Modulated TRPC1 Expression Predicts Sensitivity of Breast Cancer to Doxorubicin and Magnetic Field Therapy: Segue Towards a Precision Medicine Approach
Chemotherapy is the mainstream treatment modality for invasive breast cancer. Unfortunately, chemotherapy-associated adverse events can result in early termination of treatment. Paradoxical effects of chemotherapy are also sometimes observed, whereby prolonged exposure to high doses of chemotherapeu...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-01-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.783803/full |
| _version_ | 1818482375251722240 |
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| author | Yee Kit Tai Yee Kit Tai Karen Ka Wing Chan Karen Ka Wing Chan Charlene Hui Hua Fong Charlene Hui Hua Fong Sharanya Ramanan Sharanya Ramanan Jasmine Lye Yee Yap Jasmine Lye Yee Yap Jocelyn Naixin Yin Jocelyn Naixin Yin Yun Sheng Yip Wei Ren Tan Angele Pei Fern Koh Nguan Soon Tan Nguan Soon Tan Ching Wan Chan Ching Wan Chan Ruby Yun Ju Huang Ruby Yun Ju Huang Jing Ze Li Jürg Fröhlich Jürg Fröhlich Jürg Fröhlich Alfredo Franco-Obregón Alfredo Franco-Obregón Alfredo Franco-Obregón Alfredo Franco-Obregón Alfredo Franco-Obregón Alfredo Franco-Obregón |
| author_facet | Yee Kit Tai Yee Kit Tai Karen Ka Wing Chan Karen Ka Wing Chan Charlene Hui Hua Fong Charlene Hui Hua Fong Sharanya Ramanan Sharanya Ramanan Jasmine Lye Yee Yap Jasmine Lye Yee Yap Jocelyn Naixin Yin Jocelyn Naixin Yin Yun Sheng Yip Wei Ren Tan Angele Pei Fern Koh Nguan Soon Tan Nguan Soon Tan Ching Wan Chan Ching Wan Chan Ruby Yun Ju Huang Ruby Yun Ju Huang Jing Ze Li Jürg Fröhlich Jürg Fröhlich Jürg Fröhlich Alfredo Franco-Obregón Alfredo Franco-Obregón Alfredo Franco-Obregón Alfredo Franco-Obregón Alfredo Franco-Obregón Alfredo Franco-Obregón |
| author_sort | Yee Kit Tai |
| collection | DOAJ |
| description | Chemotherapy is the mainstream treatment modality for invasive breast cancer. Unfortunately, chemotherapy-associated adverse events can result in early termination of treatment. Paradoxical effects of chemotherapy are also sometimes observed, whereby prolonged exposure to high doses of chemotherapeutic agents results in malignant states resistant to chemotherapy. In this study, potential synergism between doxorubicin (DOX) and pulsed electromagnetic field (PEMF) therapy was investigated in: 1) MCF-7 and MDA-MB-231 cells in vitro; 2) MCF-7 tumors implanted onto a chicken chorioallantoic membrane (CAM) and; 3) human patient-derived and MCF-7 and MDA-MB-231 breast cancer xenografts implanted into NOD-SCID gamma (NSG) mice. In vivo, synergism was observed in patient-derived and breast cancer cell line xenograft mouse models, wherein PEMF exposure and DOX administration individually reduced tumor size and increased apoptosis and could be augmented by combined treatments. In the CAM xenograft model, DOX and PEMF exposure also synergistically reduced tumor size as well as reduced Transient Receptor Potential Canonical 1 (TRPC1) channel expression. In vitro, PEMF exposure alone impaired the survival of MCF-7 and MDA-MB-231 cells, but not that of non-malignant MCF10A breast cells; the selective vulnerability of breast cancer cells to PEMF exposure was corroborated in human tumor biopsy samples. Stable overexpression of TRPC1 enhanced the vulnerability of MCF-7 cells to both DOX and PEMF exposure and promoted proliferation, whereas TRPC1 genetic silencing reduced sensitivity to both DOX and PEMF treatments and mitigated proliferation. Chronic exposure to DOX depressed TRPC1 expression, proliferation, and responses to both PEMF exposure and DOX in a manner that was reversible upon removal of DOX. TRPC1 channel overexpression and silencing positively correlated with markers of epithelial-mesenchymal transition (EMT), including SLUG, SNAIL, VIMENTIN, and E-CADHERIN, indicating increased and decreased EMT, respectively. Finally, PEMF exposure was shown to attenuate the invasiveness of MCF-7 cells in correlation with TRPC1 expression. We thus demonstrate that the expression levels of TRPC1 consistently predicted breast cancer sensitivity to DOX and PEMF interventions and positively correlated to EMT status, providing an initial rationale for the use of PEMF-based therapies as an adjuvant to DOX chemotherapy for the treatment of breast cancers characterized by elevated TRPC1 expression levels. |
