LRRC32 Mediates Resistance to Everolimus in Hormone Receptor-Positive, HER2-Negative Breast Cancer

Abstract

Aim Everolimus is approved for hormone receptor-positive, HER2-negative breast cancer, but resistance mechanisms remain incompletely understood. This study aimed to investigate the functional role of LRRC32 in mediating Everolimus resistance using patient-derived organoid (PDO) models of this breast cancer subtype. Materials and Methods Everolimus-resistant and sensitive breast cancer organoids were established from patient-derived tumor tissues. RNA sequencing was performed to compare expression profiles. In vitro functional assays were conducted, including LRRC32 overexpression and shRNA-mediated knockdown, MTT cell viability assay, flow cytometric apoptosis detection, and flow cytometric cell cycle analysis. Results RNA sequencing identified significant LRRC32 upregulation in resistant cells with a fold change of 180.46 (p < 0.001). LRRC32 overexpression reduced apoptosis and enhanced cell survival, whereas knockdown increased apoptosis. Cell cycle analysis showed that LRRC32 knockdown in resistant cells significantly increased the G1-phase fraction, hindering G0/G1-to-S transition. Conclusion Our findings suggest that LRRC32 plays a pivotal role in modulating the sensitivity of breast cancer cells to Everolimus.