Improved aptamers for the diagnosis and potential treatment of HER2-positive cancer

[en] Aptamers provide a potential source of alternative targeting molecules for existing antibody diagnostics and therapeutics. In this work, we selected novel DNA aptamers targeting the HER2 receptor by an adherent whole-cell SELEX approach. Individual aptamers were identified by next generation sequencing and bioinformatics analysis. Two aptamers, HeA2_1 and HeA2_3, were shown to bind the HER2 protein with affinities in the nanomolar range. In addition, both aptamers were able to bind with high specificity to HER2-overexpressing cells and HER2-positive tumor tissue samples. Furthermore, we demonstrated that aptamer HeA2_3 is being internalized into cancer cells and has an inhibitory effect on cancer cell growth and viability. In the end, we selected novel DNA aptamers with great potential for the diagnosis and possible treatment of HER2-positive cancer. © 2016 by the authors; licensee MDPI, Basel, Switzerland.

Disciplines :

Biotechnology

Author, co-author :

Gijs, M.; Radiobiology Unit, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium, Cyclotron Research Centre, University of Liège, Liège, Belgium

Penner, G.; NeoVentures Biotechnology Inc, London, ON, Canada

Blackler, G. B.; NeoVentures Biotechnology Inc, London, ON, Canada

Impens, N. R. E. N.; Radiobiology Unit, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium

Baatout, S.; Radiobiology Unit, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium

Luxen, André ; Université de Liège - ULiège > Centre de Recherches du Cyclotron

Aerts, A. M.; Radiobiology Unit, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium

Title :

Improved aptamers for the diagnosis and potential treatment of HER2-positive cancer

Publication date :

2016

Journal title :

Pharmaceuticals

eISSN :

1424-8247

Publisher :

MDPI AG

Volume :

