Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2 + breast cancer patients
Open accessAbstract
Clinical benefits from trastuzumab and other anti-HER2 therapies in patients with HER2 amplified breast cancer remain limited by primary or acquired resistance. To identify potential mechanisms of resistance, we established trastuzumab-resistant HER2 amplified breast cancer cells by chronic exposure to trastuzumab treatment. Genomewide copy-number variation analyses of the resistant cells compared with parental cells revealed a focal amplification of genomic DNA containing the cyclin E gene. In a cohort of 34 HER2(+) patients treated with trastuzumab-based therapy, we found that cyclin E amplification/overexpression was associated with a worse clinical benefit (33.3% compared with 87.5%, P < 0.02) and a lower progression-free survival (6 mo vs. 14 mo, P < 0.002) compared with nonoverexpressing cyclin E tumors. To dissect the potential role of cyclin E in trastuzumab resistance, we studied the effects of cyclin E overexpression and cyclin E suppression. Cyclin E overexpression resulted in resistance to trastuzumab both in vitro and in vivo. Inhibition of cyclin E activity in cyclin E-amplified trastuzumab resistant clones, either by knockdown of cyclin E expression or treatment with cyclin-dependent kinase 2 (CDK2) inhibitors, led to a dramatic decrease in proliferation and enhanced apoptosis. In vivo, CDK2 inhibition significantly reduced tumor growth of trastuzumab-resistant xenografts. Our findings point to a causative role for cyclin E overexpression and the consequent increase in CDK2 activity in trastuzumab resistance and suggest that treatment with CDK2 inhibitors may be a valid strategy in patients with breast tumors with HER2 and cyclin E coamplification/overexpression.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In a cohort of patients with HER2+ breast cancers treated with trastuzumab, amplification of cyclin E was associated with a diminished clinical response.
“Further, in a cohort of patients with HER2+ breast cancers treated with trastuzumab, amplification of cyclin E was associated with a diminished clinical response.”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Scaltriti et al., 2011
Cell lines made resistant to trastuzumab by chronic exposure exhibited focal amplification of cyclin E.
“Cell lines made resistant to trastuzumab by chronic exposure exhibited focal amplification of cyclin E.”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Scaltriti et al., 2011
CDK2 inhibitors reduced growth of these trastuzumab-resistant xenografts.
“CDK2 inhibitors reduced growth of these trastuzumab-resistant xenografts (Scaltriti et al., 2011).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Scaltriti et al., 2011
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Slamon, D. J., Clark, G. M., Wong, S. G., Levin, W. J., Ullrich, A., & McGuire, W. L. (1987) · Science · doi:10.1126/science.3798106 · Cited by 11,760 · see citing works
Slamon, D. J., Leyland-Jones, B., Shak, S., Fuchs, H., Paton, V., Bajamonde, A., Fleming, T., Eiermann, W., Wolter, J., Pegram, M., et al. (2001) · New England Journal of Medicine · doi:10.1056/nejm200103153441101 · Cited by 11,500 · see citing works
Self-citationStudies of the HER-2/ neu Proto-Oncogene in Human Breast and Ovarian Cancer
Slamon, D. J., Godolphin, W. J., Jones, L. A., Holt, J. A., Wong, S., Keith, D. E., Levin, W. J., Stuart, S. G., Udove, J. A., Ullrich, A., et al. (1989) · Science · doi:10.1126/science.2470152 · Cited by 6,817 · see citing works
Trastuzumab-Induced Hepatotoxicity: A Case Report
