Inhibition of TFF3 synergizes with c-MET inhibitors to decrease the CSC-like phenotype and metastatic burden in ER+HER2+ mammary carcinoma
Abstract The interaction between HER2 and ERα signaling pathways contributes to resistance to anti-estrogen and HER2-targeted therapies, presenting substantial treatment challenges in ER-positive (ER+) HER2-positive (HER2+) mammary carcinoma (MC). Trefoil Factor-3 (TFF3) has been reported to mediate...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07387-5 |
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| author | Chuyu He Xuejuan Wang Yi-Shiou Chiou Basappa Basappa Tao Zhu Vijay Pandey Peter E. Lobie |
| author_facet | Chuyu He Xuejuan Wang Yi-Shiou Chiou Basappa Basappa Tao Zhu Vijay Pandey Peter E. Lobie |
| author_sort | Chuyu He |
| collection | DOAJ |
| description | Abstract The interaction between HER2 and ERα signaling pathways contributes to resistance to anti-estrogen and HER2-targeted therapies, presenting substantial treatment challenges in ER-positive (ER+) HER2-positive (HER2+) mammary carcinoma (MC). Trefoil Factor-3 (TFF3) has been reported to mediate resistance to both anti-estrogen and anti-HER2 targeted therapies in ER+ and ER+HER2+ MC, respectively. Herein, the function and mechanism of TFF3 in ER+HER2+ MC were delineated; and novel combinatorial therapeutic strategies were identified. Elevated expression of TFF3 promoted the oncogenicity of ER+HER2+ MC cells, including enhanced cell proliferation, survival, anchorage-independent growth, 3D growth, cancer stem cell-like (CSC-like) phenotype, migration, invasion, and xenograft growth. Targeting TFF3 with an interfering RNA plasmid or a small-molecule inhibitor (AMPC) inhibited these oncogenic characteristics, highlighting the therapeutic potential of targeting TFF3 in ER+HER2+ MC. Furthermore, a high-throughput combinatorial anti-cancer compound library screening revealed that AMPC preferentially synergized with receptor tyrosine kinase c-MET inhibitors (c-METis) to reduce cell survival and the CSC-like phenotype. The combination of AMPC and c-METis also synergistically suppressed the in vivo growth of ER+HER2+ MC cell-derived xenografts and abrogated lung metastasis. Mechanistically, TFF3 was observed to activate c-MET signaling through a positive-feedback loop to enhance the CSC-like phenotype of ER+HER2+ MC. Therefore, proof of concept is provided herein that antagonizing of TFF3 is a promising therapeutic strategy in combination with c-MET inhibition for the treatment of ER+HER2+ MC. |
| format | Article |
| id | doaj-art-4d0fd495f0bf4b6a8300d4ee375f06f2 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-4d0fd495f0bf4b6a8300d4ee375f06f22025-02-09T12:56:46ZengNature Publishing GroupCell Death and Disease2041-48892025-02-0116111910.1038/s41419-025-07387-5Inhibition of TFF3 synergizes with c-MET inhibitors to decrease the CSC-like phenotype and metastatic burden in ER+HER2+ mammary carcinomaChuyu He0Xuejuan Wang1Yi-Shiou Chiou2Basappa Basappa3Tao Zhu4Vijay Pandey5Peter E. Lobie6Institute of Biopharmaceutical and Health Engineering and Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua UniversityInstitute of Biopharmaceutical and Health Engineering and Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua UniversityInstitute of Biopharmaceutical and Health Engineering and Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua UniversityLaboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of MysoreShenzhen Bay LaboratoryInstitute of Biopharmaceutical and Health Engineering and Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua UniversityInstitute of Biopharmaceutical and Health Engineering and Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua UniversityAbstract The interaction between HER2 and ERα signaling pathways contributes to resistance to anti-estrogen and HER2-targeted therapies, presenting substantial treatment challenges in ER-positive (ER+) HER2-positive (HER2+) mammary carcinoma (MC). Trefoil Factor-3 (TFF3) has been reported to mediate resistance to both anti-estrogen and anti-HER2 targeted therapies in ER+ and ER+HER2+ MC, respectively. Herein, the function and mechanism of TFF3 in ER+HER2+ MC were delineated; and novel combinatorial therapeutic strategies were identified. Elevated expression of TFF3 promoted the oncogenicity of ER+HER2+ MC cells, including enhanced cell proliferation, survival, anchorage-independent growth, 3D growth, cancer stem cell-like (CSC-like) phenotype, migration, invasion, and xenograft growth. Targeting TFF3 with an interfering RNA plasmid or a small-molecule inhibitor (AMPC) inhibited these oncogenic characteristics, highlighting the therapeutic potential of targeting TFF3 in ER+HER2+ MC. Furthermore, a high-throughput combinatorial anti-cancer compound library screening revealed that AMPC preferentially synergized with receptor tyrosine kinase c-MET inhibitors (c-METis) to reduce cell survival and the CSC-like phenotype. The combination of AMPC and c-METis also synergistically suppressed the in vivo growth of ER+HER2+ MC cell-derived xenografts and abrogated lung metastasis. Mechanistically, TFF3 was observed to activate c-MET signaling through a positive-feedback loop to enhance the CSC-like phenotype of ER+HER2+ MC. Therefore, proof of concept is provided herein that antagonizing of TFF3 is a promising therapeutic strategy in combination with c-MET inhibition for the treatment of ER+HER2+ MC.https://doi.org/10.1038/s41419-025-07387-5 |
| spellingShingle | Chuyu He Xuejuan Wang Yi-Shiou Chiou Basappa Basappa Tao Zhu Vijay Pandey Peter E. Lobie Inhibition of TFF3 synergizes with c-MET inhibitors to decrease the CSC-like phenotype and metastatic burden in ER+HER2+ mammary carcinoma Cell Death and Disease |
| title | Inhibition of TFF3 synergizes with c-MET inhibitors to decrease the CSC-like phenotype and metastatic burden in ER+HER2+ mammary carcinoma |
| title_full | Inhibition of TFF3 synergizes with c-MET inhibitors to decrease the CSC-like phenotype and metastatic burden in ER+HER2+ mammary carcinoma |
| title_fullStr | Inhibition of TFF3 synergizes with c-MET inhibitors to decrease the CSC-like phenotype and metastatic burden in ER+HER2+ mammary carcinoma |
| title_full_unstemmed | Inhibition of TFF3 synergizes with c-MET inhibitors to decrease the CSC-like phenotype and metastatic burden in ER+HER2+ mammary carcinoma |
| title_short | Inhibition of TFF3 synergizes with c-MET inhibitors to decrease the CSC-like phenotype and metastatic burden in ER+HER2+ mammary carcinoma |
| title_sort | inhibition of tff3 synergizes with c met inhibitors to decrease the csc like phenotype and metastatic burden in er her2 mammary carcinoma |
| url | https://doi.org/10.1038/s41419-025-07387-5 |
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