| first_indexed | 2024-12-10T11:46:55Z |
| format | Article |
| id | doaj.art-8966f7af1cf7441cad9994a85e837885 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-10T11:46:55Z |
| publishDate | 2022-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-8966f7af1cf7441cad9994a85e8378852022-12-22T01:50:02ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-01-011110.3389/fonc.2021.783803783803Modulated TRPC1 Expression Predicts Sensitivity of Breast Cancer to Doxorubicin and Magnetic Field Therapy: Segue Towards a Precision Medicine ApproachYee Kit Tai0Yee Kit Tai1Karen Ka Wing Chan2Karen Ka Wing Chan3Charlene Hui Hua Fong4Charlene Hui Hua Fong5Sharanya Ramanan6Sharanya Ramanan7Jasmine Lye Yee Yap8Jasmine Lye Yee Yap9Jocelyn Naixin Yin10Jocelyn Naixin Yin11Yun Sheng Yip12Wei Ren Tan13Angele Pei Fern Koh14Nguan Soon Tan15Nguan Soon Tan16Ching Wan Chan17Ching Wan Chan18Ruby Yun Ju Huang19Ruby Yun Ju Huang20Jing Ze Li21Jürg Fröhlich22Jürg Fröhlich23Jürg Fröhlich24Alfredo Franco-Obregón25Alfredo Franco-Obregón26Alfredo Franco-Obregón27Alfredo Franco-Obregón28Alfredo Franco-Obregón29Alfredo Franco-Obregón30Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeBiolonic Currents Electromagnetic Pulsing Systems Laboratory (BICEPS), National University of Singapore, Singapore, SingaporeDepartment of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeBiolonic Currents Electromagnetic Pulsing Systems Laboratory (BICEPS), National University of Singapore, Singapore, SingaporeDepartment of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeBiolonic Currents Electromagnetic Pulsing Systems Laboratory (BICEPS), National University of Singapore, Singapore, SingaporeDepartment of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeBiolonic Currents Electromagnetic Pulsing Systems Laboratory (BICEPS), National University of Singapore, Singapore, SingaporeDepartment of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeBiolonic Currents Electromagnetic Pulsing Systems Laboratory (BICEPS), National University of Singapore, Singapore, SingaporeDepartment of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeBiolonic Currents Electromagnetic Pulsing Systems Laboratory (BICEPS), National University of Singapore, Singapore, SingaporeLee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, SingaporeLee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, SingaporeCancer Science Institute of Singapore, National University of Singapore, Singapore, SingaporeLee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, SingaporeSchool of Biological Sciences, Nanyang Technological University Singapore, Singapore, SingaporeDivision of General Surgery (Breast Surgery), Department of Surgery, National University Hospital, Singapore, SingaporeDivision of Surgical Oncology, National University Cancer Institute, Singapore, SingaporeCancer Science Institute of Singapore, National University of Singapore, Singapore, SingaporeDepartment of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeDepartment of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeDepartment of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeFields at Work GmbH, Zürich, Switzerland0Institute of Electromagnetic Fields , ETH Zürich (Swiss Federal Institute of Technology in Zürich), Zürich, SwitzerlandDepartment of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeBiolonic Currents Electromagnetic Pulsing Systems Laboratory (BICEPS), National University of Singapore, Singapore, Singapore1Institute for Health Innovation & Technology (iHealthtech), National University of Singapore, Singapore, Singapore2Competence Center for Applied Biotechnology and Molecular Medicine, University of Zürich, Zürich, Switzerland3Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore4Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeChemotherapy is the mainstream treatment modality for invasive breast cancer. Unfortunately, chemotherapy-associated adverse events can result in early termination of treatment. Paradoxical effects of chemotherapy are also sometimes observed, whereby prolonged exposure to high doses of chemotherapeutic agents results in malignant states resistant to chemotherapy. In this study, potential synergism between doxorubicin (DOX) and pulsed electromagnetic field (PEMF) therapy was investigated in: 1) MCF-7 and MDA-MB-231 cells in vitro; 2) MCF-7 tumors implanted onto a chicken chorioallantoic membrane (CAM) and; 3) human patient-derived and MCF-7 and MDA-MB-231 breast cancer xenografts implanted into NOD-SCID gamma (NSG) mice. In vivo, synergism was observed in patient-derived and breast cancer cell line xenograft mouse models, wherein PEMF exposure and DOX administration individually reduced tumor size and increased apoptosis and could be augmented by combined treatments. In the CAM xenograft model, DOX and PEMF exposure also synergistically reduced tumor size as well as reduced Transient Receptor Potential Canonical 1 (TRPC1) channel expression. In vitro, PEMF exposure alone impaired the survival of MCF-7 and MDA-MB-231 cells, but not that of non-malignant MCF10A breast cells; the selective vulnerability of breast cancer cells to PEMF exposure was corroborated in human tumor biopsy samples. Stable overexpression of TRPC1 enhanced the vulnerability of MCF-7 cells to both DOX and PEMF exposure and promoted proliferation, whereas TRPC1 genetic silencing reduced sensitivity to both DOX and PEMF treatments and mitigated proliferation. Chronic exposure to DOX depressed TRPC1 expression, proliferation, and responses to both PEMF exposure and DOX in a manner that was reversible upon removal of DOX. TRPC1 channel overexpression and silencing positively correlated with markers of epithelial-mesenchymal transition (EMT), including SLUG, SNAIL, VIMENTIN, and E-CADHERIN, indicating increased and decreased EMT, respectively. Finally, PEMF exposure was shown to attenuate the invasiveness of MCF-7 cells in correlation with TRPC1 expression. We thus demonstrate that the expression levels of TRPC1 consistently predicted breast cancer sensitivity to DOX and PEMF interventions and positively correlated to EMT status, providing an initial rationale for the use of PEMF-based therapies as an adjuvant to DOX chemotherapy for the treatment of breast cancers characterized by elevated TRPC1 expression levels.https://www.frontiersin.org/articles/10.3389/fonc.2021.783803/fullbreast cancerPEMFsEMTpatient-derived xenograftchorioallantoic membranedoxorubicin |
| spellingShingle | Yee Kit Tai Yee Kit Tai Karen Ka Wing Chan Karen Ka Wing Chan Charlene Hui Hua Fong Charlene Hui Hua Fong Sharanya Ramanan Sharanya Ramanan Jasmine Lye Yee Yap Jasmine Lye Yee Yap Jocelyn Naixin Yin Jocelyn Naixin Yin Yun Sheng Yip Wei Ren Tan Angele Pei Fern Koh Nguan Soon Tan Nguan Soon Tan Ching Wan Chan Ching Wan Chan Ruby Yun Ju Huang Ruby Yun Ju Huang Jing Ze Li Jürg Fröhlich Jürg Fröhlich Jürg Fröhlich Alfredo Franco-Obregón Alfredo Franco-Obregón Alfredo Franco-Obregón Alfredo Franco-Obregón Alfredo Franco-Obregón Alfredo Franco-Obregón Modulated TRPC1 Expression Predicts Sensitivity of Breast Cancer to Doxorubicin and Magnetic Field Therapy: Segue Towards a Precision Medicine Approach Frontiers in Oncology breast cancer PEMFs EMT patient-derived xenograft chorioallantoic membrane doxorubicin |
| title | Modulated TRPC1 Expression Predicts Sensitivity of Breast Cancer to Doxorubicin and Magnetic Field Therapy: Segue Towards a Precision Medicine Approach |
| title_full | Modulated TRPC1 Expression Predicts Sensitivity of Breast Cancer to Doxorubicin and Magnetic Field Therapy: Segue Towards a Precision Medicine Approach |
| title_fullStr | Modulated TRPC1 Expression Predicts Sensitivity of Breast Cancer to Doxorubicin and Magnetic Field Therapy: Segue Towards a Precision Medicine Approach |
| title_full_unstemmed | Modulated TRPC1 Expression Predicts Sensitivity of Breast Cancer to Doxorubicin and Magnetic Field Therapy: Segue Towards a Precision Medicine Approach |
| title_short | Modulated TRPC1 Expression Predicts Sensitivity of Breast Cancer to Doxorubicin and Magnetic Field Therapy: Segue Towards a Precision Medicine Approach |
| title_sort | modulated trpc1 expression predicts sensitivity of breast cancer to doxorubicin and magnetic field therapy segue towards a precision medicine approach |
| topic | breast cancer PEMFs EMT patient-derived xenograft chorioallantoic membrane doxorubicin |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.783803/full |
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