Toll-like receptor 2 promotes breast cancer progression and resistance to chemotherapy
Cancer stem cells (CSCs) are the main drivers of disease progression and chemotherapy resistance in breast cancer. Tumor progression and chemoresistance might then be prevented by CSC-targeted therapies. We previously demonstrated that Toll-like Receptor (TLR)2 is overexpressed in CSCs and fuels the...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2086752 |
| _version_ | 1828328236624379904 |
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| author | Antonino Di Lorenzo Elisabetta Bolli Roberto Ruiu Giuseppe Ferrauto Enza Di Gregorio Lidia Avalle Aurora Savino Pietro Poggio Irene Fiore Merighi Federica Riccardo Mara Brancaccio Elena Quaglino Federica Cavallo Laura Conti |
| author_facet | Antonino Di Lorenzo Elisabetta Bolli Roberto Ruiu Giuseppe Ferrauto Enza Di Gregorio Lidia Avalle Aurora Savino Pietro Poggio Irene Fiore Merighi Federica Riccardo Mara Brancaccio Elena Quaglino Federica Cavallo Laura Conti |
| author_sort | Antonino Di Lorenzo |
| collection | DOAJ |
| description | Cancer stem cells (CSCs) are the main drivers of disease progression and chemotherapy resistance in breast cancer. Tumor progression and chemoresistance might then be prevented by CSC-targeted therapies. We previously demonstrated that Toll-like Receptor (TLR)2 is overexpressed in CSCs and fuels their self-renewal. Here, we show that high TLR2 expression is linked to poor prognosis in breast cancer patients, therefore representing a candidate target for breast cancer treatment. By using a novel mammary cancer-prone TLR2KO mouse model, we demonstrate that TLR2 is required for CSC pool maintenance and for regulatory T cell induction. Accordingly, cancer-prone TLR2KO mice display delayed tumor onset and increased survival. Transplantation of TLR2WT and TLR2KO cancer cells in either TLR2WT or TLR2KO hosts shows that tumor initiation is mostly sustained by TLR2 expression in cancer cells. TLR2 host deficiency partially impairs cancer cell growth, implying a pro-tumorigenic effect of TLR2 expression in immune cells. Finally, we demonstrate that doxorubicin-induced release of HMGB1 activates TLR2 signaling in cancer cells, leading to a chemotherapy-resistant phenotype. Unprecedented use of TLR2 inhibitors in vivo reduces tumor growth and potentiates doxorubicin efficacy with no negative impact on the host immune system, opening new perspectives for the treatment of breast cancer patients. |
| first_indexed | 2024-04-13T20:06:55Z |
| format | Article |
| id | doaj.art-4d7f2d53f71c4553ae2ce00f7fd2960b |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-04-13T20:06:55Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-4d7f2d53f71c4553ae2ce00f7fd2960b2022-12-22T02:31:58ZengTaylor & Francis GroupOncoImmunology2162-402X2022-12-0111110.1080/2162402X.2022.2086752Toll-like receptor 2 promotes breast cancer progression and resistance to chemotherapyAntonino Di Lorenzo0Elisabetta Bolli1Roberto Ruiu2Giuseppe Ferrauto3Enza Di Gregorio4Lidia Avalle5Aurora Savino6Pietro Poggio7Irene Fiore Merighi8Federica Riccardo9Mara Brancaccio10Elena Quaglino11Federica Cavallo12Laura Conti13Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Turin, Turin, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Turin, Turin, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Turin, Turin, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Turin, Turin, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Turin, Turin, ItalyHuman Technopole, Milan, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Turin, Turin, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Turin, Turin, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Turin, Turin, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Turin, Turin, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Turin, Turin, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Turin, Turin, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Turin, Turin, ItalyCancer stem cells (CSCs) are the main drivers of disease progression and chemotherapy resistance in breast cancer. Tumor progression and chemoresistance might then be prevented by CSC-targeted therapies. We previously demonstrated that Toll-like Receptor (TLR)2 is overexpressed in CSCs and fuels their self-renewal. Here, we show that high TLR2 expression is linked to poor prognosis in breast cancer patients, therefore representing a candidate target for breast cancer treatment. By using a novel mammary cancer-prone TLR2KO mouse model, we demonstrate that TLR2 is required for CSC pool maintenance and for regulatory T cell induction. Accordingly, cancer-prone TLR2KO mice display delayed tumor onset and increased survival. Transplantation of TLR2WT and TLR2KO cancer cells in either TLR2WT or TLR2KO hosts shows that tumor initiation is mostly sustained by TLR2 expression in cancer cells. TLR2 host deficiency partially impairs cancer cell growth, implying a pro-tumorigenic effect of TLR2 expression in immune cells. Finally, we demonstrate that doxorubicin-induced release of HMGB1 activates TLR2 signaling in cancer cells, leading to a chemotherapy-resistant phenotype. Unprecedented use of TLR2 inhibitors in vivo reduces tumor growth and potentiates doxorubicin efficacy with no negative impact on the host immune system, opening new perspectives for the treatment of breast cancer patients.https://www.tandfonline.com/doi/10.1080/2162402X.2022.2086752Breast cancerToll-like receptor 2HER2HMGB1chemoresistance |
| spellingShingle | Antonino Di Lorenzo Elisabetta Bolli Roberto Ruiu Giuseppe Ferrauto Enza Di Gregorio Lidia Avalle Aurora Savino Pietro Poggio Irene Fiore Merighi Federica Riccardo Mara Brancaccio Elena Quaglino Federica Cavallo Laura Conti Toll-like receptor 2 promotes breast cancer progression and resistance to chemotherapy OncoImmunology Breast cancer Toll-like receptor 2 HER2 HMGB1 chemoresistance |
| title | Toll-like receptor 2 promotes breast cancer progression and resistance to chemotherapy |
| title_full | Toll-like receptor 2 promotes breast cancer progression and resistance to chemotherapy |
| title_fullStr | Toll-like receptor 2 promotes breast cancer progression and resistance to chemotherapy |
| title_full_unstemmed | Toll-like receptor 2 promotes breast cancer progression and resistance to chemotherapy |
| title_short | Toll-like receptor 2 promotes breast cancer progression and resistance to chemotherapy |
| title_sort | toll like receptor 2 promotes breast cancer progression and resistance to chemotherapy |
| topic | Breast cancer Toll-like receptor 2 HER2 HMGB1 chemoresistance |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2086752 |
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