling induces epithelial-mesenchymal transition in breast cancer cells. BMC Cancer 13:383. http://dx.doi.org/10.1186/1471-2407-13-383
21. Asrani K, Keri RA, Galisteo R, Brown SA, Morgan SJ, Ghosh A, Tran NL, Winkles JA. 2013. The HER2-and heregulin beta1 (HRG)-inducible TNFRsuperfamily member Fn14 promotes HRG-driven breast cancer cell migration, invasion, and MMP9 expression. Mol Cancer Res 11:393-404. http://dx.doi.org/10.1158/1541-7786.MCR-12-0542
22. Seoane S, Montero JC, Ocana A, Pandiella A. 2016. Breast cancer dissemination promoted by a neuregulin-collagenase 3 signalling node. Oncogene 35:2756-2765. http://dx.doi.org/10.1038/onc.2015.337
23. Tang CK, Perez C, Grunt T, Waibel C, Cho C, Lupu R. 1996. Involvement of heregulin-beta2 in the acquisition of the hormone-independent phenotype of breast cancer cells. Cancer Res 56:3350-3358
24. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, Janne PA. 2007.METamplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039-1043. http://dx.doi.org/10.1126/science.1141478
25. Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, Ercan D, Rogers A, Roncalli M, Takeda M, Fujisaka Y, Philips J, Shimizu T, Maenishi O, Cho Y, Sun J, Destro A, Taira K, Takeda K, Okabe T, Swanson J, Itoh H, Takada M, Lifshits E, Okuno K, Engelman JA, Shivdasani RA, Nishio K, Fukuoka M, Varella-Garcia M, Nakagawa K, Janne PA. 2011. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med 3:99ra86. http://dx.doi.org/10.1126/scitranslmed.3002442
26. Wilson TR, Lee DY, Berry L, Shames DS, Settleman J. 2011. Neuregulin-1-mediated autocrine signaling underlies sensitivity to HER2 kinase inhibitors in a subset of human cancers. Cancer Cell 20:158-172. http://dx.doi.org/10.1016/j.ccr.2011.07.011
27. Ma J, Lyu H, Huang J, Liu B. 2014. Targeting of erbB3 receptor to overcome resistance in cancer treatment. Mol Cancer 13:105. http://dx.doi.org/10.1186/1476-4598-13-105
28. Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Blattler WA, Lambert JM, Chari RV, Lutz RJ, Wong WL, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spencer SD, Sliwkowski MX. 2008. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res 68:9280-9290. http://dx.doi.org/10.1158/0008-5472.CAN-08-1776
29. Dey G, Bharti R, Dhanarajan G, Das S, Dey KK, Kumar BN, Sen R, Mandal M. 2015. Marine lipopeptide Iturin A inhibits Akt mediated GSK3beta and FoxO3a signaling and triggers apoptosis in breast cancer. Sci Rep 5:10316. http://dx.doi.org/10.1038/srep10316
30. Tsai MS, Shamon-Taylor LA, Mehmi I, Tang CK, Lupu R. 2003. Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer. Oncogene 22:761-768. http://dx.doi.org/10.1038/sj.onc.1206130
31. Kang JC, Poovassery JS, Bansal P, You S, Manjarres IM, Ober RJ, Ward ES. 2014. Engineering multivalent antibodies to target heregulin-induced HER3 signaling in breast cancer cells. MAbs 6:340-353. http://dx.doi.org/10.4161/mabs.27658
32. Gaborit N, Lindzen M, Yarden Y. 2016. Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3. Hum Vaccin Immunother 12:576-592. http://dx.doi.org/10.1080/21645515.2015.1102809
33. Wali VB, Gilmore-Hebert M, Mamillapalli R, Haskins JW, Kurppa KJ, Elenius K, Booth CJ, Stern DF. 2014. Overexpression of ERBB4 JM-a CYT-1 and CYT-2 isoforms in transgenic mice reveals isoform-specific roles in mammary gland development and carcinogenesis. Breast Cancer Res 16:501. http://dx.doi.org/10.1186/s13058-014-0501-z
