Breast cancer remains one of the most challenging cancers, mainly due to its heterogeneity and metastatic propensity. The Notch signaling pathway is required for multiple cellular processes and is involved in the development and progression of breast cancer. Noncoding RNAs (ncRNAs) have now become key regulators of gene expression, which can affect the biology of cancer by interacting with the Notch signaling pathway. Noncoding RNAs include microRNAs, long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs). Recently, in a review report published in the international journal Gene Expression, entitled "Non-coding RNAs Affect Breast Cancer Development Through the Notch Signaling Pathway: An Overview", researchers from Tabriz University outlined the importance of ncRNAs in human breast cancer and their potential as therapeutic targets, paving the way for the development of innovative therapies to significantly impact patient care and prognosis.
In breast cancer, ncRNAs can act as tumor suppressors or oncogenes, affecting the proliferation, invasion, and metastasis of cancer cells. The Notch signaling pathway mainly involves the interaction between Notch receptors (Notch1-4) and their ligands, which leads to the release of Notch intracellular domain (NICD). NICD can translocate to the nucleus to regulate gene expression, and aberrations in the Notch signaling pathway are often associated with multiple breast cancer subtypes. For example, Notch1, Notch3, and Notch4 are upregulated in invasive breast cancer subtypes such as triple-negative breast cancer, leading to poor prognosis for patients.
NcRNAs can affect the Notch signaling pathway through a variety of mechanisms, and miRNAs can directly target mRNAs encoding Notch receptors or ligands to regulate the activity of the pathway. LncRNAs can act as molecular sponges, sequestering miRNAs and preventing them from always targeting mRNAs, which can lead to changes in Notch signals. circRNAs can play a similar role by binding to miRNAs, thereby indirectly affecting the signaling pathway.
Figure 1. NcRNAs interfere with diverse components of the Notch signaling pathway. (Ahmadi A, et al., 2024)
MicroRNAs are small, approximately 22 nucleotide-long RNAs that help regulate gene expression post-transcriptionally. Specific miRNAs such as miR-34a and the miR-200 family are known to target components of the Notch pathway, thereby affecting breast cancer progression. These miRNAs can inhibit the expression of Notch receptors or ligands, thereby inhibiting activation of the signaling pathway and reducing tumor growth and metastasis. Long noncoding RNAs are longer transcripts that regulate gene expression at multiple levels, including chromatin modification, transcription, and post-transcriptional processing. In breast cancer, lncRNAs such as MALAT1 and HOTAIR are thought to regulate the Notch signaling pathway, either as scaffolds for the assembly of protein complexes that regulate transcription of Notch-targeted genes or through sponge miRNAs that target components of the Notch signaling pathway. Circular RNAs are a class of ncRNAs formed by backsplicing events that form covalently closed loop structures. These molecules can act as miRNA sponges, regulating the availability of miRNA-targeted mRNAs. For example, circRNA CDR1as has been shown to sequester miR-7, thereby regulating Notch signaling and affecting the proliferation and invasion of breast cancer cells.
Understanding the interaction between ncRNAs and the Notch signaling pathway may provide new insights into the diagnosis and treatment of breast cancer. NcRNAs can serve as effective biomarkers for breast cancer subtypes, prognosis, and response to therapy. Therapeutically, targeting ncRNAs or their interactions with components of the Notch signaling pathway can enhance the efficacy of current therapies and help develop new therapeutic strategies. For example, ncRNA-based therapies can be designed to restore the normal function of tumor suppressor miRNAs or inhibit oncogenic lncRNAs and circRNAs, thereby regulating the Notch signaling pathway and inhibiting tumor growth and metastasis.
NcRNAs play a critical role in regulating the Notch signaling pathway in breast cancer. By understanding these regulatory mechanisms, researchers can develop better diagnostic tools and therapeutic strategies to more effectively manage breast cancer. Continued research on the interaction between the ncRNA-Notch signaling pathway may lead to significant advances in breast cancer treatment and patient outcomes.
Reference
Ahmadi A, et al. Non-coding RNAs Affect Breast Cancer Development Through the Notch Signaling Pathway: An Overview. Gene Expression, 2024, 23(1): 44-56.