Inosine monophosphate dehydrogenase 2 (IMPDH2) modulates response to therapy and chemo-resistance in triple negative breast cancer
Abstract Triple negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer, whose high frequency of relapse is often due to resistance to chemotherapy. Here, we identify inosine monophosphate dehydrogenase 2 (IMPDH2) as a contributor to doxorubicin resistance, in multiple TNBC m...
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Nature Portfolio
2025-01-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-024-85094-5 |
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| author | Tatiane da Silva Fernandes Bryan M. Gillard Tao Dai Jeffrey C. Martin Kanita A. Chaudhry Scott M. Dugas Alyssa A. Fisher Pia Sharma RongRong Wu Kristopher M. Attwood Subhamoy Dasgupta Kazuaki Takabe Spencer R. Rosario Anna Bianchi-Smiraglia |
| author_facet | Tatiane da Silva Fernandes Bryan M. Gillard Tao Dai Jeffrey C. Martin Kanita A. Chaudhry Scott M. Dugas Alyssa A. Fisher Pia Sharma RongRong Wu Kristopher M. Attwood Subhamoy Dasgupta Kazuaki Takabe Spencer R. Rosario Anna Bianchi-Smiraglia |
| author_sort | Tatiane da Silva Fernandes |
| collection | DOAJ |
| description | Abstract Triple negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer, whose high frequency of relapse is often due to resistance to chemotherapy. Here, we identify inosine monophosphate dehydrogenase 2 (IMPDH2) as a contributor to doxorubicin resistance, in multiple TNBC models. Analysis of publicly available datasets reveals elevated IMPDH2 expression to associate with worse overall TNBC prognosis in the clinic, including lower recurrence-free survival post adjuvant/neoadjuvant therapy. Importantly, both genetic depletion and pharmacological inhibition of IMPDH2 leads to reduction of pro-tumorigenic phenotypes in multiple doxorubicin-resistant TNBC models, both in vitro and in vivo. Overall, we propose IMPDH2 as a novel vulnerability that could be leveraged therapeutically to suppress and/or prevent the growth of chemo-resistant lesions. |
| format | Article |
| id | doaj-art-c7f7456bc7664779a86c60f03df8722f |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-c7f7456bc7664779a86c60f03df8722f2025-01-12T12:23:56ZengNature PortfolioScientific Reports2045-23222025-01-0115111410.1038/s41598-024-85094-5Inosine monophosphate dehydrogenase 2 (IMPDH2) modulates response to therapy and chemo-resistance in triple negative breast cancerTatiane da Silva Fernandes0Bryan M. Gillard1Tao Dai2Jeffrey C. Martin3Kanita A. Chaudhry4Scott M. Dugas5Alyssa A. Fisher6Pia Sharma7RongRong Wu8Kristopher M. Attwood9Subhamoy Dasgupta10Kazuaki Takabe11Spencer R. Rosario12Anna Bianchi-Smiraglia13Department of Cell Stress Biology, Roswell Park Comprehensive Cancer CenterDepartment of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer CenterDepartment of Cell Stress Biology, Roswell Park Comprehensive Cancer CenterDepartment of Cell Stress Biology, Roswell Park Comprehensive Cancer CenterDepartment of Cell Stress Biology, Roswell Park Comprehensive Cancer CenterDepartment of Cell Stress Biology, Roswell Park Comprehensive Cancer CenterDepartment of Cell Stress Biology, Roswell Park Comprehensive Cancer CenterDepartment of Breast Surgery, Roswell Park Comprehensive Cancer CenterDepartment of Breast Surgery, Roswell Park Comprehensive Cancer CenterDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterDepartment of Cell Stress Biology, Roswell Park Comprehensive Cancer CenterDepartment of Breast Surgery, Roswell Park Comprehensive Cancer CenterDepartment of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer CenterDepartment of Cell Stress Biology, Roswell Park Comprehensive Cancer CenterAbstract Triple negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer, whose high frequency of relapse is often due to resistance to chemotherapy. Here, we identify inosine monophosphate dehydrogenase 2 (IMPDH2) as a contributor to doxorubicin resistance, in multiple TNBC models. Analysis of publicly available datasets reveals elevated IMPDH2 expression to associate with worse overall TNBC prognosis in the clinic, including lower recurrence-free survival post adjuvant/neoadjuvant therapy. Importantly, both genetic depletion and pharmacological inhibition of IMPDH2 leads to reduction of pro-tumorigenic phenotypes in multiple doxorubicin-resistant TNBC models, both in vitro and in vivo. Overall, we propose IMPDH2 as a novel vulnerability that could be leveraged therapeutically to suppress and/or prevent the growth of chemo-resistant lesions.https://doi.org/10.1038/s41598-024-85094-5TNBCChemo-resistanceDoxorubicinPaclitaxelIMPDH2GTP metabolism |
| spellingShingle | Tatiane da Silva Fernandes Bryan M. Gillard Tao Dai Jeffrey C. Martin Kanita A. Chaudhry Scott M. Dugas Alyssa A. Fisher Pia Sharma RongRong Wu Kristopher M. Attwood Subhamoy Dasgupta Kazuaki Takabe Spencer R. Rosario Anna Bianchi-Smiraglia Inosine monophosphate dehydrogenase 2 (IMPDH2) modulates response to therapy and chemo-resistance in triple negative breast cancer Scientific Reports TNBC Chemo-resistance Doxorubicin Paclitaxel IMPDH2 GTP metabolism |
| title | Inosine monophosphate dehydrogenase 2 (IMPDH2) modulates response to therapy and chemo-resistance in triple negative breast cancer |
| title_full | Inosine monophosphate dehydrogenase 2 (IMPDH2) modulates response to therapy and chemo-resistance in triple negative breast cancer |
| title_fullStr | Inosine monophosphate dehydrogenase 2 (IMPDH2) modulates response to therapy and chemo-resistance in triple negative breast cancer |
| title_full_unstemmed | Inosine monophosphate dehydrogenase 2 (IMPDH2) modulates response to therapy and chemo-resistance in triple negative breast cancer |
| title_short | Inosine monophosphate dehydrogenase 2 (IMPDH2) modulates response to therapy and chemo-resistance in triple negative breast cancer |
| title_sort | inosine monophosphate dehydrogenase 2 impdh2 modulates response to therapy and chemo resistance in triple negative breast cancer |
| topic | TNBC Chemo-resistance Doxorubicin Paclitaxel IMPDH2 GTP metabolism |
| url | https://doi.org/10.1038/s41598-024-85094-5 |
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