34. Haskins JW, Nguyen DX, Stern DF. 2014. Neuregulin 1-activated ERBB4 interacts with YAP to induce Hippo pathway target genes and promote cell migration. Sci Signal 7:ra116. http://dx.doi.org/10.1126/scisignal.2005770
35. Yang C, Liu Y, Lemmon MA, Kazanietz MG. 2006. Essential role for Rac in heregulin beta1 mitogenic signaling: a mechanism that involves epidermal growth factor receptor and is independent of ErbB4. Mol Cell Biol 26:831-842. http://dx.doi.org/10.1128/MCB.26.3.831-842.2006
36. Lopez-Haber C, Kazanietz MG. 2013. Cucurbitacin I inhibits Rac1 activation in breast cancer cells by a reactive oxygen species-mediated mechanism and independently of Janus tyrosine kinase 2 and P-Rex1. Mol Pharmacol 83:1141-1154. http://dx.doi.org/10.1124/mol.112.084293
37. Jaffe AB, Hall A. 2005. Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21:247-269. http://dx.doi.org/10.1146/annurev.cellbio.21.020604.150721
38. Rossman KL, Der CJ, Sondek J. 2005. GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol 6:167-180
39. Wertheimer E, Gutierrez-Uzquiza A, Rosemblit C, Lopez-Haber C, Sosa MS, Kazanietz MG. 2012. Rac signaling in breast cancer: a tale of GEFs and GAPs. Cell Signal 24:353-362. http://dx.doi.org/10.1016/j.cellsig.2011.08.011
40. Sosa MS, Lopez-Haber C, Yang C, Wang H, Lemmon MA, Busillo JM, Luo J, Benovic JL, Klein-Szanto A, Yagi H, Gutkind JS, Parsons RE, Kazanietz MG. 2010. Identification of the Rac-GEF P-Rex1 as an essential mediator of ErbB signaling in breast cancer. Mol Cell 40:877-892. http://dx.doi.org/10.1016/j.molcel.2010.11.029
41. Citterio C, Menacho-Marquez M, Garcia-Escudero R, Larive RM, Barreiro O, Sanchez-Madrid F, Paramio JM, Bustelo XR. 2012. The rho exchange factors vav2 and vav3 control a lung metastasis-specific transcriptional program in breast cancer cells. Sci Signal 5:ra71. http://dx.doi.org/10.1126/scisignal.2002962
42. Barrio-Real L, Benedetti LG, Engel N, Tu Y, Cho S, Sukumar S, Kazanietz MG. 2014. Subtype-specific overexpression of the Rac-GEF P-REX1 in breast cancer is associated with promoter hypomethylation. Breast Cancer Res 16:441. http://dx.doi.org/10.1186/s13058-014-0441-7
43. Montero JC, Seoane S, Ocana A, Pandiella A. 2011. P-Rex1 participates in Neuregulin-ErbB signal transduction and its expression correlates with patient outcome in breast cancer. Oncogene 30:1059-1071. http://dx.doi.org/10.1038/onc.2010.489
44. Dillon LM, Bean JR, Yang W, Shee K, Symonds LK, Balko JM, Mc-Donald WH, Liu S, Gonzalez-Angulo AM, Mills GB, Arteaga CL, Miller TW. 2015. P-REX1 creates a positive feedback loop to activate growth factor receptor, PI3K/AKT and MEK/ERK signaling in breast cancer. Oncogene 34:3968-3976. http://dx.doi.org/10.1038/onc.2014.328
45. Welch HC. 2015. Regulation and function of P-Rex family Rac-GEFs. Small GTPases 6:49-70. http://dx.doi.org/10.4161/21541248.2014.973770
46. Qin J, Xie Y, Wang B, Hoshino M, WolffDW, Zhao J, Scofield MA, Dowd FJ, Lin MF, Tu Y. 2009. Upregulation of PIP3-dependent Rac exchanger 1 (P-Rex1) promotes prostate cancer metastasis. Oncogene 28: 1853-1863. http://dx.doi.org/10.1038/onc.2009.30
