MiR-301a-3p Promotes Triple-Negative Breast Cancer Progression via PTEN Suppression in Tumor Cells and the Microenvironment

Abstract

Background: Triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype, poses a severe threat to women’s health. Adipose-derived stem cells (ADSCs) and microRNAs (miRNAs) critically influence tumor progression within the tumor microenvironment (TME), but the role of the miR-301a-3p/PTEN axis in TNBC requires elucidation.

Methods: PTEN expression and effects were assessed by comparing clinical TNBC tissues with adjacent normal tissues. Mechanisms were investigated using integrated dataset analysis, luciferase reporter assays, functional cell experiments (assessing malignant phenotypes), co-culture models with ADSCs, and in vivo tumor models. Molecular expression (PTEN, vascular endothelial growth factor A (VEGFA)) and pathway activity (phosphoinositide 3-kinase (PI3K)/AKT) were evaluated.

Results: MiR-301a-3p was upregulated in TNBC and directly bound PTEN’s 3'-UTR to suppress its expression. Functionally, miR-301a-3p enhanced tumor cell malignancy. Tumor cell-derived exosomes transported miR-301a-3p to ADSCs in the TME, suppressing PTEN, activating the PI3K/AKT pathway, and upregulating VEGFA secretion. In vivo, modulating miR-301a-3p levels significantly altered tumor growth, PTEN expression, and VEGFA production in tumor and peritumoral tissues.

Conclusion: MiR-301a-3p drives TNBC progression via exosome-mediated crosstalk with ADSCs, forming a PTEN/PI3K/AKT/VEGFA signaling axis. It represents a promising therapeutic target and novel biomarker with significant clinical value for TNBC treatment.