CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer
<p>Triple-negative breast cancer (TNBC), which lacks estrogen receptor α (ERα), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression, is closely related to basal-like breast cancer. Previously, we and others report that cyclin E/cyclin-dependent kinase 2 (CDK2)...
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| مؤلفون آخرون: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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2019
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| _version_ | 1864513515098734592 |
|---|---|
| author | Lei Nie (556344) |
| author2 | Yongkun Wei (9694532) Fei Zhang (85787) Yi-Hsin Hsu (14917341) Li-Chuan Chan (14917344) Weiya Xia (454357) Baozhen Ke (18614872) Cihui Zhu (14894885) Rong Deng (137189) Jun Tang (32983) Jun Yao (9646) Yu-Yi Chu (636524) Xixi Zhao (4251673) Ye Han (261096) Junwei Hou (2793103) Longfei Huo (361824) How-Wen Ko (10852734) Wan-Chi Lin (313304) Hirohito Yamaguchi (14884460) Jung-Mao Hsu (14889527) Yi Yang (116183) Dean N. Pan (18208070) Jennifer L. Hsu (245027) Celina G. Kleer (14683138) Nancy E. Davidson (463811) Gabriel N. Hortobagyi (14888835) Mien-Chie Hung (102628) |
| author2_role | author author author author author author author author author author author author author author author author author author author author author author author author author author |
| author_facet | Lei Nie (556344) Yongkun Wei (9694532) Fei Zhang (85787) Yi-Hsin Hsu (14917341) Li-Chuan Chan (14917344) Weiya Xia (454357) Baozhen Ke (18614872) Cihui Zhu (14894885) Rong Deng (137189) Jun Tang (32983) Jun Yao (9646) Yu-Yi Chu (636524) Xixi Zhao (4251673) Ye Han (261096) Junwei Hou (2793103) Longfei Huo (361824) How-Wen Ko (10852734) Wan-Chi Lin (313304) Hirohito Yamaguchi (14884460) Jung-Mao Hsu (14889527) Yi Yang (116183) Dean N. Pan (18208070) Jennifer L. Hsu (245027) Celina G. Kleer (14683138) Nancy E. Davidson (463811) Gabriel N. Hortobagyi (14888835) Mien-Chie Hung (102628) |
| author_role | author |
| dc.creator.none.fl_str_mv | Lei Nie (556344) Yongkun Wei (9694532) Fei Zhang (85787) Yi-Hsin Hsu (14917341) Li-Chuan Chan (14917344) Weiya Xia (454357) Baozhen Ke (18614872) Cihui Zhu (14894885) Rong Deng (137189) Jun Tang (32983) Jun Yao (9646) Yu-Yi Chu (636524) Xixi Zhao (4251673) Ye Han (261096) Junwei Hou (2793103) Longfei Huo (361824) How-Wen Ko (10852734) Wan-Chi Lin (313304) Hirohito Yamaguchi (14884460) Jung-Mao Hsu (14889527) Yi Yang (116183) Dean N. Pan (18208070) Jennifer L. Hsu (245027) Celina G. Kleer (14683138) Nancy E. Davidson (463811) Gabriel N. Hortobagyi (14888835) Mien-Chie Hung (102628) |
| dc.date.none.fl_str_mv | 2019-11-08T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41467-019-13105-5 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/CDK2-mediated_site-specific_phosphorylation_of_EZH2_drives_and_maintains_triple-negative_breast_cancer/25903975 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis Triple-negative breast cancer (TNBC) Estrogen receptor α (ERα) Progesterone receptor Human epidermal growth factor receptor 2 (HER2) Basal-like breast cancer Cyclin E |
| dc.title.none.fl_str_mv | CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p>Triple-negative breast cancer (TNBC), which lacks estrogen receptor α (ERα), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression, is closely related to basal-like breast cancer. Previously, we and others report that cyclin E/cyclin-dependent kinase 2 (CDK2) phosphorylates enhancer of zeste homolog 2 (EZH2) at T416 (pT416-EZH2). Here, we show that transgenic expression of phospho-mimicking EZH2 mutant EZH2T416D in mammary glands leads to tumors with TNBC phenotype. Coexpression of EZH2T416D in mammary epithelia of HER2/Neu transgenic mice reprograms HER2-driven luminal tumors into basal-like tumors. Pharmacological inhibition of CDK2 or EZH2 allows re-expression of ERα and converts TNBC to luminal ERα-positive, rendering TNBC cells targetable by tamoxifen. Furthermore, the combination of either CDK2 or EZH2 inhibitor with tamoxifen effectively suppresses tumor growth and markedly improves the survival of the mice bearing TNBC tumors, suggesting that the mechanism-based combination therapy may be an alternative approach to treat TNBC.</p> <p>Author Correction: CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer. <a href="https://dx.doi.org/10.1038/s41467-020-14429-3" target="_blank">https://dx.doi.org/10.1038/s41467-020-14429-3</a>, published online 29 January 2020.</p> <h2>Other Information</h2> <p>Published in: Nature Communications<br> License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br> See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41467-019-13105-5" target="_blank">https://dx.doi.org/10.1038/s41467-019-13105-5</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_df04641a3760efba57bf26839c87fd52 |