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 20 February 2018

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Bibliography

Slamon, D.J, Clark, G.M, Wong, S.G, Levin, W.J, Ullrich, A, McGuire, W.L. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987, 235, 177-182. [CrossRef] [PubMed]
Slamon, D.J, Godolphin, W, Jones, L.A, Holt, J.A.; Wong, S.G, Keith, D.E, Levin, W.J, Stuart, S.G, Udove, J, Ullrich, A, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989, 244, 707-712. [CrossRef] [PubMed]
Zhang, J, Liu, Y. HER2 over-expression and response to different chemotherapy regimens in breast cancer. J. Zhejiang Univ. Sci. B 2008, 9, 5-9. [CrossRef] [PubMed]
Musolino, A, Ciccolallo, L, Panebianco, M, Fontana, E, Zanoni, D, Bozzetti, C, Michiara, M, Silini, E.M, Ardizzoni, A. Multifactorial central nervous system recurrence susceptibility in patients with HER2-positive breast cancer: Epidemiological and clinical data from a population-based cancer registry study. Cancer 2011, 117, 1837-1846. [CrossRef] [PubMed]
Rouanet, P, Roger, P, Rousseau, E, Thibault, S, Romieu, G, Mathieu, A, Cretin, J, Barneon, G, Granier, M, Maran-Gonzalez, A, et al. HER2 overexpression a major risk factor for recurrence in pT1a-bN0M0 breast cancer: Results from a French regional cohort. Cancer Med. 2014, 3, 134-142. [CrossRef] [PubMed]
Fight HER2+ Breast Cancer with Herceptin. Available online: http://www.herceptin.com (accessed on 25 June 2015)
Bartsch, R, Wenzel, C, Steger, G.G. Trastuzumab in the management of early and advanced stage breast cancer. Biologics 2007, 1, 19-31. [PubMed]
Claret, F.X, Vu, T.T. Trastuzumab: Updated mechanisms of action and resistance in breast cancer. Front. Oncol. 2012, 2. [CrossRef]
Sengupta, P.P, Northfelt, D.W, Gentile, F, Zamorano, J.L, Khandheria, B.K. Trastuzumab-induced cardiotoxicity: Heart failure at the crossroads. Mayo Clin. Proc. 2008, 83, 197-203. [CrossRef]
Ulrich, H. RNA aptamers: From basic science towards therapy. In RNA towards Medicine; Erdmann, V., Barciszewski, J., Brosius, J., Eds, Springer: Berlin/Heidelberg, Germany, 2006; Volume 173, pp. 305-326.
Bouchard, P.R, Hutabarat, R.M, Thompson, K.M. Discovery and development of therapeutic aptamers. Annu. Rev. Pharmacol. Toxicol. 2010, 50, 237-257. [CrossRef] [PubMed]
Hu, M, Zhang, K. The application of aptamers in cancer research: An up-to-date review. Future Oncol. 2013, 9, 369-376. [CrossRef] [PubMed]
Barbas, A.S, Mi, J, Clary, B.M, White, R.R. Aptamer applications for targeted cancer therapy. Future Oncol. 2010, 6, 1117-1126. [CrossRef] [PubMed]
Bruno, J.G. A review of therapeutic aptamer conjugates with emphasis on new approaches. Pharmaceuticals 2013, 6, 340-357. [CrossRef] [PubMed]
Meyer, C, Hahn, U, Rentmeister, A. Cell-specific aptamers as emerging therapeutics. J. Nucleic Acids 2011, 2011. [CrossRef] [PubMed]
Thiel, K.W, Giangrande, P.H. Therapeutic applications of DNA and RNA aptamers. Oligonucleotides 2009, 19, 209-222. [CrossRef] [PubMed]
Keefe, A.D, Pai, S, Ellington, A. Aptamers as therapeutics. Nat. Rev. Drug Discov. 2010, 9, 537-550. [CrossRef] [PubMed]
Weinberg, M.S. Therapeutic aptamers march on. Mol. Ther. Nucleic Acids 2014, 3. [CrossRef] [PubMed]
Sundaram, P, Kurniawan, H, Byrne, M.E, Wower, J. Therapeutic RNA aptamers in clinical trials. Eur. J. Pharm. Sci. 2013, 48, 259-271. [CrossRef] [PubMed]
Tuerk, C, Gold, L. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 1990, 249, 505-510. [CrossRef] [PubMed]
Ellington, A.D, Szostak, J.W. In vitro selection of RNA molecules that bind specific ligands. Nature 1990, 346, 818-822. [CrossRef] [PubMed]
