Lnc-DC promotes estrogen independent growth and tamoxifen resistance in breast cancer
Abstract Selective estrogen receptor modulators (SERMs) such as tamoxifen have proven to be effective in the treatment of estrogen receptor (ER) positive breast cancer. However, a major obstacle for such endocrine therapy is estrogen independent growth, leading to resistance, and the underlying mech...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-10-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-04288-1 |
| _version_ | 1818690478940356608 |
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| author | Wan-Xin Peng Pratirodh Koirala Huaixiang Zhou Jiahong Jiang Ziqiang Zhang Liu Yang Yin-Yuan Mo |
| author_facet | Wan-Xin Peng Pratirodh Koirala Huaixiang Zhou Jiahong Jiang Ziqiang Zhang Liu Yang Yin-Yuan Mo |
| author_sort | Wan-Xin Peng |
| collection | DOAJ |
| description | Abstract Selective estrogen receptor modulators (SERMs) such as tamoxifen have proven to be effective in the treatment of estrogen receptor (ER) positive breast cancer. However, a major obstacle for such endocrine therapy is estrogen independent growth, leading to resistance, and the underlying mechanism is not fully understood. The purpose of this study was to determine whether long non-coding RNAs (lncRNAs) are involved in regulation of estrogen independent growth and tamoxifen resistance in ER positive breast cancer. Using a CRISPR/Cas9-based SAM (synergistic activation mediator) library against a focus group of lncRNAs, we identify Lnc-DC as a candidate lncRNA. Further analysis suggests that Lnc-DC is able to reduce tamoxifen-induced apoptosis by upregulation of anti-apoptotic genes such as Bcl2 and Bcl-xL. Furthermore, Lnc-DC activates STAT3 by phosphorylation (pSTAT3Y705), and the activated STAT3 subsequently induces expression of cytokines which in turn activate STAT3, forming an autocrine loop. Clinically, upregulation of Lnc-DC is associated with poor prognosis. In particular, analysis of a tamoxifen-treated patient cohort indicates that Lnc-DC expression can predict the response to tamoxifen. Together, this study demonstrates a previously uncharacterized function of Lnc-DC/STAT3/cytokine axis in estrogen independent growth and tamoxifen resistance, and Lnc-DC may serve as a potential predictor for tamoxifen response. |
| first_indexed | 2024-12-17T12:26:39Z |
| format | Article |
| id | doaj.art-92ea29efb17a48399b9e5fa8f6e03dea |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-17T12:26:39Z |
| publishDate | 2021-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-92ea29efb17a48399b9e5fa8f6e03dea2022-12-21T21:48:44ZengNature Publishing GroupCell Death and Disease2041-48892021-10-01121111010.1038/s41419-021-04288-1Lnc-DC promotes estrogen independent growth and tamoxifen resistance in breast cancerWan-Xin Peng0Pratirodh Koirala1Huaixiang Zhou2Jiahong Jiang3Ziqiang Zhang4Liu Yang5Yin-Yuan Mo6Center of Oncology, Department of Medical Oncology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical CollegeCancer Institute, University of Mississippi Medical CenterCenter of Oncology, Department of Medical Oncology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical CollegeCenter of Oncology, Department of Medical Oncology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical CollegeDepartment of Pulmonary Medicine, Tongji Hospital, Tongji UniversityCenter of Oncology, Department of Medical Oncology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical CollegeCancer Institute, University of Mississippi Medical CenterAbstract Selective estrogen receptor modulators (SERMs) such as tamoxifen have proven to be effective in the treatment of estrogen receptor (ER) positive breast cancer. However, a major obstacle for such endocrine therapy is estrogen independent growth, leading to resistance, and the underlying mechanism is not fully understood. The purpose of this study was to determine whether long non-coding RNAs (lncRNAs) are involved in regulation of estrogen independent growth and tamoxifen resistance in ER positive breast cancer. Using a CRISPR/Cas9-based SAM (synergistic activation mediator) library against a focus group of lncRNAs, we identify Lnc-DC as a candidate lncRNA. Further analysis suggests that Lnc-DC is able to reduce tamoxifen-induced apoptosis by upregulation of anti-apoptotic genes such as Bcl2 and Bcl-xL. Furthermore, Lnc-DC activates STAT3 by phosphorylation (pSTAT3Y705), and the activated STAT3 subsequently induces expression of cytokines which in turn activate STAT3, forming an autocrine loop. Clinically, upregulation of Lnc-DC is associated with poor prognosis. In particular, analysis of a tamoxifen-treated patient cohort indicates that Lnc-DC expression can predict the response to tamoxifen. Together, this study demonstrates a previously uncharacterized function of Lnc-DC/STAT3/cytokine axis in estrogen independent growth and tamoxifen resistance, and Lnc-DC may serve as a potential predictor for tamoxifen response.https://doi.org/10.1038/s41419-021-04288-1 |
| spellingShingle | Wan-Xin Peng Pratirodh Koirala Huaixiang Zhou Jiahong Jiang Ziqiang Zhang Liu Yang Yin-Yuan Mo Lnc-DC promotes estrogen independent growth and tamoxifen resistance in breast cancer Cell Death and Disease |
| title | Lnc-DC promotes estrogen independent growth and tamoxifen resistance in breast cancer |
| title_full | Lnc-DC promotes estrogen independent growth and tamoxifen resistance in breast cancer |
| title_fullStr | Lnc-DC promotes estrogen independent growth and tamoxifen resistance in breast cancer |
| title_full_unstemmed | Lnc-DC promotes estrogen independent growth and tamoxifen resistance in breast cancer |
| title_short | Lnc-DC promotes estrogen independent growth and tamoxifen resistance in breast cancer |
| title_sort | lnc dc promotes estrogen independent growth and tamoxifen resistance in breast cancer |
| url | https://doi.org/10.1038/s41419-021-04288-1 |
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