47. Carretero-Ortega J, Walsh CT, Hernandez-Garcia R, Reyes-Cruz G, Brown JH, Vazquez-Prado J. 2010. Phosphatidylinositol 3,4,5-triphosphate-dependent Rac exchanger 1 (P-Rex-1), a guanine nucleotide exchange factor for Rac, mediates angiogenic responses to stromal cellderived factor-1/chemokine stromal cell derived factor-1 (SDF-1/CXCL-12. linked to Rac activation, endothelial cell migration, and in vitro angiogenesis. Mol Pharmacol 77:435-442. http://dx.doi.org/10.1124/mol.109.060400
48. Zlotnik A, Burkhardt AM, Homey B. 2011. Homeostatic chemokine receptors and organ-specific metastasis. Nat Rev Immunol 11:597-606. http://dx.doi.org/10.1038/nri3049
49. Ray P, Stacer AC, Fenner J, Cavnar SP, Meguiar K, Brown M, Luker KE, Luker GD. 2015. CXCL12-gamma in primary tumors drives breast cancer metastasis. Oncogene 34:2043-2051. http://dx.doi.org/10.1038/onc.2014.157
50. Chen Y, Stamatoyannopoulos G, Song CZ. 2003. Down-regulation of CXCR4 by inducible small interfering RNA inhibits breast cancer cell invasion in vitro. Cancer Res 63:4801-4804
51. Helbig G, Christopherson KW II, Bhat-Nakshatri P, Kumar S, Kishimoto H, Miller KD, Broxmeyer HE, Nakshatri H. 2003. NFkappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem 278: 21631-21638. http://dx.doi.org/10.1074/jbc. M300609200
52. Smith MC, Luker KE, Garbow JR, Prior JL, Jackson E, Piwnica-Worms D, Luker GD. 2004. CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Res 64:8604-8612. http://dx.doi.org/10.1158/0008-5472.CAN-04-1844
53. Liang Z, Wu H, Reddy S, Zhu A, Wang S, Blevins D, Yoon Y, Zhang Y, Shim H. 2007. Blockade of invasion and metastasis of breast cancer cells via targeting CXCR4 with an artificial microRNA. Biochem Biophys Res Commun 363:542-546. http://dx.doi.org/10.1016/j.bbrc.2007.09.007
54. Xu TP, Shen H, Liu LX, Shu YQ. 2013. The impact of chemokine receptor CXCR4 on breast cancer prognosis: a meta-analysis. Cancer Epidemiol 37:725-731. http://dx.doi.org/10.1016/j.canep.2013.04.017
55. Okuyama Kishima M, de Oliveira CE, Banin-Hirata BK, Losi-Guembarovski R, Brajao de Oliveira K, Amarante MK, Watanabe MA. 2015. Immunohistochemical expression of CXCR4 on breast cancer and its clinical significance. Anal Cell Pathol 2015:891020. http://dx.doi.org/10.1155/2015/891020
56. Li YM, Pan Y, Wei Y, Cheng X, Zhou BP, Tan M, Zhou X, Xia W, Hortobagyi GN, Yu D, Hung MC. 2004. Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. Cancer Cell 6:459-469. http://dx.doi.org/10.1016/j.ccr.2004.09.027
57. Liu Y, Ji R, Li J, Gu Q, Zhao X, Sun T, Wang J, Li J, Du Q, Sun B. 2010. Correlation effect of EGFR and CXCR4 and CCR7 chemokine receptors in predicting breast cancer metastasis and prognosis. J Exp Clin Cancer Res 29:16. http://dx.doi.org/10.1186/1756-9966-29-16
58. von Burstin VA, Xiao L, Kazanietz MG. 2010. Bryostatin 1 inhibits phorbol ester-induced apoptosis in prostate cancer cells by differentially modulating protein kinase C (PKC) delta translocation and preventing PKCdelta-mediated release of tumor necrosis factor-alpha. Mol Pharmacol 78:325-332. http://dx.doi.org/10.1124/mol.110.064741
59. Caloca MJ, Wang H, Kazanietz MG. 2003. Characterization of the Rac-GAP(Rac-GTPase-activating protein) activity of beta2-chimaerin, a 'nonprotein kinase C' phorbol ester receptor. Biochem J 375:313-321. http://dx.doi.org/10.1042/bj20030727
60. Deliard S, Zhao J, Xia Q, Grant SF. 19 April 2013. Generation of high quality chromatin immunoprecipitation DNA template for highthroughput sequencing (ChIP-seq). J Vis Exp http://dx.doi.org/10.3791/50286