Robertson, D.L, Joyce, G.F. Selection in vitro of an RNA enzyme that specifically cleaves single-stranded DNA. Nature 1990, 344, 467-468. [CrossRef] [PubMed]
Graham, J.C, Zarbl, H. Use of cell-selex to generate DNA aptamers as molecular probes of HPV-associated cervical cancer cells. PLoS ONE 2012, 7, e36103. [CrossRef] [PubMed]
Penner, G. Dubbles, an Alternative to Selex. Available online: https://www.youtube.com/watch?v=rmpvqCX1WqA (accessed on 25 June 2015)
Blind, M, Blank, M. Aptamer selection technology and recent advances. Mol. Ther. Nucleic Acids 2015, 4. [CrossRef]
Pan, W, Xin, P, Patrick, S, Dean, S, Keating, C, Clawson, G. Primer-free aptamer selection using a random DNA library. J. Vis. Exp. 2010. [CrossRef] [PubMed]
Pan, W, Clawson, G.A. The shorter the better: Reducing fixed primer regions of oligonucleotide libraries for aptamer selection. Molecules 2009, 14, 1353-1369. [CrossRef] [PubMed]
Marimuthu, C, Tang, T.H, Tominaga, J, Tan, S.C, Gopinath, S.C. Single-stranded DNA (ssDNA) production in DNA aptamer generation. Analyst 2012, 137, 1307-1315. [CrossRef] [PubMed]
Le, L.C, Cruz-Aguado, J.A, Penner, G.A. DNA Ligands for Aflatoxin and Zearalenone. U.S. Patent 20,120,225,494, 6 September 2011.
Penner, G. Detection Systems. Available online: http://neoventures.ca/products/mycotoxin-testing/ (accessed on 26 June 2015)
Schütze, T, Wilhelm, B, Greiner, N, Braun, H, Peter, F, Mörl, M, Erdmann, V.A, Lehrach, H, Konthur, Z, Menger, M, et al. Probing the SELEX process with next-generation sequencing. PLoS ONE 2011, 6, e29604. [CrossRef] [PubMed]
Cho, M, Xiao, Y, Nie, J, Stewart, R, Csordas, A.T, Oh, S.S, Thomson, J.A, Soh, H.T. Quantitative selection of DNA aptamers through microfluidic selection and high-throughput sequencing. Proc. Natl. Acad. Sci. USA 2010, 107, 15373-15378. [CrossRef] [PubMed]
Dausse, E, Taouji, S, Evade, L, di Primo, C, Chevet, E, Toulme, J.J. HAPIscreen, a method for high-throughput aptamer identification. J. Nanobiotechnol. 2011, 9. [CrossRef] [PubMed]
Thiel, W.H, Bair, T, Thiel, K.W, Dassie, J.P, Rockey, W.M, Howell, C.A, Liu, X.Y, Dupuy, A.J, Huang, L, Owczarzy, R, et al. Nucleotide bias observed with a short SELEX RNA aptamer library. Nucleic Acid Ther. 2011, 21, 253-263. [CrossRef] [PubMed]
Kang, H.-S, Huh, Y.-M, Kim, S, Lee, D.K. Isolation of RNA aptamers targeting HER2-overexpressing breast cancer cells using cell-SELEX. Bull. Korean Chem. Soc. 2009, 30, 1827-1831
Kim, M.Y, Jeong, S. In vitro selection of RNA aptamer and specific targeting of ErbB2 in breast cancer cells. Nucleic Acid Ther. 2011, 21, 173-178. [CrossRef] [PubMed]
Thiel, K.W, Hernandez, L.I, Dassie, J.P, Thiel, W.H, Liu, X, Stockdale, K.R, Rothman, A.M, Hernandez, F.J, McNamara, J.O.,; Giangrande, P.H. Delivery of chemo-sensitizing siRNAs to HER2+-breast cancer cells using RNA aptamers. Nucleic Acids Res. 2012, 40, 6319-6337. [CrossRef] [PubMed]
Gupta, S, Thirstrup, D, Jarvis, T.C, Schneider, D.J, Wilcox, S.K, Carter, J, Zhang, C, Gelinas, A, Weiss, A, Janjic, N, et al. Rapid histochemistry using slow off-rate modified aptamers with anionic competition. Appl. Immunohistochem. Mol. Morphol. 2011, 19, 273-278. [CrossRef] [PubMed]
Liu, Z, Duan, J.-H, Song, Y.-M, Ma, J, Wang, F.-D, Lu, X, Yang, X.-D. Novel HER2 aptamer selectively delivers cytotoxic drug to HER2-positive breast cancer cells in vitro. J. Transl. Med. 2012, 10, 148. [CrossRef] [PubMed]
Mahlknecht, G, Maron, R, Mancini, M, Schechter, B, Sela, M, Yarden, Y. Aptamer to ErbB-2/HER2 enhances degradation of the target and inhibits tumorigenic growth. Proc. Natl. Acad. Sci. USA 2013, 110, 8170-8175. [CrossRef] [PubMed]
