Quercetin inhibits truncated isoform of dopamine- and cAMP-regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in HER2-positive breast cancer
Trastuzumab resistance is one of the causes of poor prognosis in patients with human epidermal growth factor receptor 2 (HER2)-positive (HER2+) breast cancer (BC). The truncated isoform of dopamine- and cAMP-regulated phosphoprotein (t-DARPP) has been reported to be involved in trastuzumab therapy r...
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| Format: | Article |
| Language: | English |
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Tsinghua University Press
2024-09-01
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| Series: | Food Science and Human Wellness |
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| Online Access: | https://www.sciopen.com/article/10.26599/FSHW.2022.9250213 |
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| author | Han-Sheng Chang Tzu-Chun Cheng Shih-Hsin Tu Chih-Hsiung Wu You-Cheng Liao Jungshan Chang Min-Hsiung Pan Li-Ching Chen Yuan-Soon Ho |
| author_facet | Han-Sheng Chang Tzu-Chun Cheng Shih-Hsin Tu Chih-Hsiung Wu You-Cheng Liao Jungshan Chang Min-Hsiung Pan Li-Ching Chen Yuan-Soon Ho |
| author_sort | Han-Sheng Chang |
| collection | DOAJ |
| description | Trastuzumab resistance is one of the causes of poor prognosis in patients with human epidermal growth factor receptor 2 (HER2)-positive (HER2+) breast cancer (BC). The truncated isoform of dopamine- and cAMP-regulated phosphoprotein (t-DARPP) has been reported to be involved in trastuzumab therapy resistance and promoting tumor progression. To evaluate the t-DARPP expression in BC, paired tumors and surrounding normal tissues were analyzed by real-time polymerase chain reaction and confirmed higher DARPP-32 kDa family mRNA expression in HER2+ BC tumor tissues. We established 2 patient-derived xenografts (PDX) mice models to test the efficacy of trastuzumab, named model 1 (non-responder) and model 2 (responder). t-DARPP and p95-HER2 protein-protein interactions were detected in PDX tumor tissue from non-responders using Förster resonance energy transfer assays. Instead, there is no response from the responder. Furthermore, mechanistic studies using transwell and western blot assays demonstrated that t-DARPP could upregulate epithelial-mesenchymal transition signaling proteins, enhance p95-HER2 expression and promote cell migration. We found that quercetin effectively reduced t-DARPP expression in HER2+ BC cells. In t-DARPP ShRNA-suppressed cells, quercetin synergistically enhanced trastuzumab-induced apoptotic cell death and G2/M phase arrest. In conclusion, the combination of quercetin and trastuzumab treatment by targeting t-DARPP in HER2+ BC patients has the potential as a biomarker for mitigating drug resistance. |
| format | Article |
| id | doaj-art-5de7ba049e1846b098f1fafdfb1c22c4 |
| institution | Kabale University |
| issn | 2097-0765 2213-4530 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | Tsinghua University Press |
| record_format | Article |
| series | Food Science and Human Wellness |
| spelling | doaj-art-5de7ba049e1846b098f1fafdfb1c22c42025-01-10T06:56:56ZengTsinghua University PressFood Science and Human Wellness2097-07652213-45302024-09-011352653266710.26599/FSHW.2022.9250213Quercetin inhibits truncated isoform of dopamine- and cAMP-regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in HER2-positive breast cancerHan-Sheng Chang0Tzu-Chun Cheng1Shih-Hsin Tu2Chih-Hsiung Wu3You-Cheng Liao4Jungshan Chang5Min-Hsiung Pan6Li-Ching Chen7Yuan-Soon Ho8Department of Biological Science &Technology, College of Life Sciences, China Medical University, Taichung 406, Taiwan, ChinaInstitute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung 406, Taiwan, ChinaDepartment of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ChinaDepartment of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ChinaGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ChinaGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ChinaInstitute of Food Sciences and Technology, National Taiwan University, Taipei 106, Taiwan, ChinaDepartment of Biological Science &Technology, College of Life Sciences, China Medical University, Taichung 406, Taiwan, ChinaInstitute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung 406, Taiwan, ChinaTrastuzumab resistance is one of the causes of poor prognosis in patients with human epidermal growth factor receptor 2 (HER2)-positive (HER2+) breast cancer (BC). The truncated isoform of dopamine- and cAMP-regulated phosphoprotein (t-DARPP) has been reported to be involved in trastuzumab therapy resistance and promoting tumor progression. To evaluate the t-DARPP expression in BC, paired tumors and surrounding normal tissues were analyzed by real-time polymerase chain reaction and confirmed higher DARPP-32 kDa family mRNA expression in HER2+ BC tumor tissues. We established 2 patient-derived xenografts (PDX) mice models to test the efficacy of trastuzumab, named model 1 (non-responder) and model 2 (responder). t-DARPP and p95-HER2 protein-protein interactions were detected in PDX tumor tissue from non-responders using Förster resonance energy transfer assays. Instead, there is no response from the responder. Furthermore, mechanistic studies using transwell and western blot assays demonstrated that t-DARPP could upregulate epithelial-mesenchymal transition signaling proteins, enhance p95-HER2 expression and promote cell migration. We found that quercetin effectively reduced t-DARPP expression in HER2+ BC cells. In t-DARPP ShRNA-suppressed cells, quercetin synergistically enhanced trastuzumab-induced apoptotic cell death and G2/M phase arrest. In conclusion, the combination of quercetin and trastuzumab treatment by targeting t-DARPP in HER2+ BC patients has the potential as a biomarker for mitigating drug resistance.https://www.sciopen.com/article/10.26599/FSHW.2022.9250213p95-human epidermal growth factor receptor 2 (her2)her2-positive breast cancerquercetintrastuzumab resistancetruncated isoform of dopamine- and camp-regulated phosphoprotein |
| spellingShingle | Han-Sheng Chang Tzu-Chun Cheng Shih-Hsin Tu Chih-Hsiung Wu You-Cheng Liao Jungshan Chang Min-Hsiung Pan Li-Ching Chen Yuan-Soon Ho Quercetin inhibits truncated isoform of dopamine- and cAMP-regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in HER2-positive breast cancer Food Science and Human Wellness p95-human epidermal growth factor receptor 2 (her2) her2-positive breast cancer quercetin trastuzumab resistance truncated isoform of dopamine- and camp-regulated phosphoprotein |
| title | Quercetin inhibits truncated isoform of dopamine- and cAMP-regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in HER2-positive breast cancer |
| title_full | Quercetin inhibits truncated isoform of dopamine- and cAMP-regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in HER2-positive breast cancer |
| title_fullStr | Quercetin inhibits truncated isoform of dopamine- and cAMP-regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in HER2-positive breast cancer |
| title_full_unstemmed | Quercetin inhibits truncated isoform of dopamine- and cAMP-regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in HER2-positive breast cancer |
| title_short | Quercetin inhibits truncated isoform of dopamine- and cAMP-regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in HER2-positive breast cancer |
| title_sort | quercetin inhibits truncated isoform of dopamine and camp regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in her2 positive breast cancer |
| topic | p95-human epidermal growth factor receptor 2 (her2) her2-positive breast cancer quercetin trastuzumab resistance truncated isoform of dopamine- and camp-regulated phosphoprotein |
| url | https://www.sciopen.com/article/10.26599/FSHW.2022.9250213 |
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