The Role of Hexosamine Flux-Driven HIF-1α Overexpression in Insulin Resistance in Women with Breast Cancer

Breast cancer (BC) imposes a tremendous global health burden. In 2022, approximately 2.3 million women were diagnosed with BC, resulting in 685,000 deaths worldwide (IARC, 2024). Female gender is the primary risk factor for BC, accounting for over 99% of all cases compared to less than 1% in men. Ovarian hormones (estrogen and progesterone), along with adipose tissue signaling in obesity, play critical roles in BC etiology (IARC, 2024; Marshall et al., 1991). Breast cancer remains the most frequently diagnosed malignancy and a leading cause of cancer-related morbidity and mortality worldwide, presenting a profound public health and financial challenge. By integrating multi-omics data (genomics, transcriptomics, proteomics, and metabolomics), recent studies have established a strong bidirectional association between BC and metabolic syndrome (MetS), a clinical cluster defined by hyperglycemia, hypertension, hypertriglyceridemia, and central obesity. Warburg originally hypothesized that cancer cells import excessive glucose to undergo aerobic glycolysis, prioritizing it over mitochondrial oxidative phosphorylation even under normoxic conditions (Warburg effect). Cancer cells obtain nutrients and energy by hijacking physiological metabolic pathways, reprogramming their internal metabolism to fuel rapid proliferation via the hexosamine biosynthetic pathway (HBP). Enhanced hexosamine flux, driven by increased glutamine-fructose-6-phosphate transaminase 1 (GFAT1 / GFPT1) expression and hypoxia-inducible factor 1-alpha (HIF-1α) activation within the hypoxic tumor microenvironment (TME), promotes proteasomal degradation of insulin receptor substrate 1 (IRS1), thereby precipitating cellular insulin resistance (Akella et al., 2019; Ferrer et al., 2014; Buse, 2006). This study investigates dysregulation of canonical insulin signaling cascades, specifically IRS1, PI3K/Akt, and GLUT4 (encoded by SLC2A4), which drive insulin resistance, hyperinsulinemia, and increased insulin-like growth factor 1 (IGF-1) receptor signaling (Biello et al., 2021). We evaluated gene expression profiles in MCF-10A (a non-tumorigenic human mammary epithelial cell line) and MCF-7 (an estrogen receptor-positive human breast cancer cell line). Target genes included key adipokines/myokines: adiponectin (ADIPOQ), retinol-binding protein 4 (RBP4), chemerin (RARRES2), adipocyte fatty acid-binding protein (FABP4), and fibroblast growth factor 21 (FGF21), alongside metabolic regulators (IRS1, SLC2A4, SLC2A1 [GLUT1], and GFPT1). RNA was extracted and performed sequencing using Nanopore technology. Differential expression analysis (edgeR) and functional enrichment (GO/KEGG) revealed that ADIPOQ, SLC2A4, RBP4, and IRS1 were significantly downregulated in MCF-7 cells compared to MCF-10A cells, whereas SLC2A1, GFPT1, and FABP4 were significantly upregulated in MCF-7 cells. These findings indicate that hyperactive hexosamine flux (driven by GFPT1) and a shift in the GLUT1/GLUT4 expression ratio serve as critical drivers of cellular insulin resistance and metabolic rewiring in breast cancer. It is recommend targeting HBP and insulin signaling components to reverse metabolic drug resistance and improve therapeutic outcomes in breast cancer.