| identifier_str_mv | 10.1038/s41467-019-13105-5 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25903975 |
| publishDate | 2019 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancerLei Nie (556344)Yongkun Wei (9694532)Fei Zhang (85787)Yi-Hsin Hsu (14917341)Li-Chuan Chan (14917344)Weiya Xia (454357)Baozhen Ke (18614872)Cihui Zhu (14894885)Rong Deng (137189)Jun Tang (32983)Jun Yao (9646)Yu-Yi Chu (636524)Xixi Zhao (4251673)Ye Han (261096)Junwei Hou (2793103)Longfei Huo (361824)How-Wen Ko (10852734)Wan-Chi Lin (313304)Hirohito Yamaguchi (14884460)Jung-Mao Hsu (14889527)Yi Yang (116183)Dean N. Pan (18208070)Jennifer L. Hsu (245027)Celina G. Kleer (14683138)Nancy E. Davidson (463811)Gabriel N. Hortobagyi (14888835)Mien-Chie Hung (102628)Biomedical and clinical sciencesClinical sciencesOncology and carcinogenesisTriple-negative breast cancer (TNBC)Estrogen receptor α (ERα)Progesterone receptorHuman epidermal growth factor receptor 2 (HER2)Basal-like breast cancerCyclin E<p>Triple-negative breast cancer (TNBC), which lacks estrogen receptor α (ERα), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression, is closely related to basal-like breast cancer. Previously, we and others report that cyclin E/cyclin-dependent kinase 2 (CDK2) phosphorylates enhancer of zeste homolog 2 (EZH2) at T416 (pT416-EZH2). Here, we show that transgenic expression of phospho-mimicking EZH2 mutant EZH2T416D in mammary glands leads to tumors with TNBC phenotype. Coexpression of EZH2T416D in mammary epithelia of HER2/Neu transgenic mice reprograms HER2-driven luminal tumors into basal-like tumors. Pharmacological inhibition of CDK2 or EZH2 allows re-expression of ERα and converts TNBC to luminal ERα-positive, rendering TNBC cells targetable by tamoxifen. Furthermore, the combination of either CDK2 or EZH2 inhibitor with tamoxifen effectively suppresses tumor growth and markedly improves the survival of the mice bearing TNBC tumors, suggesting that the mechanism-based combination therapy may be an alternative approach to treat TNBC.</p> <p>Author Correction: CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer. <a href="https://dx.doi.org/10.1038/s41467-020-14429-3" target="_blank">https://dx.doi.org/10.1038/s41467-020-14429-3</a>, published online 29 January 2020.</p> <h2>Other Information</h2> <p>Published in: Nature Communications<br> License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br> See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41467-019-13105-5" target="_blank">https://dx.doi.org/10.1038/s41467-019-13105-5</a></p>2019-11-08T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41467-019-13105-5https://figshare.com/articles/journal_contribution/CDK2-mediated_site-specific_phosphorylation_of_EZH2_drives_and_maintains_triple-negative_breast_cancer/25903975CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/259039752019-11-08T03:00:00Z |
| spellingShingle | CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer Lei Nie (556344) Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis Triple-negative breast cancer (TNBC) Estrogen receptor α (ERα) Progesterone receptor Human epidermal growth factor receptor 2 (HER2) Basal-like breast cancer Cyclin E |
| status_str | publishedVersion |
| title | CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer |
| title_full | CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer |
| title_fullStr | CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer |
| title_full_unstemmed | CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer |
| title_short | CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer |
| title_sort | CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer |
| topic | Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis Triple-negative breast cancer (TNBC) Estrogen receptor α (ERα) Progesterone receptor Human epidermal growth factor receptor 2 (HER2) Basal-like breast cancer Cyclin E |