Epigenetic silencing of SALL2 confers tamoxifen resistance in breast cancer
Abstract Resistance to tamoxifen is a clinically major challenge in breast cancer treatment. Although downregulation of estrogen receptor‐alpha (ERα) is the dominant mechanism of tamoxifen resistance, the reason for ERα decrease during tamoxifen therapy remains elusive. Herein, we reported that Spal...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2019-10-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201910638 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849343077773213696 |
|---|---|
| author | Liping Ye Chuyong Lin Xi Wang Qiji Li Yue Li Meng Wang Zekun Zhao Xianqiu Wu Dongni Shi Yunyun Xiao Liangliang Ren Yunting Jian Meisongzhu Yang Ruizhang Ou Guangzheng Deng Ying Ouyang Xiangfu Chen Jun Li Libing Song |
| author_facet | Liping Ye Chuyong Lin Xi Wang Qiji Li Yue Li Meng Wang Zekun Zhao Xianqiu Wu Dongni Shi Yunyun Xiao Liangliang Ren Yunting Jian Meisongzhu Yang Ruizhang Ou Guangzheng Deng Ying Ouyang Xiangfu Chen Jun Li Libing Song |
| author_sort | Liping Ye |
| collection | DOAJ |
| description | Abstract Resistance to tamoxifen is a clinically major challenge in breast cancer treatment. Although downregulation of estrogen receptor‐alpha (ERα) is the dominant mechanism of tamoxifen resistance, the reason for ERα decrease during tamoxifen therapy remains elusive. Herein, we reported that Spalt‐like transcription factor 2 (SALL2) expression was significantly reduced during tamoxifen therapy through transcription profiling analysis of 9 paired primary pre‐tamoxifen‐treated and relapsed tamoxifen‐resistant breast cancer tissues. SALL2 transcriptionally upregulated ESR1 and PTEN through directly binding to the DNA promoters. By contrast, silencing SALL2 induced downregulation of ERα and PTEN and activated the Akt/mTOR signaling, resulting in estrogen‐independent growth and tamoxifen resistance in ERα‐positive breast cancer. Furthermore, hypermethylation of SALL2 promoter was found in tamoxifen‐resistant breast cancer. Importantly, in vivo experiments showed that DNA methyltransferase inhibitor‐mediated SALL2 restoration resensitized tamoxifen‐resistant breast cancer to tamoxifen therapy. These findings shed light on the mechanism of SALL2 in regulation of ER and represent a potential clinical signature that can be used to categorize breast cancer patients who may benefit from co‐therapy with tamoxifen and DNMT inhibitor. |
| format | Article |
| id | doaj-art-9d1e2d7aba0149b99b9ad9389ece5549 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2019-10-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-9d1e2d7aba0149b99b9ad9389ece55492025-08-20T03:43:10ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-10-01111211910.15252/emmm.201910638Epigenetic silencing of SALL2 confers tamoxifen resistance in breast cancerLiping Ye0Chuyong Lin1Xi Wang2Qiji Li3Yue Li4Meng Wang5Zekun Zhao6Xianqiu Wu7Dongni Shi8Yunyun Xiao9Liangliang Ren10Yunting Jian11Meisongzhu Yang12Ruizhang Ou13Guangzheng Deng14Ying Ouyang15Xiangfu Chen16Jun Li17Libing Song18State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‐sen University Cancer CenterDepartment of Orthopaedic Surgery, The Seventh Affiliated Hospital, Sun Yat‐sen UniversityState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‐sen University Cancer CenterDivision of Biosciences, University College LondonClinical Experimental Center, Department of Pathology (Clinical Biobanks), Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat‐sen UniversityState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‐sen University Cancer CenterDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat‐sen UniversityState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‐sen University Cancer CenterDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat‐sen UniversityDepartment of Pathology, School of Basic Medical Science, Southern Medical UniversityState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‐sen University Cancer CenterDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat‐sen UniversityState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‐sen University Cancer CenterAbstract Resistance to tamoxifen is a clinically major challenge in breast cancer treatment. Although downregulation of estrogen receptor‐alpha (ERα) is the dominant mechanism of tamoxifen resistance, the reason for ERα decrease during tamoxifen therapy remains elusive. Herein, we reported that Spalt‐like transcription factor 2 (SALL2) expression was significantly reduced during tamoxifen therapy through transcription profiling analysis of 9 paired primary pre‐tamoxifen‐treated and relapsed tamoxifen‐resistant breast cancer tissues. SALL2 transcriptionally upregulated ESR1 and PTEN through directly binding to the DNA promoters. By contrast, silencing SALL2 induced downregulation of ERα and PTEN and activated the Akt/mTOR signaling, resulting in estrogen‐independent growth and tamoxifen resistance in ERα‐positive breast cancer. Furthermore, hypermethylation of SALL2 promoter was found in tamoxifen‐resistant breast cancer. Importantly, in vivo experiments showed that DNA methyltransferase inhibitor‐mediated SALL2 restoration resensitized tamoxifen‐resistant breast cancer to tamoxifen therapy. These findings shed light on the mechanism of SALL2 in regulation of ER and represent a potential clinical signature that can be used to categorize breast cancer patients who may benefit from co‐therapy with tamoxifen and DNMT inhibitor.https://doi.org/10.15252/emmm.201910638breast cancerESR1methylationSALL2tamoxifen resistance |
| spellingShingle | Liping Ye Chuyong Lin Xi Wang Qiji Li Yue Li Meng Wang Zekun Zhao Xianqiu Wu Dongni Shi Yunyun Xiao Liangliang Ren Yunting Jian Meisongzhu Yang Ruizhang Ou Guangzheng Deng Ying Ouyang Xiangfu Chen Jun Li Libing Song Epigenetic silencing of SALL2 confers tamoxifen resistance in breast cancer EMBO Molecular Medicine breast cancer ESR1 methylation SALL2 tamoxifen resistance |
| title | Epigenetic silencing of SALL2 confers tamoxifen resistance in breast cancer |
| title_full | Epigenetic silencing of SALL2 confers tamoxifen resistance in breast cancer |
| title_fullStr | Epigenetic silencing of SALL2 confers tamoxifen resistance in breast cancer |
| title_full_unstemmed | Epigenetic silencing of SALL2 confers tamoxifen resistance in breast cancer |
| title_short | Epigenetic silencing of SALL2 confers tamoxifen resistance in breast cancer |
| title_sort | epigenetic silencing of sall2 confers tamoxifen resistance in breast cancer |
| topic | breast cancer ESR1 methylation SALL2 tamoxifen resistance |
| url | https://doi.org/10.15252/emmm.201910638 |
| work_keys_str_mv | AT lipingye epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer AT chuyonglin epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer AT xiwang epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer AT qijili epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer AT yueli epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer AT mengwang epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer AT zekunzhao epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer AT xianqiuwu epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer AT dongnishi epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer AT yunyunxiao epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer AT liangliangren epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer AT yuntingjian epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer AT meisongzhuyang epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer AT ruizhangou epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer AT guangzhengdeng epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer AT yingouyang epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer AT xiangfuchen epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer AT junli epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer AT libingsong epigeneticsilencingofsall2conferstamoxifenresistanceinbreastcancer |