ERRα activates SHMT2 transcription to enhance the resistance of breast cancer to lapatinib via modulating the mitochondrial metabolic adaption
Open accessAbstract
Lapatinib, a tyrosine kinase inhibitor, can initially benefit the patients with breast tumors but fails in later treatment due to the inevitable development of drug resistance. Estrogen-related receptor α (ERRα) modulates the metabolic adaptations in lapatinib-resistant cancer cells; however, the underlying mechanism remains unclear. ERRα was predicted to bind to the serine hydroxymethyltransferase 2 (SHMT2) transcription initiation site in the ER- and HER2-positive cell line BT-474; thus, we hypothesize that ERRα might modulate the resistance of breast cancer to lapatinib via regulating SHMT2. In the present study, we revealed that 2.5 and 5 µM lapatinib treatment could significantly decrease the expression and protein levels of ERRα and SHMT2; ERRα and SHMT2 expression and protein levels were significantly up-regulated in breast cancer cells, in particularly in breast cancer cells with resistance to lapatinib. ERRα knockdown restored the inhibitory effects of lapatinib on the BT-474R cell viability and migration; in the meantime, ERRα knockdown rescued the production of reactive oxygen species (ROS) whereas decreased the ratio of glutathione (GSH)/oxidized glutathione (GSSG) upon lapatinib treatment. Via targeting SHMT2 promoter region, ERRα activated the transcription of SHMT2. The effects of ERRα knockdown on BT-474R cells under lapatinib treatment could be significantly reversed by SHMT2 overexpression. In conclusion, ERRα knockdown suppresses the detoxification and the mitochondrial metabolic adaption in breast cancer resistant to lapatinib; ERRα activates SHMT2 transcription via targeting its promoter region, therefore enhancing breast cancer resistance to lapatinib.
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SHMT2 promotes chemosensitivity or resistance in a context-specific manner.
“SHMT2 seems to promote chemosensitivity or resistance in a context-specific manner.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [122]
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1 retracted
Lin, C., Zhang, Y., Chen, Y., Bai, Y., & Zhang, Y. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1352-4 · Cited by 70 · see citing works
RetractedSiegel, R. L., Miller, K. D., & Jemal, A. (2016) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21332 · Cited by 16,003 · see citing works
Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer
Geyer, C. E., Forster, J. K., Lindquist, D. L., Chan, S. Y. T., Romieu, C. G., Pieńkowski, T., Jagiełło-Gruszfeld, A., Crown, J. P., Chan, A., Kaufman, B., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa064320 · Cited by 3,426 · 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
The ERBB network: at last, cancer therapy meets systems biology
Yarden, Y., & Pines, G. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3309 · Cited by 998 · see citing works
Identification of a new class of steroid hormone receptors
Giguère, V., Yang, N., Segui, P., & Evans, R. M. (1988) · Nature · doi:10.1038/331091a0 · Cited by 867 · see citing works
Transcriptional Control of Energy Homeostasis by the Estrogen-Related Receptors
Giguère, V. (2008) · Endocrine Reviews · doi:10.1210/er.2008-0017 · Cited by 584 · see citing works
Cowey, S. L., & Hardy, R. W. (2006) · American Journal Of Pathology · doi:10.2353/ajpath.2006.051090 · Cited by 429 · see citing works
Zhou, M., Liu, Z., Zhao, Y., Ding, Y., Liu, H., Xi, Y., Xiong, W., Li, G., Lu, J., Fodstad, Ø., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.083337 · Cited by 424 · see citing works
Xia, W., Bacus, S., Hegde, P., Husain, I., Strum, J., Liu, L., Paulazzo, G., Lyass, L., Trusk, P., Hill, J., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602468103 · Cited by 374 · see citing works
The metabolic syndrome and risk of incident colorectal cancer