Vucicevic, D., Carey, E. J., & Karlin, N. J. (2013) · Breast Care · doi:10.1159/000346844 · Cited by 4,432 · see citing works
The landscape of somatic copy-number alteration across human cancers
Beroukhim, R., Mermel, C. H., Porter, D., Wei, G., Raychaudhuri, S., Donovan, J., Barretina, J., Boehm, J. S., Dobson, J., Urashima, M., et al. (2010) · Nature · doi:10.1038/nature08822 · Cited by 4,017 · see citing works
Self-citationInhibitory Fc receptors modulate in vivo cytoxicity against tumor targets
Clynes, R. A., Towers, T. L., Presta, L. G., & Ravetch, J. V. (2000) · Nature Medicine · doi:10.1038/74704 · Cited by 2,768 · see citing works
G1 phase progression: Cycling on cue
Sherr, C. J. (1994) · Cell · doi:10.1016/0092-8674(94)90540-1 · Cited by 2,675 · see citing works
The ErbB signaling network: receptor heterodimerization in development and cancer
Olayioye, M. A., Neve, R. M., Lane, H. A., & Hynes, N. E. (2000) · The EMBO Journal · doi:10.1093/emboj/19.13.3159 · Cited by 2,438 · see citing works
EGF–ERBB signalling: towards the systems level
Citri, A., & Yarden, Y. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1962 · Cited by 2,004 · see citing works
Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints
Bartkova, J., Rezaei, N., Liontos, M., Karakaidos, P., Kletsas, D., Issaeva, N., Vassiliou, L.-V. F., Kolettas, E., Niforou, K., Zoumpourlis, V. C., et al. (2006) · Nature · doi:10.1038/nature05268 · Cited by 1,986 · see citing works
Nagata, Y., Lan, K.-H., Zhou, X., Tan, M., Esteva, F. J., Sahin, A. A., Klos, K. S., Li, P., Monia, B. P., Nguyen, N. T., et al. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.06.022 · Cited by 1,858 · see citing works
Berns, K., Horlings, H. M., Hennessy, B. T., Madiredjo, M., Hijmans, E. M., Beelen, K., Linn, S. C., Gonzalez-Angulo, A. M., Stemke-Hale, K., Hauptmann, M., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.08.030 · Cited by 1,627 · see citing works
Marty, M. E., Cognetti, F., Maraninchi, D., Snyder, R., Mauriac, L., Tubiana-Hulin, M., Chan, S. Y. T., Grimes, D., Antón, A., Lluch, A. M., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.04.173 · Cited by 1,588 · see citing works
Smith, I., Procter, M. J., Gelber, R. D., Guillaume, S., Feyereislova, A., Dowsett, M., Goldhirsch, A., Untch, M., Mariani, G., Baselga, J. M., et al. (2007) · The Lancet · doi:10.1016/s0140-6736(07)60028-2 · Cited by 1,503 · see citing works
Self-citationLamon, D. E. J. S., Eyland, B. R. L., Hak, S. T. S., Uchs, H. A. F., Aton, V. I. P., Ajamonde, A. L. B., LeMing, T., Iermann, W. O. E., Olter, J. A. W., Egram, M. A. P., et al. (2009) · Cited by 1,199 · see citing works
Novel anticancer targets: revisiting ERBB2 and discovering ERBB3
Baselga, J. M., & Swain, S. M. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2656 · Cited by 1,144 · see citing works
Self-citationHuman Cyclin E, a Nuclear Protein Essential for the G1-to-S Phase Transition
Ohtsubo, M., Theodoras, A. M., Schumacher, J. M., Roberts, J. M., & Pagano, M. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.5.2612 · Cited by 1,142 · see citing works
Cyclin E-CDK2 is a regulator of p27Kip1.Preprint
Sheaff, R. J., Groudine, M. T., Gordon, M., Roberts, J., & Clurman, B. E. (1997) · Genes & Development · doi:10.1101/gad.11.11.1464 · Cited by 910 · see citing works
Scaltriti, M., Rojo, F., Ocana, A., Anido, J., Guzman, M., Cortes, J., Di Cosimo, S., Matias-Guiu, X., Ramon y Cajal, S., Arribas, J., et al. (2007) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djk134 · Cited by 895 · see citing works
Self-citationJunttila, T. T., Akita, R. W., Parsons, K. L., Fields, C. T., Phillips, G. D. L., Friedman, L. S., Sampath, D., & Sliwkowski, M. X. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.03.020 · Cited by 829 · see citing works
