Cuproptosis-related genes predict prognosis and trastuzumab therapeutic response in HER2-positive breast cancer

www.nature.com/scientificreports OPEN Cuproptosis‑related genes predict prognosis and trastuzumab therapeutic response in HER2‑positive breast cancer Rui Sha 1,8, Xinrui Dong 2,8, Shanshan Yan 3,8, Huijuan Dai 4, Liuxia You 5*, Zongjin Guo 6* & Aijun Sun 7* Breast cancer is the most common diagnosed cancer, the HER2-positive subtype account for 15% of all breast cancer. HER2-targeted therapy is the mainstay treatment for HER2-positive breast cancer. Cuproptosis is a novel form of programmed cell death, and is caused by mitochondrial lipoylation and destabilization of iron-sulfur proteins triggered by copper, which was considered as a key player in various biological processes. However, the roles of cuproptosis-related genes in HER2-positive breast cancer remain largely unknown. In the present study, we constructed a prognostic prediction model of HER2-positive breast cancer patients using TCGA database. Dysregulated genes for cells resistant to HER2-targeted therapy were analyzed in the GEO dataset. KEGG pathway, GO enrichment and GSEA was performed respectively. The immune landscape of DLAT was analyzed by CIBERSORT algorithm and TIDE algorithm. HER2-positive breast cancer patients with high CRGs risk score showed shorter OS. DLAT was downregulated and correlated with better survival of HER2-positive breast cancer patients (HR = 3.30, p = 0.022). High expressed DLAT was associated with resistant to HER2-targeted therapy. Knocking down DLAT with siRNA increased sensitivity of breast cancer to trastuzumab. KEGG pathway and GO enrichment of DEGs indicated that DLAT participates in various pathways correlated with organelle fission, chromosome segregation, nuclear division, hormone-mediated signaling pathway, regulation of intracellular estrogen receptor signaling pathway, condensed chromosome and PPAR signaling pathway. There was a negative correlation between TIDE and DLAT expression (r = − 0.292, p < 0.001), which means high DLAT expression is an indicator of sensitivity to immunotherapy. In conclusion, our study constructed a four CRGs signature prognostic prediction model and identified DLAT as an independent prognostic factor and associated with resistant to HER2-targeted therapy for HER2-positive breast cancer patients. Breast cancer (BC) has become the most frequently diagnosed cancer, and it is also the leading cause of cancerrelated death in women worldwide1,2. BC can be divided into four conventional subtypes, Luminal A, Luminal B, human epidermal growth factor 2 (HER2) positive and triple negative breast cancer (TNBC)3. Endocrine therapy is used for individuals with hormone receptor positive disease, chemotherapy is the primary treatment option for TNBC, and HER2-targeted therapy is utilized for patients whose tumors overexpress H ER24,5. About 15% of patients developed HER2-positive BC, which was characterized by a high recurrence rates, aggressive phenotype, and poor survival outcomes6,7. The monoclonal antibody trastuzumab significantly 1 Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), 2 Zheshan West Road, Wuhu 241001, Anhui, China. 2Department of Breast Surgery, The First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu, China. 3Center for Medical Ultrasound, Suzhou Municipal Hospital, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou 215000, Jiangsu, China. 4Renji Hospital, School of Medicine, Shanghai Jiaotong University, 1630 Dongfang Road, Shanghai 200127, China. 5Department of Clinical Laboratory, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian, China. 6Department of Interventional Radiology, The University of HongKong-Shenzhen Hospital, Shenzhen 518053, China. 7Department of Thyroid and Breast Oncological Surgery, Xuzhou Medical College Affiliated Huaian Hospital, 62 Huaihai South Road, Huaian 223001, Jiangsu, China. 8These authors contributed equally: Rui Sha, Xinrui Dong and Shanshan Yan. *email: ; ; Scientific Reports | (2024) 14:2908 | https://doi.org/10.1038/s41598-024-52638-8 1 Vol.:(0123456789) www.nature.com/scientificreports/ improves the prognosis of HER2-positive individuals8–10. Over the past 20 years, significant progress has been achieved in the treatment of HER2-positive BC, and the U.S. Food and Drug Administration (FDA) has approved 7 kinds of HER2-targeted therapies for the treatment of early and/or advanced d isease11. These treatment advances have converted into higher cure rates for early-stage disease, as well as significantly longer progression free survival (PFS) and overall survival (OS) in metastatic p atients12. Despite these advances, HER2-positive metastatic BC remains an almost invariably fatal disease, and the efficacy of a single HER2-targeted therapy is transient, particularly for patients who relapse after neoadjuvant therapy containing monoclonal antibody, with median PFS of approximately 1 year and less than 1 year in the first and second lines, r espectively13. While primary resistance to HER2-targeted therapy is possible, most treatment failures stem from acquired resistance to cell subclones gradually selected over the course of treatment. Primary or secondary resistance to HER2-targeted therapy, however, remains a vexing p roblem11,14. In fact, BC is a heterogeneous disease with distinct molecular features, biological characteristics and clinical outcomes15,16. In this context, treatments that can induce other forms of regulated cell death (RCD), including apoptosis, ferroptosis, pyroptosis, necroptosis, have emerged as potential strategies to treat drug-resistant BC and improve s urvival17,18. Cuproptosis is a recently identified RCD, which is a process occurs via direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle19. The intracellular copper concentration is controlled by copper importers SCL31A1 and copper exporters ATP7A and ATP7B. In addition, serum copper concentrations in BC patients are higher than that in healthy controls and patients with benign breast disease, suggesting that elevated serum copper levels may be associated with an increased risk of BC20. In many other kinds of cancers, like lung cancer21, colorectal c ancer22, thyroid cancer23 and prostate cancer24, copper concentrations are also higher than in healthy people. There is increasing evidence suggest that copper as involved in cancer development and spreading (epithelial to mesenchymal transition, angiogenesis), and the responsiveness of many copper complexes to cancer cells has been studied over the past four decades, many of which may become drug options for cancer t reatment25. There are 14 cuproptosis-related genes (CRGs) so far. Since the concept of cuproptosis was proposed, CRGs have been considered valuable in predicting prognosis and immune infiltration in patients with BC26–28. However, the (...truncated)