Ahmed, R. L., Schmitz, K. H., Anderson, K. E., Rosamond, W. D., & Folsom, A. R. (2006) · Cancer · doi:10.1002/cncr.21950 · Cited by 326 · see citing works
Mitochondrial translation requires folate-dependent tRNA methylation
Morscher, R. J., Ducker, G. S., Li, H., Mayer, J., Gitai, Z., Sperl, W., & Rabinowitz, J. D. (2018) · Nature · doi:10.1038/nature25460 · Cited by 278 · see citing works
Ariazi, E. A., Clark, G. M., & Mertz, J. E. (2002) · PubMed · Cited by 276 · see citing works
Ducker, G. S., Ghergurovich, J. M., Mainolfi, N., Suri, V., Jeong, S. K., Hsin-Jung Li, S., Friedman, A., Manfredi, M. G., Gitai, Z., Kim, H., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1706617114 · Cited by 261 · see citing works
An updated report on the trends in cancer incidence and mortality in Japan, 1958–2013
Katanoda, K., Hori, M., Matsuda, T., Shibata, A., Nishino, Y., Hattori, M., Soda, M., Ioka, A., Sobue, T., & Nishimoto, H. (2015) · Japanese Journal of Clinical Oncology · doi:10.1093/jjco/hyv002 · Cited by 250 · see citing works
SHMT2 Desuccinylation by SIRT5 Drives Cancer Cell Proliferation
Yang, X. P., Wang, Z., Li, X., Liu, B., Liu, M., Liu, L., Chen, S., Ren, M., Wang, Y., Yu, M., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-1912 · Cited by 231 · see citing works
Self-citationOestrogen-related receptors in breast cancer: control of cellular metabolism and beyond
Deblois, G., & Giguère, V. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3396 · Cited by 226 · see citing works
Estrogen-Related Receptor α in Human Breast Carcinoma as a Potent Prognostic Factor
Suzuki, T., Miki, Y., Moriya, T., Shimada, N., Ishida, T., Hirakawa, H., Ohuchi, N., & Sasano, H. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0250 · Cited by 219 · see citing works
European cancer mortality predictions for the year 2016 with focus on leukaemias
Malvezzi, M., Carioli, G., Bertuccio, P., Rosso, T., Boffetta, P., Levi, F., Vecchia, C. L., & Negri, E. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw022 · Cited by 206 · see citing works
Comparative Oncogenomics Identifies PSMB4 and SHMT2 as Potential Cancer Driver Genes
Lee, G. Y., Haverty, P. M., Li, L., Kljavin, N. M., Bourgon, R., Lee, J., Stern, H. M., Modrusan, Z. D., Seshagiri, S., Zhang, Z., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-2683 · Cited by 162 · see citing works
Immunohistochemical Surrogates for Molecular Classification of Breast Carcinoma: A 2015 Update
Tang, P. T. P., & Tse, G. M.-K. (2016) · Archives of Pathology & Laboratory Medicine · doi:10.5858/arpa.2015-0133-ra · Cited by 155 · see citing works
ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer
Deblois, G., Smith, H. W., Tam, I. S., Gravel, S., Caron, M., Savage, P., Labbé, D. P., Bégin, L. R., Tremblay, M. L., Park, M., et al. (2016) · Nature Communications · doi:10.1038/ncomms12156 · Cited by 120 · see citing works
Komurov, K., Tseng, J., Muller, M., Seviour, E. G., Moss, T. J., Yang, L., Nagrath, D., & Ram, P. T. (2012) · Molecular Systems Biology · doi:10.1038/msb.2012.25 · Cited by 117 · see citing works
Proteomic profiling of breast cancer metabolism identifies SHMT2 and ASCT2 as prognostic factors
Bernhardt, S., Bayerlová, M., Vetter, M., Wachter, A., Mitra, D., Hanf, V., Lantzsch, T., Uleer, C., Peschel, S., John, J., et al. (2017) · Breast Cancer Research · doi:10.1186/s13058-017-0905-7 · Cited by 101 · see citing works
Ariazi, E. A., Kraus, R. J., Farrell, M. L., Jordan, V. C., & Mertz, J. E. (2007) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-06-0227 · Cited by 100 · see citing works
Kim, S. K., Jung, W. H., & Koo, J. S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0101004 · Cited by 98 · see citing works
Barry, J. B., & Giguère, V. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-0922 · Cited by 88 · see citing works
