Introduction:

Breast cancer (BC) is highly heterogeneous, with varying molecular characteristics. Autophagy, a critical cellular degradation process, helps cells survive under stress, but its regulation can be influenced by altered microRNA (miRNA) expression. Studying miRNA changes during starvation-induced autophagy in both mammary epithelial cells and BC cells could reveal potential molecular targets.

Methods:

BC cell lines and rat mammary epithelial cells were subjected to starvation using Earle’s Balanced Salt Solution (EBSS) or treated with cell medium (CM). The STRING database identified proteins related to autophagy and starvation, which were cross-referenced with known miRNA interactions. Total RNA from both CM- and EBSS-treated cells was analyzed for miRNA expression changes and validated using the TCGA dataset.

Results:

Starvation induced autophagy, reduced cell proliferation in all cell types, and increased the invasive capacity of BC cells. We identified a miRNA signature related to starvation, comprising 27 miRNAs. Six miRNAs had elevated baseline expression, while another six, including miR-218a-5p, were reduced in BC cells compared to healthy cells. Starvation caused significant miRNA dysregulation, with miR-218a-5p being notably affected. Bioinformatic analysis showed that although miR-218a-5p is less expressed in primary BC tissues compared to normal tissues, its expression increases with advanced N status and is higher in metaplastic BC.

Conclusion:

The response to starvation varies between rat BC cells and normal cells. Baseline miRNA expression related to starvation and autophagy differs between breast cancer and healthy cells. Starvation induces BC-specific miRNA dysregulation, particularly affecting miR-218a-5p, which could have therapeutic implications through autophagy modulation.

This research was funded by the Medical University of Warsaw (69/M/MG/N/23) and the Polish Ministry of Science and Higher Education (SKN/SP/569610/2023).