Quercetin inhibits truncated isoform of dopamine- and cAMP-regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in HER2-positive breast cancer

• Published in: Food science and human wellness 2024-09, Vol.13 (5), p.2653-2667
• Main Authors: Chang, Han-Sheng, Cheng, Tzu-Chun, Tu, Shih-Hsin, Wu, Chih-Hsiung, Liao, You-Cheng, Chang, Jungshan, Pan, Min-Hsiung, Chen, Li-Ching, Ho, Yuan-Soon
• Format: Article
• Language: English
• Subjects: HER2-positive breast cancer; p95-Human epidermal growth factor receptor 2 (HER2); Quercetin; Trastuzumab resistance; Truncated isoform of dopamine- and cAMP-regulated phosphoprotein
• ISSN: 2213-4530; 2097-0765; 2213-4530
• DOI: 10.26599/FSHW.2022.9250213

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. [Display omitted] •This study confirmed that higher DARPP-32 and t-DARPP mRNA and protein levels are detected in HER2+ breast cancer tissues.•This study demonstrated that the HER2 intracellular domain (HER2-ICD, p95-HER2) detected in breast cancer cells positively correlates with t-DARPP protein expression.•This PDX mice model study demonstrated that the t-DARPP/p95-HER2 interaction is a potential diagnostic marker that could help clinicians identify patients resistant to Trastuzumab therapy (Non-responder).•This study confirmed that Quercetin attenuated Trastuzumab resistance by inhibiting the t-DARPP expression and downregulating p95-HER2 -mediated signal activation (Responder).