Nahta, R., Yuan, L. X. H., Zhang, B., Kobayashi, R., & Esteva, F. J. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3841 · Cited by 793 · see citing works
Shin, I., Yakes, F. M., Rojo, F., Shin, N.-Y., Bakin, A. V., Baselga, J. M., & Arteaga, C. L. (2002) · Nature Medicine · doi:10.1038/nm759 · Cited by 790 · see citing works
Self-citationHess, K. R., Anderson, K., Symmans, W. F., Valero, V., Ibrahim, N. K., Mejia, J. A., Booser, D. J., Theriault, R. L., Buzdar, A. U., Dempsey, P. J., et al. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2006.05.6861 · Cited by 720 · see citing works
Cyclin E Ablation in the Mouse
Geng, Y., Yu, Q., Sicińska, E., Das, M., Schneider, J. E., Bhattacharya, S., Rideout, W. M., Bronson, R. T., Gardner, H., & Siciński, P. (2003) · Cell · doi:10.1016/s0092-8674(03)00645-7 · Cited by 663 · see citing works
Cyclin E and Survival in Patients with Breast Cancer
Keyomarsi, K., Tucker, S. L., Buchholz, T. A., Callister, M. D., Ding, Y., Hortobágyi, G. N., Bedrosian, I., Knickerbocker, C., Toyofuku, W. M., Lowe, M., et al. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa021153 · Cited by 562 · see citing works
Eichhorn, P. J. A., Gili, M., Scaltriti, M., Serra, V., Guzman, M., Nijkamp, W., Beijersbergen, R. L., Valero, V., Seoane, J., Bernards, R., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-1740 · Cited by 499 · see citing works
Self-citationMet receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells
Shattuck, D. L., Miller, J. K., Carraway, K. L., & Sweeney, C. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5962 · Cited by 473 · see citing works
Scaltriti, M., Verma, C. S., Guzmán, M., Jimenez, J., Parra, J.-L., Pedersen, K., Smith, D. J., Landolfi, S., y Cajal, S. R., Arribas, J., et al. (2008) · Oncogene · doi:10.1038/onc.2008.432 · Cited by 439 · see citing works
Self-citationPickl, M., & Ries, C. H. (2008) · Oncogene · doi:10.1038/onc.2008.394 · Cited by 403 · see citing works
Klapper, L. N., Waterman, H., Sela, M., & Yarden, Y. (2000) · PubMed · Cited by 351 · see citing works
Weigelt, B., Lo, A. T., Park, C. C., Gray, J. W., & Bissell, M. J. (2009) · Breast Cancer Research and Treatment · doi:10.1007/s10549-009-0502-2 · Cited by 336 · see citing works
Mittendorf, E. A., Wu, Y., Scaltriti, M., Meric-Bernstam, F., Hunt, K. K., Dawood, S., Esteva, F. J., Buzdar, A. U., Chen, H., Eksambi, S., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-1735 · Cited by 330 · see citing works
Self-citationP27kip1 Down-Regulation Is Associated with Trastuzumab Resistance in Breast Cancer Cells
Nahta, R., Takahashi, T., Ueno, N. T., Hung, M.-C., & Esteva, F. J. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-3900 · Cited by 298 · see citing works
Lane, H. A., Beuvink, I., Motoyama, A. B., Daly, J. M., Neve, R. M., & Hynes, N. E. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.9.3210-3223.2000 · Cited by 298 · see citing works
Huang, X., Gao, L., Wang, S., McManaman, J. L., Thor, A. D., Yang, X.-H., Esteva, F. J., & Liu, B. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3321 · Cited by 244 · see citing works
Butt, A. J., McNeil, C. M., Musgrove, E. A., & Sutherland, R. L. (2005) · Endocrine Related Cancer · doi:10.1677/erc.1.00993 · Cited by 244 · see citing works
Correction: IGF-IR/HER-2 Contributes to Trastuzumab Resistance
(2008) · Cancer Research · doi:10.1158/0008-5472.can-68-22-cor1 · Cited by 230 · see citing works
Cyclin E overexpression and amplification in human tumours
Schraml, P., Bucher, C., Bissig, H., et al. (2003) · The Journal of Pathology · doi:10.1002/path.1356 · Cited by 152 · see citing works
