Abstract

Breast cancer (BC) ranks first among female malignant tumors and involves hormonal changes and genetic as well as environmental risk factors. In recent years, with the improvement of medical treatment, a variety of therapeutic approaches for breast cancer have emerged and have strengthened to accommodate molecular diversity. However, the primary way to improve the effective treatment of breast cancer patients is to overcome treatment resistance. Recent studies have provided insights into the mechanisms of resistance to exosome effects in BC. Exosomes are membrane-bound vesicles secreted by both healthy and malignant cells that facilitate intercellular communication. Specifically, exosomes released by tumor cells transport their contents to recipient cells, altering their properties and promoting oncogenic components, ultimately resulting in drug resistance. As important coordinators, non-coding RNAs (ncRNAs) are involved in this process and are aberrantly expressed in various human cancers. Exosome-derived ncRNAs, including microRNAs (miRNAs), long-noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as crucial components in understanding drug resistance in breast cancer. This review provides insights into the mechanism of exosome-derived ncRNAs in breast cancer drug resistance, thereby suggesting new strategies for the treatment of BC.

 Introduction

Cancer is a devastating disease that poses a significant threat to human life and health worldwide. Breast cancer (BC) is one of the most common types of cancer and continues to be the focus of intensive research [1,2,3]. Studies have shown that breast cancer is responsible for approximately 2.26 million deaths in 2020, making it the primary cause of high mortality among women [4, 5]. Breast cancer exhibits considerable morphological and molecular heterogeneity and can be categorized into several subtypes, including Luminal A, Luminal B, HER2-positive, triple-negative, and basal-like [6]. Currently, treatment options for breast cancer include surgery, radiotherapy, chemotherapy, immunotherapy, and targeted therapy [7]. Chemotherapy is one of the primary treatments for tumors and plays an important role in controlling tumor progression. Of course, long-term use of chemotherapeutic agents is often accompanied by the development of drug resistance, which further leads to treatment failure. Therefore, the mechanism of tumor drug resistance and drug resistance prevention or reversal strategies have been a hot issue in tumor therapy research. Mechanisms of drug resistance in breast cancer patients include alterations in drug transporters, changes in target molecules, and activation of survival pathways. Therefore, understanding these mechanisms of drug resistance in breast cancer is crucial for developing new treatments and improving patient outcomes.

Exosomes are small extracellular vesicles encapsulated by a lipid bilayer, ranging in size from 40 to 100 nm. Early endosomes are formed by the plasma membrane and subsequently develop into late endosomes, which can eventually give rise to multivesicular bodies (MVBs). These MVBs partly release exosomes through cytosolic exocytosis and partly fuse with lysosomes for material degradation [8,9,10]. Recent studies have highlighted the involvement of exosomes in drug resistance, demonstrating that exosomes released by drug-resistant cancer cells can induce drug resistance in other cells [11]. In breast cancer, exosomes play a crucial role in drug resistance due to their diverse cargo, which includes various types of RNA (messenger RNAs (mRNAs), microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs)), DNA, proteins, lipids, and metabolites [12,13,14]. Importantly, the levels of exosomes in the sera of breast cancer patients are often higher compared to those in healthy individuals [15, 16].

Although a significant amount of current research focuses on studying drug resistance in exosomes, the lack of a detailed systematic summary of exosome-derived RNAs in the process of resistance induction has led to unclear mechanisms of action of various drugs in the treatment of breast cancer [17, 18]. A comprehensive systematic review is necessary to elucidate further the action mechanism of the significant components of exosomes in generating drug resistance. This review covers three main areas. Firstly, it describes the mechanisms of drug resistance in breast cancer and the biogenesis and composition of exosomes. Secondly, it investigates the role of exosome-derived miRNAs, lncRNAs, and circRNAs in breast cancer drug resistance. Thirdly, it delves into the role of exosome-derived ncRNAs in breast cancer cross-resistance. Finally, it provides a comprehensive summary that highlights the significance of exosome-derived ncRNAs in addressing chemotherapy resistance in breast cancer treatment. In conclusion, this review highlights the critical role of exosome-derived ncRNAs in the development of drug resistance in breast cancer. Additionally, it underscores the significance of further research in enhancing cancer treatment outcomes. This will offer up-to-date insights and theoretical guidance for the studying drug resistance in breast cancer.

2 Mechanisms of drug resistance in breast cancer

Chemotherapy has always played an important role in the comprehensive treatment of breast cancer. The main chemotherapeutic agents currently approved are tamoxifen, doxorubicin, trastuzumab, paclitaxel and cisplatin, among others. Initially breast cancer is sensitive to chemotherapy, however, over time, breast cancer cells can employ a variety of mechanisms to develop resistance [19]. These mechanisms mainly include drug efflux and inactivation, activation of bypass signaling or survival pathways, induction of epithelial-mesenchymal transition (EMT) and stem cell-like properties [7]. Breast cancer resistance protein (BCRP or ABCG2) is involved in cancer multidrug resistance and transports anticancer drugs out of cells [20]. Alterations in the estrogen receptor pathway (e. g., ESR1 mutations) or upstream growth factor signaling pathways (e. g., PI3K/Akt/mTOR pathway) can cause drug resistance in breast cancer patients [21]. Activation of EMT can also induce breast cancer cells to acquire resistance to chemotherapy [22]. A very small number of drug-resistant cells are present in breast cancer, and this population exhibits stem cell-like properties and high tumorigenic potential

Conclusion

In conclusion, exosomes derived from breast cancer contain various ncRNAs, including miRNAs, lncRNAs, and circRNAs. Abnormal regulation of these ncRNAs has been linked to breast cancer progression, with the promotion of tumor cell proliferation, invasion, metastasis, and cachexia. This review aims to elucidate the mechanisms by which exosome-derived ncRNAs contribute to chemoresistance in cancer cells. Drug resistance poses a significant challenge in the treatment of breast cancer, and its underlying mechanisms are complex. Exosomes, which contain ncRNAs, serve as essential mediators of intercellular communication and play a vital role in breast cancer progression. A growing body of research has linked an increasing number of ncRNAs to drug resistance in breast cancer. Tumor cells release exosomes containing specific miRNAs, lncRNAs, and circRNAs, which are then transported to adjacent or distant non-resistant receptors. This transfer of exosomes enables previously drug-sensitive cells to acquire drug resistance, highlighting the importance of identifying their contents and transfer between cells. Consequently, the insights gained from this study can aid in the development of a theoretical framework and potential therapeutic targets for overcoming cancer drug resistance in a clinical setting.