S4 Induces Apoptosis, Cell Cycle Arrest, and Metabolic Alterations in Breast Cancer Cells.

INTRODUCTION Breast cancer (BC) remains a primary driver of cancer-related mortality globally, necessitating the identification of novel molecular targets. While androgen receptor (AR) signaling is a recognized modulator of breast oncology, the therapeutic efficacy of selective androgen receptor modulators (SARMs), particularly S4 (Andarine), remains poorly characterized in this context.

Methods

The anti-cancer activity of S4 was investigated across Estrogen Receptor-positive (MCF-7) and Triple- Negative (MDA-MB-231) models. Cellular viability, clonogenicity, and migratory capacity were assessed, alongside flow cytometric analysis of apoptosis and cell cycle distribution. Mechanistic insights were derived from quantitative gene expression profiling and untargeted LC-MS-based metabolomics.

Results

S4 treatment induced a significant, dose-dependent reduction in cellular viability, suppressed clonogenicity and migration, and promoted apoptosis and cell cycle arrest, with MCF-7 cells exhibiting S-phase arrest and MDA-MB-231 cells exhibiting G0/G1-S arrest. Gene expression analysis revealed modulation of genes associated with apoptosis, stress response, and cell-cycle regulation, supporting the anti-cancer effects of S4. Metabolomic analysis further demonstrated that S4 exposure leads to marked remodeling of metabolic pathways associated with amino acid turnover, nucleotide homeostasis, lipid metabolism, and cofactor utilization.

Discussion

These alterations point to a coordinated yet context-dependent metabolic response, characterized by shared core changes alongside distinct subtype-specific adaptations. Our findings suggest that S4 treatment is associated with significant alterations in breast cancer growth and metabolic pathways.

Conclusion

The subtype-specific metabolic rewiring suggests that S4 exploits unique metabolic vulnerabilities, supporting further investigation of SARMs in breast cancer models.