Le, X., Claret, F.-X., Lammayot, A., Tian, L., Deshpande, D. M., LaPushin, R., Tari, A. M., & Bast, R. C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300848200 · Cited by 151 · see citing works
Genomic Architecture Characterizes Tumor Progression Paths and Fate in Breast Cancer Patients
Russnes, H. G., Vollan, H. K. M., Lingjærde, O. C., Krasnitz, A., Lundin, P., Naume, B., Sørlie, T., Borgen, E., Rye, I. H., Langerød, A., et al. (2010) · Science Translational Medicine · doi:10.1126/scitranslmed.3000611 · Cited by 150 · see citing works
Farley, J. H., Smith, L. M., Darcy, K. M., Sobel, E. L., O’Connor, D., Henderson, B., Morrison, L. E., & Birrer, M. J. (2003) · PubMed · Cited by 118 · see citing works
Akli, S., Pelt, C. S. V., Bui, T. N., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0599 · Cited by 75 · see citing works
Porter, P. L., Barlow, W. E., Yeh, I., et al. (2006) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djj467 · Cited by 72 · see citing works
A novel interaction between HER2/neu and cyclin E in breast cancer
Mittendorf, E. A., Liu, Y., Tucker, S. L., McKenzie, T., Qiao, N., Akli, S., Biernacka, A., Liu, Y., Meijer, L., Keyomarsi, K., et al. (2010) · Oncogene · doi:10.1038/onc.2010.151 · Cited by 67 · see citing works
Wartenberg, M., Fischer, K., Hescheler, J., et al. (2002) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/s0167-4889(01)00185-9 · Cited by 35 · see citing works
Ohashi, Y., Kaneko, S. J., Cupples, T. E., et al. (2004) · Gynecologic Oncology · doi:10.1016/j.ygyno.2004.01.019 · Cited by 33 · see citing works
Le, X., Betrosian, I., Mao, W., et al. (2006) · Cell Cycle · doi:10.4161/cc.5.15.3007 · Cited by 26 · see citing works
Potemski, P., Kusińska, R., Watała, C. W., et al. (2006) · PubMed · Cited by 23 · see citing works
Cyclin E overexpression enhances cytokine-mediated apoptosis in MCF7 breast cancer cells
Dhillon, N. K., & Mudryj, M. M. (2003) · Genes and Immunity · doi:10.1038/sj.gene.6363973 · Cited by 14 · see citing works
Berglund, P., Stighall, M., Jirström, K., et al. (2007) · Journal of Clinical Pathology · doi:10.1136/jcp.2007.047688 · Cited by 12 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Genomic analyses identify molecular subtypes of pancreatic cancer
Bailey, P., Chang, D. K., Nones, K., Johns, A. L., Patch, A.-M., Gingras, M.-C., Miller, D. K., Christ, A. N., Bruxner, T. J. C., Quinn, M. C., et al. (2016) · Nature · doi:10.1038/nature16965 · Cited by 3,621 · see citing works
The history and future of targeting cyclin-dependent kinases in cancer therapy
Asghar, U., Witkiewicz, A. K., Turner, N. C., & Knudsen, E. S. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4504 · Cited by 1,767 · see citing works
Inflammation and aging: signaling pathways and intervention therapies
Li, X., Li, C., Zhang, W., Wang, Y., Qian, P., & Huang, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01502-8 · Cited by 1,443 · see citing works
ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics
Arteaga, C. L., & Engelman, J. A. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.02.025 · Cited by 1,048 · see citing works
Deng, N., Goh, L. K., Wang, H., Das, K., Tao, J., Tan, I. B., Zhang, S., Lee, M., Wu, J., Lim, K. H., et al. (2012) · Gut · doi:10.1136/gutjnl-2011-301839 · Cited by 645 · see citing works
Genome-Informed Targeted Therapy for Osteosarcoma
Sayles, L. C., Breese, M. R., Koehne, A. L., Leung, S. G., Lee, A. G., Liu, H.-Y., Spillinger, A., Shah, A. T., Tanasa, B., Straessler, K., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-1152 · Cited by 452 · see citing works
Inhibitors of cyclin-dependent kinases as cancer therapeutics.
