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t-DARPP、DARPP-32在HER2+乳癌病患肿瘤中大量表现
t-DARPP和p95-HER2之间的相互作用可以作为分子标记来确定曲妥珠单抗治疗乳癌肿瘤的疗效
图2 t-DARPP和p95-HER2之间的相互作用参与了HER2+ BC细胞的曲妥珠单抗耐药
Quercetin inhibits truncated isoform of dopamine- and cAMP-regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in HER2-positive breast cancer
Han-Sheng Changa,1, Tzu-Chun Chengb,1, Shih-Hsin Tuc,d,1, Chih-Hsiung Wuc,1, You-Cheng Liaoe, Jungshan Change, Min-Hsiung Panf, Li-Ching Chena,*, Yuan-Soon Hob,*
a Department of Biological Science &Technology, College of Life Sciences, China Medical University, Taichung 406, Taiwan, China
b Institute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung 406, Taiwan, China
c Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, China
d Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, China
e Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, China
f Institute of Food Sciences and Technology, National Taiwan University, Taipei 106, Taiwan, China
1 Both authors contributed equally.
*Corresponding author.
Abstract
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.
Reference:
CHANG H S, CHENG T C, TU S H, et al. Quercetin inhibits truncated isoform of dopamine- and cAMP-regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in HER2-positive breast cancer[J]. Food Science and Human Wellness, 2024, 13(5): 2653-2667. DOI:10.26599/FSHW.2022.9250213.
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