Dysregulated Stem Cell Markers Musashi-1 and Musashi-2 are Associated with Resistance in Breast Cancer

Background and aim. While preliminary evidence points to pro-tumorigenic roles for the Musashi (MSI) RNA-binding proteins Musashi-1 (MSI1) and Musashi-2 (MSI2) in some breast cancer subtypes, no data exist for inflammatory breast cancer (IBC). Methods. MSI gene expression was quantified in IBC SUM149PT cells. We then used small interfering RNA-based MSI1 and MSI2 double knockdown (DKD) to understand gene expression and functional changes upon MSI depletion. We characterized cancer stem cell characteristics, cell apoptosis and cell cycle progression via flow cytometry, mammospheres via spheroid assays, migration and proliferation via digital holographic microscopy, and cell viability using BrdU assays. Chemoresistance was determined for paclitaxel and cisplatin with MTT assays and radioresistance was assessed with clonogenic analyses. In parallel, we supported our in vitro data by analyzing publicly available patient IBC gene expression datasets.Results. MSI1 and MSI2 are upregulated in breast cancer generally and IBC specifically. MSI2 is more commonly expressed compared to MSI1. MSI DKD attenuated proliferation, cell cycle progression, migration, and cell viability while increasing apoptosis. Stem cell characteristics CD44( +)/CD24(-), TERT and Oct4 were associated with MSI expression in vivo and were decreased in vitro after MSI DKD as was ALDH expression and mammosphere formation. In vivo , chemoresistant tumors were characterized by MSI upregulation upon chemotherapy application. In vitro , MSI DKD was able to alleviate chemo-and radioresistance.Conclusions. The Musashi RNA binding proteins are dysregulated in IBC and associated with tumor proliferation, cancer stem cell phenotype, chemo-and radioresistance. MSI downregulation alleviates therapy resistance and attenuates tumor proliferation in vitro .& COPY; 2023 Instituto Mexicano del Seguro Social (IMSS). Published by Elsevier Inc. All rights reserved.

Automated summary

This study reveals the crucial role of Musashi RNA-binding proteins in inflammatory breast cancer, as they are associated with tumor proliferation, cancer stem cell characteristics, and therapy resistance. Inhibiting the expression of MSI genes can alleviate drug resistance and tumor growth.