Starving Cancer: How Glucose Restriction Enhances Tamoxifen sensitivity in Breast Cancer

Abstract Background: Breast cancer cells rewire their metabolism to thrive on high glucose, and elevated blood sugar is linked to therapy resistance. We investigated whether glucose restriction can reprogram breast cancer cell behavior and enhance the efficacy of tamoxifen, a cornerstone endocrine therapy. Methods: Using estrogen receptor-positive MCF7 cells, we integrated gene expression profiling with protein–protein interaction and gene regulatory network analyses under three conditions: low-glucose (metabolic starvation), tamoxifen treatment, and their combination. Results: Glucose starvation alone triggered a broad transcriptional reprogramming (697 differentially expressed genes, DEGs) involving cell-cycle regulation and chromatin remodeling, while tamoxifen alone altered a smaller gene set (201 DEGs) linked to proliferation and apoptotic pathways. Strikingly, combined glucose restriction and tamoxifen induced a massive gene expression shift (1,294 DEGs), far exceeding either treatment alone and indicating a synergistic anti-cancer response. Network analysis revealed distinct but overlapping molecular networks: starvation preferentially upregulated DNA replication and mitotic cell-cycle modules, tamoxifen enriched for pathways suppressing cell proliferation and protein synthesis, and the combination uniquely engaged cell division and chromatin-organization networks. We identified six hub proteins and 44 genes consistently regulated across all conditions, pointing to a core stress-response program. Transcription factor analysis further uncovered 54 key regulators common to all treatments and an expanded set of master regulators (12 differentially expressed transcription factors) activated only under combined treatment, underscoring novel gene regulatory interactions behind the enhanced response. Conclusion: Our findings reveal new molecular insights into how glucose deprivation potentiates tamoxifen’s anti-tumor effects. This study underscores the interplay between cancer metabolism and hormone therapy, suggesting that targeting metabolic vulnerabilities can amplify treatment efficacy and offering a robust gene-network framework for advancing breast cancer metabolism research.