Hong, E., Levasseur, M.-P., Dufour, C. R., Perry, M.-C., & Giguère, V. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1315319110 · Cited by 70 · see citing works
Michelsen, T. M., Pripp, A. H., Tonstad, S., Trope, C. G., & Dørum, A. (2008) · European Journal of Cancer · doi:10.1016/j.ejca.2008.09.028 · Cited by 62 · see citing works
Zhang, L., Chen, Z., Xue, D., Zhang, Q., Liu, X., Luh, F., Hong, L., Zhang, H., Pan, F., Liu, Y., et al. (2016) · Oncology Reports · doi:10.3892/or.2016.5112 · Cited by 46 · see citing works
Lee, D. G., Kam, M. K., Kim, K., Kim, H. S., Kwon, O., Lee, H., & Lee, D.-S. (2018) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2018.06.005 · Cited by 45 · see citing works
Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer
Takeda, T., Yamamoto, H., Kanzaki, H., Suzawa, K., Yoshioka, T., Tomida, S., Cui, X., Murali, R., Namba, K., Sato, H., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0171356 · Cited by 41 · see citing works
Luo, Z., Yi, Z., Ou, Z., Han, T., Wan, T. Y., Tang, Y., Wang, Z., & Huang, F. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27039 · Cited by 41 · see citing works
Puła, B., Olbromski, M., Wojnar, A., Gomułkiewicz, A., Witkiewicz, W., Ugorski, M., Dzięgiel, P., & Podhorska‐Okołów, M. (2013) · Cellular Oncology · doi:10.1007/s13402-013-0151-7 · Cited by 40 · see citing works
Wang, B., Wang, W., Zhu, Z., Zhang, X., Tang, F., Wang, D., Liu, X., Xiao-ling, Y. A. N., & Zhuang, H. (2017) · Clinical Neurology and Neurosurgery · doi:10.1016/j.clineuro.2017.01.005 · Cited by 40 · see citing works
Çetin, B., Beneklı, M., Türker, İ., Koral, L., Ulaş, A., Dane, F., Öksüzoğlu, B. Ç., Ma, K., Koca, D., Boruban, C. M., et al. (2013) · Journal of Chemotherapy · doi:10.1179/1973947813y.0000000147 · Cited by 33 · see citing works
Yin, K. (2015) · OncoTargets and Therapy · doi:10.2147/ott.s82433 · Cited by 29 · see citing works
Asghari, F., Haghnavaz, N., Shanehbandi, D., Khaze, V., Baradaran, B., & Kazemi, T. (2018) · Advances in Clinical and Experimental Medicine · doi:10.17219/acem/70745 · Cited by 19 · see citing works
Flagged first, then by citations
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Sui, S., Xu, S., & Pang, D. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107992 · Cited by 114 · see citing works
Roles of Mitochondrial Serine Hydroxymethyltransferase 2 (SHMT2) in Human Carcinogenesis
Zeng, Y., Zhang, J., Xu, M., Chen, F., Zi, R., Yue, J., Zhang, Y., Chen, N., & Chin, Y. E. (2021) · Journal of Cancer · doi:10.7150/jca.60170 · Cited by 62 · see citing works
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Cuthbertson, C. R., Arabzada, Z., Bankhead, A., Kyani, A., & Neamati, N. (2021) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.0c00223 · Cited by 57 · see citing works
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Tang, J., Liu, T., Wen, X., Zhou, Z., Yan, J., Gao, J.-P., & Zuo, J. (2021) · Molecular Medicine · doi:10.1186/s10020-021-00270-x · Cited by 50 · see citing works
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Zhang, P., & Yang, Q. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.682856 · Cited by 41 · see citing works
Ge, A., He, Q., Da, Z., Li, Y., Chen, J., Deng, Y., Xiang, W., Fan, H., Wu, S., Li, Y., et al. (2023) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.18044 · Cited by 38 · see citing works
Serine hydroxymethyltransferase 2: a novel target for human cancer therapy
Xie, M., & Pei, D. (2021) · Investigational New Drugs · doi:10.1007/s10637-021-01144-z · Cited by 30 · see citing works
The role of serine metabolism in lung cancer: From oncogenesis to tumor treatment
Zhou, X., Tian, C., Cao, Y., Zhao, M., & Wang, K. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2022.1084609 · Cited by 30 · see citing works
Lin, W. Y., Wang, X., Diao, M., Wang, Y., Zhao, R., Chen, J., Liao, Y., Long, Q., & Meng, Y. (2024) · Cancer Cell International · doi:10.1186/s12935-024-03418-x · Cited by 26 · see citing works
