Harnessing the potential of long non-coding RNAs in breast cancer: from etiology to treatment resistance and clinical applications

Abstract

Breast cancer (BC) is the most common malignancy among women and a leading cause of cancer-related deaths of females worldwide. It is a complex and molecularly heterogeneous disease, with various subtypes that require different treatment strategies. Despite advances in high-resolution single-cell and multinomial technologies, distant metastasis and therapeutic resistance remain major challenges for BC treatment. Long non-coding RNAs (lncRNAs) are non-coding RNAs with more than 200 nucleotides in length. They act as competing endogenous RNAs (ceRNAs) to regulate post-transcriptional gene stability and modulate protein-protein, protein-DNA, and protein-RNA interactions to regulate various biological processes. Emerging evidence suggests that lncRNAs play essential roles in human cancers, including BC. In this review, we focus on the roles and mechanisms of lncRNAs in BC progression, metastasis, and treatment resistance, and discuss their potential value as therapeutic targets. Specifically, we summarize how lncRNAs are involved in the initiation and progression of BC, as well as their roles in metastasis and the development of therapeutic resistance. We also recapitulate the potential of lncRNAs as diagnostic biomarkers and discuss their potential use in personalized medicine. Finally, we provide lncRNA-based strategies to promote the prognosis of breast cancer patients in clinical settings, including the development of novel lncRNA-targeted therapies.

Keywords: breast cancer; competitive endogenous RNA (ceRNA); liquid biopsy; long non-coding RNA (LncRNA); metastasis; therapy resistance.

Figure 1

An overview of human breast cancer subtypes. This figure illustrates the various subtypes of breast cancer, with the approximate proportion (%) of each subtype among all breast cancer cases provided in brackets. Prognosis severity increases from top to bottom, signifying that the subtypes at the bottom are associated with worse prognoses. The figure was created in BioRender.com.

Figure 2

Comprehensive regulatory network of lncRNAs in breast cancer cells. Within the cellular environment, a complex regulatory network involving lncRNAs, their target genes, miRNAs, and interacting proteins is established. This network encompasses diverse signaling pathways, including Wnt/β-catenin, PI3K/AKT, and MAPK/ERK, coordinating various biological processes such as EMT, autophagy, the Warburg effect, oxidative phosphorylation, cell cycle arrest, angiogenesis, and treatment response in breast cancer patients. The lncRNA-miRNA-mRNA axis and ceRNA networks play pivotal roles in modulating gene expression during cancer development and progression, offering potential targets for therapeutic interventions and biomarker discovery. All lncRNAs are colored in red. “-” represents oncogene; “+” represents tumor suppressor; “┴“ represents inhibition; “↑” represents promotion. The figure was created in BioRender.com.

Figure 3

Role of circulating lncRNAs as potential biomarkers in breast cancer. Long non-coding RNAs (lncRNAs) have demonstrated potential as biomarkers in various aspects of breast cancer, including diagnosis, prognosis, subtype classification, and treatment response. Utilizing a combination of multiple lncRNAs may offer a viable strategy for leveraging lncRNA-based biomarkers in clinical applications. The figure was generated using BioRender.com.