Hu, Y, Duan, J, Cao, B, Zhang, L, Lu, X, Wang, F, Yao, F, Zhu, Z, Yuan, W, Wang, C, et al. Selection of a novel DNA thioaptamer against HER2 structure. Clin. Transl. Oncol. 2015, 17, 647-656. [CrossRef] [PubMed]
Ozer, A, Pagano, J.M, Lis, J.T. New technologies provide quantum changes in the scale, speed, and success of SELEX methods and aptamer characterization. Mol. Ther. Nucleic Acids 2014, 3. [CrossRef] [PubMed]
Bishop, J.S, Guy-Caffey, J.K, Ojwang, J.O, Smith, S.R, Hogan, M.E, Cossum, P.A, Rando, R.F, Chaudhary, N. Intramolecular G-quartet motifs confer nuclease resistance to a potent anti-HIV oligonucleotide. J. Biol. Chem. 1996, 271, 5698-5703. [CrossRef] [PubMed]
Casals, J, Viladoms, J, Pedroso, E, Gonzalez, C. Structure and stability of a dimeric G-quadruplex formed by cyclic oligonucleotides. J. Nucleic Acids 2010, 2010. [CrossRef] [PubMed]
Breaker, R.R. DNA aptamers and DNA enzymes. Curr. Opin. Chem. Biol. 1997, 1, 26-31. [CrossRef]
Tucker, W.O, Shum, K.T, Tanner, J.A. G-quadruplex DNA aptamers and their ligands: Structure, function and application. Curr. Pharm. Des. 2012, 18, 2014-2026. [CrossRef] [PubMed]
Kikin, O, D’Antonio, L, Bagga, P.S. QGRS mapper: A web-based server for predicting G-quadruplexes in nucleotide sequences. Nucleic Acids Res. 2006, 34, W676-W682. [CrossRef] [PubMed]
Cload, S.T, McCauley, T.G, Keefe, A.D, Healy, J.M.; Wilson, C. Properties of therapeutic aptamers. In The Aptamer Handbook; Wiley-VCH Verlag GmbH & Co. KGaA:Weinheim, Germany, 2006; pp. 363-416
Zuker, M. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res. 2003, 31, 3406-3415. [CrossRef] [PubMed]
The UnafoldWeb Server. Available online: http://mfold.rna.albany.edu/ (accessed on 25 June 2015)
DeFazio-Eli, L, Strommen, K, Dao-Pick, T, Parry, G, Goodman, L, Winslow, J. Quantitative assays for the measurement of HER1-HER2 heterodimerization and phosphorylation in cell lines and breast tumors: Applications for diagnostics and targeted drug mechanism of action. Breast Cancer Res. 2011, 13. [CrossRef] [PubMed]
Tolmachev, V. Imaging of HER2 overexpression in tumors for guiding therapy. Curr. Pharm. Des. 2008, 14, 2999-3019. [CrossRef] [PubMed]
Subik, K, Lee, J.F, Baxter, L, Strzepek, T, Costello, D, Crowley, P, Xing, L, Hung, M.C, Bonfiglio, T, Hicks, D.G, et al. The expression patterns of ER, PR, HER2, CK5/6, EGFR, Ki-67 and AR by immunohistochemical analysis in breast cancer cell lines. Breast Cancer 2010, 4, 35-41. [PubMed]
Savinainen, K.J, Saramaki, O.R, Linja, M.J, Bratt, O, Tammela, T.L, Isola, J.J, Visakorpi, T. Expression and gene copy number analysis of ErbB2 oncogene in prostate cancer. Am. J. Pathol. 2002, 160, 339-345. [CrossRef]
Hermanto, U, Zong, C.S.; Wang, L.H. ErbB2-overexpressing human mammary carcinoma cells display an increased requirement for the phosphatidylinositol 3-kinase signaling pathway in anchorage-independent growth. Oncogene 2001, 20, 7551-7562. [CrossRef] [PubMed]
Ginestier, C, Adelaide, J, Goncalves, A, Repellini, L, Sircoulomb, F, Letessier, A, Finetti, P, Geneix, J, Charafe-Jauffret, E, Bertucci, F, et al. ErbB2 phosphorylation and trastuzumab sensitivity of breast cancer cell lines. Oncogene 2007, 26, 7163-7169. [CrossRef] [PubMed]
Magnifico, A, Albano, L, Campaner, S, Delia, D, Castiglioni, F, Gasparini, P, Sozzi, G, Fontanella, E, Menard, S, Tagliabue, E. Tumor-initiating cells of HER2-positive carcinoma cell lines express the highest oncoprotein levels and are sensitive to trastuzumab. Clin. Cancer Res. 2009, 15, 2010-2021. [CrossRef] [PubMed]
