Comparative analysis of cytotoxicity, apoptosis, and tumor-progression gene expressions in MCF-7 breast cancer cells treated with Ribociclib, Everolimus, and Doxorubicin: An integrative bioinformatics and experimental study.

Abstract

BACKGROUND: Targeted therapy with small-molecule inhibitors (SMIs) is the standard of care for estrogen receptor-positive breast cancer (ER+ BC). While targets for SMIs are known, cellular responses remain unclear. This study compares the effects of the CDK4/6 inhibitor ribociclib (Rib) and the mTOR inhibitor everolimus (Eve) to the anthracycline chemotherapeutic doxorubicin (Dox) in the MCF-7 BC cell line. METHODS AND RESULTS: The expression, prognostic value, and immune infiltration correlates of Programmed death-ligand 1 (PD-L1), Matrix metalloproteinase-9 (MMP-9), Transforming growth factor-β (TGF-β) and Vascular endothelial growth factor A (VEGF-A) in luminal BC were assessed using UALCAN, KM-Plotter and TIMER2.0. MCF-7 cells were treated with Rib, Eve, and Dox. Half-maximal inhibitory concentrations (IC50) were determined using MTT assay. Apoptosis was analyzed by flow cytometry, and mRNA expression was measured by Real-Time PCR. Target genes were differentially expressed across BC subtypes; high MMP-9 and VEGF-A expression predicted poorer survival; PD-L1, MMP-9, and TGF-β were correlated with immune infiltration. The IC50 values were 11.95 µM, 36.34 µM and 1.396 µM for Rib, Eve, and Dox, respectively. At IC50 concentrations, the percentage of apoptotic cells was significantly higher with Dox. Dox significantly upregulated PD-L1, VEGF-A, and MMP-9. Rib upregulated PD-L1 and induced non-significant increases in VEGF-A and MMP-9, while Eve slightly decreased MMP-9. TGF-β levels remained constant, with increases under Dox and Eve. CONCLUSION: Cytostatic SMIs preserved a more favorable molecular profile, whereas Dox, despite potent cytotoxicity, paradoxically induced a tumor-progression phenotype in residual cells. Rib-induced PD-L1 overexpression suggests a mechanism of adaptive immune resistance.

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