Loss function of tumor suppressor FRMD8 confers resistance to tamoxifen therapy via a dual mechanism
Approximately 40% ERα-positive breast cancer patients suffer from therapeutic resistance to tamoxifen. Although reduced ERα level is the major cause of tamoxifen resistance, the underlying mechanisms remain elusive. Here, we report that FRMD8 raises the level of ERα at both transcriptional and post-...
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eLife Sciences Publications Ltd
2025-04-01
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| Online Access: | https://elifesciences.org/articles/101888 |
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| author | Weijie Wu Miao Yu Qianchen Li Yiqian Zhao Lei Zhang Yi Sun Zhenbin Wang Yuqing Gong Wenjing Wang Chenying Liu Jing Zhang Yan Tang Xiaojie Xu Xiaojing Guo Jun Zhan Hongquan Zhang |
| author_facet | Weijie Wu Miao Yu Qianchen Li Yiqian Zhao Lei Zhang Yi Sun Zhenbin Wang Yuqing Gong Wenjing Wang Chenying Liu Jing Zhang Yan Tang Xiaojie Xu Xiaojing Guo Jun Zhan Hongquan Zhang |
| author_sort | Weijie Wu |
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| description | Approximately 40% ERα-positive breast cancer patients suffer from therapeutic resistance to tamoxifen. Although reduced ERα level is the major cause of tamoxifen resistance, the underlying mechanisms remain elusive. Here, we report that FRMD8 raises the level of ERα at both transcriptional and post-translational layers. FRMD8 deficiency in MMTV-Cre+; Frmd8fl/fl; PyMT mice accelerates mammary tumor growth and loss of luminal phenotype, and confers tamoxifen resistance. Single-cell RNA profiling reveals that Frmd8 loss decreases the proportion of hormone-sensing differentiated epithelial cells and downregulates the levels of ERα. Mechanically, on one hand, loss of FRMD8 inhibits ESR1 transcription via suppressing the expression of FOXO3A, a transcription factor of ESR1. On the other hand, FRMD8 interacts both with ERα and UBE3A, and disrupts the interaction of UBE3A with ERα, thereby blocking UBE3A-mediated ERα degradation. In breast cancer patients, FRMD8 gene promoter is found hypermethylated and low level of FRMD8 predicts poor prognosis. Therefore, FRMD8 is an important regulator of ERα and may control therapeutic sensitivity to tamoxifen in ERα-positive breast cancer patients. |
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| issn | 2050-084X |
| language | English |
| publishDate | 2025-04-01 |
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| spelling | doaj-art-9a02ecd5223945ebac4c106f7fae35cc2025-08-20T02:15:41ZengeLife Sciences Publications LtdeLife2050-084X2025-04-011310.7554/eLife.101888Loss function of tumor suppressor FRMD8 confers resistance to tamoxifen therapy via a dual mechanismWeijie Wu0https://orcid.org/0009-0001-4621-7243Miao Yu1https://orcid.org/0000-0002-2256-0231Qianchen Li2Yiqian Zhao3Lei Zhang4Yi Sun5Zhenbin Wang6Yuqing Gong7Wenjing Wang8Chenying Liu9Jing Zhang10Yan Tang11Xiaojie Xu12Xiaojing Guo13Jun Zhan14Hongquan Zhang15https://orcid.org/0000-0001-8193-0899Program for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University International Cancer Institute, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, ChinaProgram for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University International Cancer Institute, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, ChinaProgram for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University International Cancer Institute, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, ChinaProgram for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University International Cancer Institute, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, ChinaProgram for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University International Cancer Institute, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, ChinaProgram for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University International Cancer Institute, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, ChinaProgram for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University International Cancer Institute, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, ChinaProgram for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University International Cancer Institute, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, ChinaDepartment of Gastroenterology, Beijing Friendship Hospital, Capital Medical University; State Key Laboratory for Digestive Health; National Clinical Research Center for Digestive Diseases, Beijing, ChinaDepartment of Breast Pathology and Lab, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy of Ministry of Education of China, Tianjin Medical University, Tianjin’s Clinical Research Center for Cancer, Tianjin, ChinaProgram for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University International Cancer Institute, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, ChinaProgram for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University International Cancer Institute, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, ChinaDepartment of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, ChinaDepartment of Breast Pathology and Lab, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy of Ministry of Education of China, Tianjin Medical University, Tianjin’s Clinical Research Center for Cancer, Tianjin, ChinaProgram for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University International Cancer Institute, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, ChinaProgram for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University International Cancer Institute, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, ChinaApproximately 40% ERα-positive breast cancer patients suffer from therapeutic resistance to tamoxifen. Although reduced ERα level is the major cause of tamoxifen resistance, the underlying mechanisms remain elusive. Here, we report that FRMD8 raises the level of ERα at both transcriptional and post-translational layers. FRMD8 deficiency in MMTV-Cre+; Frmd8fl/fl; PyMT mice accelerates mammary tumor growth and loss of luminal phenotype, and confers tamoxifen resistance. Single-cell RNA profiling reveals that Frmd8 loss decreases the proportion of hormone-sensing differentiated epithelial cells and downregulates the levels of ERα. Mechanically, on one hand, loss of FRMD8 inhibits ESR1 transcription via suppressing the expression of FOXO3A, a transcription factor of ESR1. On the other hand, FRMD8 interacts both with ERα and UBE3A, and disrupts the interaction of UBE3A with ERα, thereby blocking UBE3A-mediated ERα degradation. In breast cancer patients, FRMD8 gene promoter is found hypermethylated and low level of FRMD8 predicts poor prognosis. Therefore, FRMD8 is an important regulator of ERα and may control therapeutic sensitivity to tamoxifen in ERα-positive breast cancer patients.https://elifesciences.org/articles/101888FRMD8breast cancerERαtamoxifen resistanceUBE3A |
| spellingShingle | Weijie Wu Miao Yu Qianchen Li Yiqian Zhao Lei Zhang Yi Sun Zhenbin Wang Yuqing Gong Wenjing Wang Chenying Liu Jing Zhang Yan Tang Xiaojie Xu Xiaojing Guo Jun Zhan Hongquan Zhang Loss function of tumor suppressor FRMD8 confers resistance to tamoxifen therapy via a dual mechanism eLife FRMD8 breast cancer ERα tamoxifen resistance UBE3A |
| title | Loss function of tumor suppressor FRMD8 confers resistance to tamoxifen therapy via a dual mechanism |
| title_full | Loss function of tumor suppressor FRMD8 confers resistance to tamoxifen therapy via a dual mechanism |
| title_fullStr | Loss function of tumor suppressor FRMD8 confers resistance to tamoxifen therapy via a dual mechanism |
| title_full_unstemmed | Loss function of tumor suppressor FRMD8 confers resistance to tamoxifen therapy via a dual mechanism |
| title_short | Loss function of tumor suppressor FRMD8 confers resistance to tamoxifen therapy via a dual mechanism |
| title_sort | loss function of tumor suppressor frmd8 confers resistance to tamoxifen therapy via a dual mechanism |
| topic | FRMD8 breast cancer ERα tamoxifen resistance UBE3A |
| url | https://elifesciences.org/articles/101888 |
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