Whittaker, S. R., Mallinger, A., Workman, P., & Clarke, P. A. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.02.008 · Cited by 384 · see citing works
Kambara, T., Amatya, V., Kushitani, K., Fujii, Y., Endo, I., & Takeshima, Y. (2022) · Oncology Letters · doi:10.3892/ol.2022.13294 · Cited by 9 · see citing works
Resistance Mechanisms to Cyclin-Dependent Kinase Inhibitors
Wiedemeyer, W. R. (2018) · Resistance to Targeted Anti-Cancer Therapeutics · doi:10.1007/978-3-319-67932-7_8 · Cited by 7 · see citing works
- Authors
- Scaltriti, M., Eichhorn, P. J., Cortés, J., Prudkin, L., Aura, C., Jiménez, J., Chandarlapaty, S., Serra, V., Prat, A., Ibrahim, Y. H., Guzmán, M., Gili, M., Rodríguez, O., Rodríguez, S., Pérez, J., Green, S. R., Mai, S., Rosen, N., Hudis, C., & Baselga, J.
- Affiliations
- Harvard University (US)
- Vanderbilt University (US)
- Vall d'Hebron Institute of Oncology (ES)
- Molecular Pathology, Vall d'Hebron Institute of Oncology, 08035 Barcelona, Spain;
- Memorial Sloan Kettering Cancer Center (US)
- Departments of aMedical Oncology and
- Cyclacel Pharmaceuticals (United Kingdom) (GB)
- Manitoba Institute of Cell Biology, Winnipeg, MB, Canada R3E 0V9; and
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-02-14
- Volume
- 108
- Issue
- 9
- Pages
- 3761-3766
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3048107
- OpenAlex
- W1966937303
- Cited by
- 337
- References
- 50
- Citations by year
- 2026: 16 · 2025: 13 · 2024: 17 · 2023: 16 · 2022: 26 · 2021: 22 · 2020: 20 · 2019: 18 · 2018: 20 · 2017: 24 · 2016: 29 · 2015: 22 · 2014: 24 · 2013: 28 · 2012: 27
- FWCI
- 14.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Breast Cancer Research Foundation
- National Institutes of Health (5k08ca134833-02)
- Instituto de Salud Carlos III
- National Cancer Institute (K08-CA134833, P30CA008748)
- FP7 Ideas: European Research Council (250244)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- cyclin E, trastuzumab resistance, HER2-positive breast cancer, HER2 amplification, CDK2 inhibitors, CDK2, gene amplification, copy number variation, progression-free survival, apoptosis, tumor cell proliferation, HER2-targeted therapy
- MeSH terms
- Trastuzumab, Antibodies, Monoclonal, Breast Neoplasms, Female, Gene Amplification, Humans, Models, Biological, Oncogene Proteins, Erb-b2 Receptor Tyrosine Kinases, Receptor, ErbB-2, Drug Resistance, Neoplasm, Cyclin E, Cell Line, Tumor, Protein Kinase Inhibitors, Cyclin-Dependent Kinase 2, Antibodies, Monoclonal, Humanized
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