61. Wang H, Gutierrez-Uzquiza A, Garg R, Barrio-Real L, Abera MB, Lopez-Haber C, Rosemblit C, Lu H, Abba M, Kazanietz MG. 2014. Transcriptional regulation of oncogenic protein kinase C (PKC) by STAT1 and Sp1 proteins. J Biol Chem 289:19823-19838. http://dx.doi.org/10.1074/jbc. M114.548446
62. Yu P, Kodadek T. 2007. Dynamics of the hypoxia-inducible factor-1-vascular endothelial growth factor promoter complex. J Biol Chem 282: 35035-35045. http://dx.doi.org/10.1074/jbc. M707557200
63. Semenza GL. 2003. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721-732. http://dx.doi.org/10.1038/nrc1187
64. Majmundar AJ, Wong WJ, Simon MC. 2010. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell 40:294-309. http://dx.doi.org/10.1016/j.molcel.2010.09.022
65. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. 2001. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 21:3995-4004. http://dx.doi.org/10.1128/MCB.21.12.3995-4004.2001
66. Wenger RH, Stiehl DP, Camenisch G. 2005. Integration of oxygen signaling at the consensus HRE. Sci STKE 2005:re12
67. Lee K, Lee JH, Boovanahalli SK, Jin Y, Lee M, Jin X, Kim JH, Hong YS, Lee JJ. 2007. (Aryloxyacetylamino)benzoic acid analogues: a new class of hypoxia-inducible factor-1 inhibitors. J Med Chem 50:1675-1684. http://dx.doi.org/10.1021/jm0610292
68. Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W. 2003. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 425:307-311. http://dx.doi.org/10.1038/nature01874
69. Busillo JM, Benovic JL. 2007. Regulation of CXCR4 signaling. Biochim Biophys Acta 1768:952-963. http://dx.doi.org/10.1016/j.bbamem.2006.11.002
70. Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A, Bernasconi S, Saccani S, Nebuloni M, Vago L, Mantovani A, Melillo G, Sica A. 2003. Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med 198:1391-1402. http://dx.doi.org/10.1084/jem.20030267
71. Melchionna R, Romani M, Ambrosino V, D'Arcangelo D, Cencioni C, Porcelli D, Toietta G, Truffa S, Gaetano C, Mangoni A, Pozzoli O, Cappuzzello C, Capogrossi MC, Napolitano M. 2010. Role of HIF-1alpha in proton-mediated CXCR4 down-regulation in endothelial cells. Cardiovasc Res 86:293-301. http://dx.doi.org/10.1093/cvr/cvp393
72. de Alava E, Ocana A, Abad M, Montero JC, Esparis-Ogando A, Rodriguez CA, Otero AP, Hernandez T, Cruz JJ, Pandiella A. 2007. Neuregulin expression modulates clinical response to trastuzumab in patients with metastatic breast cancer. J Clin Oncol 25:2656-2663. http://dx.doi.org/10.1200/JCO.2006.08.6850
73. Sheng Q, Liu X, Fleming E, Yuan K, Piao H, Chen J, Moustafa Z, Thomas RK, Greulich H, Schinzel A, Zaghlul S, Batt D, Ettenberg S, Meyerson M, Schoeberl B, Kung AL, Hahn WC, Drapkin R, Livingston DM, Liu JF. 2010. An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells. Cancer Cell 17:298-310. http://dx.doi.org/10.1016/j.ccr.2009.12.047
74. Sato Y, Yashiro M, Takakura N. 2013. Heregulin induces resistance to lapatinib-mediated growth inhibition of HER2-amplified cancer cells. Cancer Sci 104:1618-1625. http://dx.doi.org/10.1111/cas.12290
75. Sun X, Cheng G, Hao M, Zheng J, Zhou X, Zhang J, Taichman RS, Pienta KJ, Wang J. 2010. CXCL12/CXCR4/CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev 29:709-722. http://dx.doi.org/10.1007/s10555-010-9256-x