Su, P., Yu, L., Mao, X., & Sun, P. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.881252 · Cited by 24 · see citing works
Huang, H., Li, J., Shen, J., Lin, L., Wu, X., Xiang, S., Li, Y., Xu, Y., Zhao, Q., Zhao, Y., et al. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01474 · Cited by 20 · see citing works
Self-citationLi, C., Tao, Y., Chen, Y., Wu, Y., He, Y., Yin, S., Xu, S., & Yu, Y. (2022) · PubMed Central · Cited by 16 · see citing works
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Kamada, S., Takeiwa, T., Ikeda, K., Horie, K., & Inoue, S. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.717881 · Cited by 15 · see citing works
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Hussein, S., Khanna, P., Yunus, N., & Gatza, M. L. (2021) · Cancers · doi:10.3390/cancers13194808 · Cited by 15 · see citing works
Liu, S., Liang, H., Yang, Z., Cai, C., Wu, Z.-Y., Wu, X., Dong, P., Li, M., Zheng, L., & Gong, W. (2022) · International Journal of Medical Sciences · doi:10.7150/ijms.68404 · Cited by 14 · see citing works
Spinelli, S., Bruschi, M., Passalacqua, M., Guida, L., Magnone, M., Sturla, L., & Zocchi, E. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25094796 · Cited by 13 · see citing works
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Shan, Y., Liu, D., Li, Y., Wu, C. L., & Ye, Y. (2024) · PeerJ · doi:10.7717/peerj.16594 · Cited by 7 · see citing works
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Fu, R., Sun, F., Wang, W., Wang, R., Zhang, H., He, X., Liu, A., & Yang, L. (2025) · Cellular Signalling · doi:10.1016/j.cellsig.2025.111977 · Cited by 7 · see citing works
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Frańczak, M., Toenshoff, I., Jansen, G., Smolenski, R. T., Giovannetti, E., & Peters, G. J. (2022) · Current Medicinal Chemistry · doi:10.2174/0929867329666220401110418 · Cited by 4 · see citing works
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Guo, S., & Addison, C. (2026) · Current Oncology · doi:10.3390/curroncol33020129 · Cited by 4 · see citing works
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Zhang, H., Du, Y., Zheng, Y., Lv, H., Yan, Z., Dong, N., Zhu, Y., & Shen, J. (2023) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026623666230515145822 · Cited by 3 · see citing works
Belisario, D. C., Sapino, A., Roato, I., Bosìa, A., Doublier, S., & Marchiò, S. (2025) · Cancers · doi:10.3390/cancers17142382 · Cited by 2 · see citing works
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Liu, J., Feng, J., Xuan, J., Huang, L., Xiao, B., Zhu, Y., Kuang, Z., Zhang, W., Song, L., Zhou, Y., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-2398014/v1
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- Authors
- Li, X., Zhang, K., Hu, Y., & Luo, N.
- Affiliations
- Central South University (CN)
- Corresponding author
- Luo, Na
- Venue
- Bioscience Reports
- Publisher
- Portland Press Ltd.
- Published
- 2020-01
- Volume
- 40
- Issue
- 1
- ISSN
- 0144-8463 (ISSN-L)
- 1573-4935
- PMC
- PMC6970080
- OpenAlex
- W2997654221
- Cited by
- 29
- References
- 38
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 4 · 2022: 6 · 2021: 7 · 2020: 1
- FWCI
- 1.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Bioscience Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- estrogen-related receptor alpha, SHMT2, lapatinib resistance, breast cancer, reactive oxygen species, glutathione, transcriptional regulation, HER2-positive breast cancer, BT474 cells, tyrosine kinase inhibitor resistance
- MeSH terms
- Lapatinib, ERRalpha Estrogen-Related Receptor, Antineoplastic Agents, Binding Sites, Breast Neoplasms, Energy Metabolism, Female, Humans, Mitochondria, Promoter Regions, Genetic, Receptors, Estrogen, Glycine Hydroxymethyltransferase, Signal Transduction, Gene Expression Regulation, Neoplastic, Reactive Oxygen Species, Drug Resistance, Neoplasm, Cell Line, Tumor, Protein Kinase Inhibitors
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