Tamoxifen-pretreated MSC exosomes promote endocrine resistance in ER-positive breast cancer cells through the miR-137/Serpina3 axis: a mechanistic study

BACKGROUND: Tamoxifen (TAM) resistance remains a challenge in estrogen receptor-positive breast cancer treatment. Current research suggested that mesenchymal stem cells (MSCs) derived exosomes may mediate chemoresistance, but the underlying mechanisms are unclear. This study investigates how exosomes from tamoxifen-pretreated MSCs (Tt-MSC-exos) promote tamoxifen resistance through the miR-137/SERPINA3 axis. METHODS: We isolated exosomes using ultracentrifugation. To investigate the effect of Tt-MSC-exos on TAM resistance, we co-cultured Tt-MSC-exos with ER-positive breast cancer cells and evaluated the cellular functional changes and apoptosis levels. Second-generation transcriptome sequencing was used to analyze the key genes for TAM resistance, and a dual luciferase reporter assay was used to detect the upstream factors of the key genes. The results were further validated by cellular function assays, xenograft modeling studies, and database analysis. RESULTS: We demonstrated that Tt-MSC-exos promote TAM resistance in ER-positive breast cancer cells. Next-generation sequencing revealed that the key gene for Tt-MSC-exos promoting resistance was SERPINA3. Downregulation of SERPINA3 expression enhances TAM resistance in breast cancer cells. In addition, we found that miR-137, which was highly expressed in Tt-MSC-exos, could bind to the 3' UTR region of SERPINA3 in breast cancer cells and thus inhibit the expression of SERPINA3. CONCLUSIONS: In this study, we clarified that Tt-MSC-exos inhibit the expression level of SERPINA3 in cancer cells by delivering miR-137 to ER-positive breast cancer cells, which in turn leads to TAM resistance in breast cancer. This study provides a new idea to overcome endocrine therapy resistance in ER-positive breast cancer.