MicroRNA cluster 7/17/155 as a potential driver for high-grade breast tumors transformation through EGFR-associated...

Breast tumor dedifferentiation and progression onto high-grade states with stem-like fea-tures are governed by complex regulatory networks within the tumor microenvironment. This study aimed to identify a potential microRNA (miRNA) cluster associated with breast tumor stemness and in-vestigate its regulatory functions inspired by mammary gland development (MGD).

We reana-lyzed microarray data and identified differentially expressed mRNAs and miRNAs in breast cancer of various grades. High-throughput transcriptomic datasets were incorporated to strengthen the discovery framework. Spatial mRNA-miRNA interactions in each breast cancer grade were identified, and a series of q-PCR, immunohistochemical analysis of epidermal growth factor receptor (EGFR) expression, and Single-cell RNA sequencing were used to validate findings.

MGD-related regulatory mecha-nisms correlated with well- and moderately-differentiated tumors but were absent in high-grade tumors. miRNAs 7, 17, and 155 were significantly upregulated in undifferentiated high-grade tumors. These tu-mors also showed marked activation of EGFR-mediated epithelial-mesenchymal transition (EMT) and elevated histological EGFR levels. scRNA-seq revealed a stem cell-like and undifferentiated cellular pop-ulation characterized by miRNAs 7, 17, and 155, as well as EGFR-associated EMT activation. Pseudotemporal trajectory analysis indicated this cluster as a potential origin of malignant breast tumor heterogeneity and stemness.

The miRNA cluster 7/17/155 may act as a potential driver of breast tumor dedifferentiation and acquisition of stem-like properties via EGFR-mediated EMT. This cluster represents a promising target for therapies to reverse tumor dedifferentiation and a biomarker for molecular classification of breast tumor differentiation status.