76. Yang C, Liu Y, Leskow FC, Weaver VM, Kazanietz MG. 2005. Rac-GAP-dependent inhibition of breast cancer cell proliferation by β2-chimerin. J Biol Chem 280:24363-24370. http://dx.doi.org/10.1074/jbc.M411629200
77. Schnelzer A, Prechtel D, Knaus U, Dehne K, Gerhard M, GraeffH, Harbeck N, Schmitt M, Lengyel E. 2000. Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene 19:3013-3020. http://dx.doi.org/10.1038/sj.onc.1203621
78. Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, Cheng E, Davis MJ, Goh G, Choi M, Ariyan S, Narayan D, Dutton-Regester K, Capatana A, Holman EC, Bosenberg M, Sznol M, Kluger HM, Brash DE, Stern DF, Materin MA, Lo RS, Mane S, Ma S, Kidd KK, Hayward NK, Lifton RP, Schlessinger J, Boggon TJ, Halaban R. 2012. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet 44:1006-1014. http://dx.doi.org/10.1038/ng.2359
79. Barrio-Real L, Kazanietz MG. 2012. Rho GEFs and cancer: linking gene expression and metastatic dissemination. Sci Signal 5:pe43. http://dx.doi.org/10.1126/scisignal.2003543
80. Campbell MR, Amin D, Moasser MM. 2010. HER3 comes of age: new insights into its functions and role in signaling, tumor biology, and cancer therapy. Clin Cancer Res 16:1373-1383. http://dx.doi.org/10.1158/1078-0432.CCR-09-1218
81. Porcile C, Bajetto A, Barbieri F, Barbero S, Bonavia R, Biglieri M, Pirani P, Florio T, Schettini G. 2005. Stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12) stimulates ovarian cancer cell growth through the EGF receptor transactivation. Exp Cell Res 308:241-253. http://dx.doi.org/10.1016/j.yexcr.2005.04.024
82. Cabioglu N, Summy J, Miller C, Parikh NU, Sahin AA, Tuzlali S, Pumiglia K, Gallick GE, Price JE. 2005. CXCL-12/stromal cell-derived factor-1alpha transactivates HER2-neu in breast cancer cells by a novel pathway involving Src kinase activation. Cancer Res 65:6493-6497. http://dx.doi.org/10.1158/0008-5472.CAN-04-1303
83. Kiuchi T, Ortiz-Zapater E, Monypenny J, Matthews DR, Nguyen LK, Barbeau J, Coban O, Lawler K, Burford B, Rolfe DJ, de Rinaldis E, Dafou D, Simpson MA, Woodman N, Pinder S, Gillett CE, Devauges V, Poland SP, Fruhwirth G, Marra P, Boersma YL, Pluckthun A, Gullick WJ, Yarden Y, Santis G, Winn M, Kholodenko BN, Martin-Fernandez ML, Parker P, Tutt A, Ameer-Beg SM, Ng T. 2014. The ErbB4 CYT2 variant protects EGFR from ligand-induced degradation to enhance cancer cell motility. Sci Signal 7:ra78. http://dx.doi.org/10.1126/scisignal.2005157
84. Weitzenfeld P, Ben-Baruch A. 2014. The chemokine system, and its CCR5 and CXCR4 receptors, as potential targets for personalized therapy in cancer. Cancer Lett 352:36-53. http://dx.doi.org/10.1016/j.canlet.2013.10.006
85. Onesto C, Shutes A, Picard V, Schweighoffer F, Der CJ. 2008. Characterization of EHT 1864, a novel small molecule inhibitor of Rac family small GTPases. Methods Enzymol 439:111-129. http://dx.doi.org/10.1016/S0076-6879(07)00409-0
86. Dharmawardhane S, Hernandez E, Vlaar C. 2013. Development of EHop-016: a small molecule inhibitor of Rac. Enzymes 33:117-146. http://dx.doi.org/10.1016/B978-0-12-416749-0.00006-3
87. Cardama GA, Comin MJ, Hornos L, Gonzalez N, Defelipe L, Turjanski AG, Alonso DF, Gomez DE, Menna PL. 2014. Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines. Anticancer Agents Med Chem 14:840-851. http://dx.doi.org/10.2174/18715206113136660334