Cuello, M, Ettenberg, S.A, Clark, A.S, Keane, M.M, Posner, R.H, Nau, M.M, Dennis, P.A, Lipkowitz, S. Down-regulation of the ErbB-2 receptor by trastuzumab (herceptin) enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast and ovarian cancer cell lines that overexpress ErbB-2. Cancer Res. 2001, 61, 4892-4900. [PubMed]
Govindarajan, S, Sivakumar, J, Garimidi, P, Rangaraj, N, Kumar, J, Rao, N, Gopal, V. Targeting human epidermal growth factor receptor 2 by a cell-penetrating peptide-affibody bioconjugate. Biomaterials 2011, 33, 2570-2582. [CrossRef] [PubMed]
Lewis, G, Figari, I, Fendly, B.; Wong, W, Carter, P, Gorman, C, Shepard, H. Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol. Immunother. 1993, 37, 255-263. [CrossRef] [PubMed]
Schnell, U, Dijk, F, Sjollema, K.A, Giepmans, B.N. Immunolabeling artifacts and the need for live-cell imaging. Nat. Methods 2012, 9, 152-158. [CrossRef] [PubMed]
Austin, C.D, de Maziere, A.M, Pisacane, P.I, van Dijk, S.M, Eigenbrot, C, Sliwkowski, M.X, Klumperman, J, Scheller, R.H. Endocytosis and sorting of ErbB2 and the site of action of cancer therapeutics trastuzumab and geldanamycin. Mol. Biol. Cell 2004, 15, 5268-5282. [CrossRef] [PubMed]
Rudnick, S.I, Lou, J, Shaller, C.C, Tang, Y, Klein-Szanto, A.J, Weiner, L.M, Marks, J.D, Adams, G.P. Influence of affinity and antigen internalization on the uptake and penetration of anti-HER2 antibodies in solid tumors. Cancer Res. 2011, 71, 2250-2259. [CrossRef] [PubMed]
De Goeij, B.E, Peipp, M, de Haij, S, van den Brink, E.N, Kellner, C, Riedl, T, de Jong, R, Vink, T, Strumane, K, Bleeker, W.K, et al. HER2 monoclonal antibodies that do not interfere with receptor heterodimerization-mediated signaling induce effective internalization and represent valuable components for rational antibody-drug conjugate design. MAbs 2014, 6, 392-402. [CrossRef] [PubMed]
Pruszynski, M, Koumarianou, E, Vaidyanathan, G, Revets, H, Devoogdt, N, Lahoutte, T, Lyerly, H.K, Zalutsky, M.R. Improved tumor targeting of anti-HER2 nanobody through N-succinimidyl 4-guanidinomethyl-3-iodobenzoate radiolabeling. J. Nucl. Med. 2014, 55, 650-656. [CrossRef] [PubMed]
Wallberg, H, Orlova, A. Slow internalization of anti-HER2 synthetic affibody monomer 111In-DOTA-ZHER2:342-pep2: Implications for development of labeled tracers. Cancer Biother. Radiopharm. 2008, 23, 435-442. [CrossRef] [PubMed]
Ahlgren, S, Orlova, A.; Wallberg, H, Hansson, M, Sandstrom, M, Lewsley, R.; Wennborg, A, Abrahmsen, L, Tolmachev, V, Feldwisch, J. Targeting of HER2-expressing tumors using 111In-ABY-025, a second-generation affibody molecule with a fundamentally reengineered scaffold. J. Nucl. Med. 2010, 51, 1131-1138. [CrossRef] [PubMed]
Xiao, Z, Levy-Nissenbaum, E, Alexis, F, Lupták, A, Teply, B.A, Chan, J.M, Shi, J, Digga, E, Cheng, J, Langer, R, et al. Engineering of targeted nanoparticles for cancer therapy using internalizing aptamers isolated by cell-uptake selection. ACS Nano 2012, 6, 696-704. [CrossRef] [PubMed]
Chen, C.H, Dellamaggiore, K.R, Ouellette, C.P, Sedano, C.D, Lizadjohry, M, Chernis, G.A, Gonzales, M, Baltasar, F.E, Fan, A.L, Myerowitz, R, et al. Aptamer-based endocytosis of a lysosomal enzyme. Proc. Natl. Acad. Sci. USA 2008, 105, 15908-15913. [CrossRef] [PubMed]
Porciani, D, Signore, G, Marchetti, L, Mereghetti, P, Nifosi, R, Beltram, F. Two interconvertible folds modulate the activity of a DNA aptamer against transferrin receptor. Mol. Ther. Nucleic Acids 2014, 3. [CrossRef] [PubMed]
Veldhoen, S, Laufer, S.D, Restle, T. Recent developments in peptide-based nucleic acid delivery. Int. J. Mol. Sci. 2008, 9, 1276-1320. [CrossRef] [PubMed]
