Cuproptosis: a promising new target for breast cancer therapy

Cancer Cell International Jiang et al. Cancer Cell International (2024) 24:414 https://doi.org/10.1186/s12935-024-03572-2 Open Access REVIEW Cuproptosis: a promising new target for breast cancer therapy Qianqian Jiang1†, Fei Tong3†, Yun Xu4†, Cheng Liu5 and Qiaoping Xu2* Abstract Breast cancer (BC) is the leading cause of cancer-related mortality among women globally, affecting approximately one-quarter of all female cancer patients and accounting for one-sixth of cancer-related deaths in women. Despite significant advancements in diagnostic and therapeutic approaches, breast cancer treatment remains challenging due to issues such as recurrence and metastasis. Recently, a novel form of regulated cell death, termed cuproptosis, has been identified. This process disrupts mitochondrial respiration by targeting the copper-dependent cellular pathways. The role of cuproptosis has been extensively investigated in various therapeutic contexts, including chemotherapy, immunotherapy, radiotherapy, and nanotherapy, with the development of novel drugs significantly improving clinical outcomes. This article aims to further elucidate the connection between cuproptosis and breast cancer, focusing on its therapeutic targets, signaling pathways, and potential biomarkers that could enhance treatment strategies. These insights may offer new opportunities for improved patient care and outcomes in breast cancer therapy. Keywords Cuproptosis, Breast cancer, Molecular mechanisms, Immunotherapy, Metastasis † Qianqian Jiang, Fei Tong and Yun Xu have contributed equally to this work *Correspondence: Qiaoping Xu 1 Department of Pharmacy, Traditional Chinese Medicine Hospital of Changshan, Quzhou 324200, P.R. China 2 Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Cancer Center, Afliated Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou 310006, China 3 Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China 4 Department of Pharmacy, Zhejiang Medical&Health Group Hangzhou Hospital, Hangzhou, Zhejiang 310022, China 5 Department of Pharmacy, The Secend People’s Hospital Of Jiande, Hangzhou 311604, P.R. China Introduction According to GLOBOCAN 2020 statistics, breast cancer has the highest incidence rate among all cancer types. Despite significant advancements in treatment, including the development of tailored therapies for various subtypes such as luminal A, luminal B, HER-2 overexpression, and triple-negative breast cancer (TNBC) [1], conventional treatments like radiation and chemotherapy often damage healthy cells in addition to targeting cancer cells, leading to undesirable side effects. As a result, researchers continue to seek more precise methods to selectively eliminate cancer cells. In 2022, Peter Tsvetkov and colleagues introduced the concept of “cuproptosis,” a novel form of cell death induced by copper, which is closely linked to mitochondrial respiration and the lipoic acid (LA) pathway in the human body [2]. Copper ionophores, which have long been explored for their potential antitumor properties, played a key role in the discovery of cuproptosis [3, 4]. As © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Jiang et al. Cancer Cell International (2024) 24:414 research on copper’s role in cellular processes expands, it is becoming evident that copper-based drugs and technologies interact directly with cancer cells. This review provides a concise overview of recent advances in understanding copper-induced cell death, presenting new opportunities for clinical anti-tumor therapies (Fig. 1). With the growing recognition of cuproptosis, the modulation of cell death via copper regulation is emerging as a promising strategy for breast cancer treatment, offering a strong biomedical foundation for addressing drug resistance in this disease. Copper homeostasis and Cuproptosis Copper is an essential trace element, playing crucial roles in mitochondrial respiration, immune response modulation, and the synthesis of vital biomolecules [5]. It exists in two forms within living organisms: cuprous ions (Cu+, the reduced state) and copper ions (Cu2+, the oxidized state), both of which are involved in numerous physiological processes. The regulation of copper homeostasis is achieved through a combination of copper intake, utilization, and excretion [6]. Maintaining this delicate balance is critical, as disruptions in copper homeostasis can lead to various health issues. Copper deficiency can result in genetic mutations, neurological disorders, cardiovascular complications, and metabolic disturbances. Conversely, excess copper can lead to copper toxicity, or copper poisoning [7]. To ensure the precise regulation of copper throughout the body, a sophisticated regulatory system is in place. This system relies on duodenal absorption and bile Page 2 of 18 excretion, which work together to maintain copper levels within a healthy range. Copper homeostasis is also controlled at the cellular level, where a complex network of proteins, including copper chaperones, cuproenzymes, and membrane transporters, carefully orchestrates copper regulation. These proteins ensure that copper levels remain within an optimal range, protecting the body from the harmful effects of both copper overload and deficiency, and preserving the balance essential for proper physiological functioning [8]. Correlation between copper and breast cancer Cuproptosis, a form of regulated cell death (RCD), is characterized by the direct binding of copper to fatty acylated components of the mitochondrial respiratory tricarboxylic acid (TCA) cycle, inducing protein toxic stress that ultimately leads to cell death. Key cancerrelated processes such as angiogenesis, proliferation, growth, and metastasis have been closely linked to copper ion homeostasis. Notably, elevated copper ion concentrations within cancer cells have been identified as a potential marker for cancer progression [9]. Research indicates that patients with malignant tumors exhibit higher levels (...truncated)