AFF3 upregulation mediates tamoxifen resistance in breast cancers
Abstract Background Although tamoxifen is a highly effective drug for treating estrogen receptor–positive (ER+) breast cancer, nearly all patients with metastasis with initially responsive tumors eventually relapse, and die from acquired drug resistance. Unfortunately, few molecular mediators of tam...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-10-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-018-0928-7 |
| _version_ | 1818357545802137600 |
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| author | Yawei Shi Yang Zhao Yunjian Zhang NiJiati AiErken Nan Shao Runyi Ye Ying Lin Shenming Wang |
| author_facet | Yawei Shi Yang Zhao Yunjian Zhang NiJiati AiErken Nan Shao Runyi Ye Ying Lin Shenming Wang |
| author_sort | Yawei Shi |
| collection | DOAJ |
| description | Abstract Background Although tamoxifen is a highly effective drug for treating estrogen receptor–positive (ER+) breast cancer, nearly all patients with metastasis with initially responsive tumors eventually relapse, and die from acquired drug resistance. Unfortunately, few molecular mediators of tamoxifen resistance have been described. Here, we describe AFF3 (AF4/FMR2 family member 3), which encodes a nuclear protein with transactivation potential that confers tamoxifen resistance and enables estrogen-independent growth. Methods We investigated AFF3 expression in breast cancer cells and in clinical breast cancer specimens with western blot and Real-time PCR. We also examined the effects of AFF3 knockdown and overexpression on breast cancer cells using luciferase, tetrazolium, colony formation, and anchorage-independent growth assays in vitro and with nude mouse xenografting in vivo. Results AFF3 was overexpressed in tamoxifen-resistant tumors. AFF3 overexpression in breast cancer cells resulted in tamoxifen resistance, whereas RNA interference–mediated gene knockdown reversed this phenotype. Furthermore, AFF3 upregulation led to estrogen-independent growth in the xenograft assays. Mechanistic investigations revealed that AFF3 overexpression activated the ER signaling pathway and transcriptionally upregulated a subset of ER-regulated genes. Clinical analysis showed that increased AFF3 expression in ER+ breast tumors was associated with worse overall survival. Conclusions These studies establish AFF3 as a key mediator of estrogen-independent growth and tamoxifen resistance and as a potential novel diagnostic and therapeutic target. |
| first_indexed | 2024-12-13T20:14:49Z |
| format | Article |
| id | doaj.art-6eac0d9e7bb743d9bd64d41f8b9fdb9d |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-13T20:14:49Z |
| publishDate | 2018-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-6eac0d9e7bb743d9bd64d41f8b9fdb9d2022-12-21T23:32:51ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662018-10-0137111010.1186/s13046-018-0928-7AFF3 upregulation mediates tamoxifen resistance in breast cancersYawei Shi0Yang Zhao1Yunjian Zhang2NiJiati AiErken3Nan Shao4Runyi Ye5Ying Lin6Shenming Wang7The Department of Breast and Thyroid surgery, the First Affiliated Hospital of Sun Yat-sen UniversityThe Department of Vascular surgery, the Third Affiliated Hospital of Sun Yat-sen UniversityThe Department of Breast and Thyroid surgery, the First Affiliated Hospital of Sun Yat-sen UniversityThe Department of General surgery, the Seventh Affiliated Hospital of Sun Yat-sen UniversityThe Department of Breast and Thyroid surgery, the First Affiliated Hospital of Sun Yat-sen UniversityThe Department of Breast and Thyroid surgery, the First Affiliated Hospital of Sun Yat-sen UniversityThe Department of Breast and Thyroid surgery, the First Affiliated Hospital of Sun Yat-sen UniversityThe Department of Breast and Thyroid surgery, the First Affiliated Hospital of Sun Yat-sen UniversityAbstract Background Although tamoxifen is a highly effective drug for treating estrogen receptor–positive (ER+) breast cancer, nearly all patients with metastasis with initially responsive tumors eventually relapse, and die from acquired drug resistance. Unfortunately, few molecular mediators of tamoxifen resistance have been described. Here, we describe AFF3 (AF4/FMR2 family member 3), which encodes a nuclear protein with transactivation potential that confers tamoxifen resistance and enables estrogen-independent growth. Methods We investigated AFF3 expression in breast cancer cells and in clinical breast cancer specimens with western blot and Real-time PCR. We also examined the effects of AFF3 knockdown and overexpression on breast cancer cells using luciferase, tetrazolium, colony formation, and anchorage-independent growth assays in vitro and with nude mouse xenografting in vivo. Results AFF3 was overexpressed in tamoxifen-resistant tumors. AFF3 overexpression in breast cancer cells resulted in tamoxifen resistance, whereas RNA interference–mediated gene knockdown reversed this phenotype. Furthermore, AFF3 upregulation led to estrogen-independent growth in the xenograft assays. Mechanistic investigations revealed that AFF3 overexpression activated the ER signaling pathway and transcriptionally upregulated a subset of ER-regulated genes. Clinical analysis showed that increased AFF3 expression in ER+ breast tumors was associated with worse overall survival. Conclusions These studies establish AFF3 as a key mediator of estrogen-independent growth and tamoxifen resistance and as a potential novel diagnostic and therapeutic target.http://link.springer.com/article/10.1186/s13046-018-0928-7AFF3Breast cancerEstrogen receptor-positiveTamoxifenResistance |
| spellingShingle | Yawei Shi Yang Zhao Yunjian Zhang NiJiati AiErken Nan Shao Runyi Ye Ying Lin Shenming Wang AFF3 upregulation mediates tamoxifen resistance in breast cancers Journal of Experimental & Clinical Cancer Research AFF3 Breast cancer Estrogen receptor-positive Tamoxifen Resistance |
| title | AFF3 upregulation mediates tamoxifen resistance in breast cancers |
| title_full | AFF3 upregulation mediates tamoxifen resistance in breast cancers |
| title_fullStr | AFF3 upregulation mediates tamoxifen resistance in breast cancers |
| title_full_unstemmed | AFF3 upregulation mediates tamoxifen resistance in breast cancers |
| title_short | AFF3 upregulation mediates tamoxifen resistance in breast cancers |
| title_sort | aff3 upregulation mediates tamoxifen resistance in breast cancers |
| topic | AFF3 Breast cancer Estrogen receptor-positive Tamoxifen Resistance |
| url | http://link.springer.com/article/10.1186/s13046-018-0928-7 |
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