Gourronc, F.A, Rockey, W.M, Thiel, W.H, Giangrande, P.H, Klingelhutz, A.J. Identification of RNA aptamers that internalize into HPV-16 E6/E7 transformed tonsillar epithelial cells. Virology 2013, 446, 325-333. [CrossRef] [PubMed]
Lodish, H, Berk, A, Kaiser, C.A, Krieger, M, Scott, M.P, Bretscher, A, Ploegh, H, Matsudaira, P. Molecular Cell Biology; W. H. Freeman: New York, NY, USA, 2000
Brockhoff, G, Heckel, B, Schmidt-Bruecken, E, Plander, M, Hofstaedter, F, Vollmann, A, Diermeier, S. Differential impact of Cetuximab, Pertuzumab and Trastuzumab on BT474 and SK-BR-3 breast cancer cell proliferation. Cell Prolif. 2007, 40, 488-507. [CrossRef] [PubMed]
Kim, S.Y, Kim, H.P, Kim, Y.J, Oh do, Y, Im, S.A, Lee, D, Jong, H.S, Kim, T.Y, Bang, Y.J. Trastuzumab inhibits the growth of human gastric cancer cell lines with HER2 amplification synergistically with cisplatin. Int. J. Oncol. 2008, 32, 89-95. [CrossRef] [PubMed]
Famulok, M, Hartig, J, Mayer, G. Functional aptamers and aptazymes in biotechnology, diagnostics, and therapy. Chem. Rev. 2007, 107, 3715-3743. [CrossRef] [PubMed]
Kaur, G, Roy, I. Therapeutic applications of aptamers. Expert Opin. Investig. Drugs 2008, 17, 43-60. [CrossRef] [PubMed]
QGRS Mapper. Available online: http://bioinformatics.ramapo.edu/QGRS/index.php (accessed on 25 June 2015)
Ohuchi, S. Cell-SELEX technology. BioRes. Open Access 2012, 1, 265-272. [CrossRef] [PubMed]
Zhang, Y, Chen, Y, Han, D, Ocsoy, I, Tan, W. Aptamers selected by cell-SELEX for application in cancer studies. Bioanalysis 2010, 2, 907-918. [CrossRef] [PubMed]
Sefah, K, Shangguan, D, Xiong, X, O’Donoghue, M.B, Tan, W. Development of DNA aptamers using cell-SELEX. Nat. Protoc. 2010, 5, 1169-1185. [CrossRef] [PubMed]
Ye, M, Hu, J, Peng, M, Liu, J, Liu, J, Liu, H, Zhao, X, Tan, W. Generating aptamers by cell-SELEX for applications in molecular medicine. Int. J. Mol. Sci. 2012, 13, 3341-3353. [CrossRef] [PubMed]
Thiel, W.H, Bair, T, Peek, A.S, Liu, X, Dassie, J, Stockdale, K.R, Behlke, M.A, Miller, F.J., Jr, Giangrande, P.H. Rapid identification of cell-specific, internalizing rna aptamers with bioinformatics analyses of a cell-based aptamer selection. PLoS ONE 2012, 7, e43836. [CrossRef] [PubMed]
Juweid, M, Neumann, R, Paik, C, Perez-Bacete, M.J, Sato, J, van Osdol, W, Weinstein, J.N. Micropharmacology of monoclonal antibodies in solid tumors: Direct experimental evidence for a binding site barrier. Cancer Res. 1992, 52, 5144-5153. [PubMed]
Fujimori, K, Covell, D.G, Fletcher, J.E, Weinstein, J.N. A modeling analysis of monoclonal antibody percolation through tumors: A binding-site barrier. J. Nucl. Med. 1990, 31, 1191-1198. [PubMed]
Van Osdol, W, Fujimori, K, Weinstein, J.N. An analysis of monoclonal antibody distribution in microscopic tumor nodules: Consequences of a “binding site barrier”. Cancer Res. 1991, 51, 4776-4784. [PubMed]
Adams, G.P, Schier, R, McCall, A.M, Simmons, H.H, Horak, E.M, Alpaugh, R.K, Marks, J.D, Weiner, L.M. High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules. Cancer Res. 2001, 61, 4750-4755. [PubMed]
Witsch, E, Sela, M, Yarden, Y. Roles for growth factors in cancer progression. Physiology 2010, 25, 85-101. [CrossRef] [PubMed]
Fink, M.Y, Chipuk, J.E. Survival of HER2-positive breast cancer cells: Receptor signaling to apoptotic control centers. Genes Cancer 2013, 4, 187-195. [CrossRef] [PubMed]
Iqbal, N, Iqbal, N. Human epidermal growth factor receptor 2 (HER2) in cancers: Overexpression and therapeutic implications. Mol. Biol. Int. 2014, 2014. [CrossRef] [PubMed]
Neve, R.M, Lane, H.A, Hynes, N.E. The role of overexpressed HER2 in transformation. Ann. Oncol. 2001, 12, S9-S13. [CrossRef] [PubMed]