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  • Network-Pathway Integration Reveals Synergy Targets for Combination Therapy in Breast Cancer

  • Fatemeh Shams,1 Elina Khannehzar,2 Amirsajad jafari,3,*
    1. Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
    2. Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
    3. Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran


  • Introduction: Single-pathway therapies struggle against the modular, compensatory architecture of breast cancer. We integrated saffron bioactive targets, validated miRNA regulation, and pathway enrichment to nominate combination strategies that collapse survival and metastatic circuits simultaneously. Significance: An integrated miRNA-gene network (18 miRNAs; 68 genes) concentrates control in a small set of hubs and pathways (apoptosis, migration/angiogenesis, xenobiotic transport, metabolic/pH control), enabling precise, orally presentable synergy hypotheses that align with druggable nodes.
  • Methods: We assembled validated human miRNA→gene interactions for an 18-miRNA panel intersecting saffron targets and breast-cancer miRNAs, restricted edges to the saffron target union, and analyzed topology in Cytoscape. Over-representation analysis (on target genes) produced GO and pathway enrichments. We then mapped druggable nodes within enriched terms and cross-referenced them with the 14-gene intersection subset to prioritize combination points.
  • Results: Ten miRNAs formed the network’s control spine (high degree), led by the miR-15/16 family (miR-16-5p, miR-15a-5p, miR-15b-5p, miR-195-5p, miR-424-5p, miR-497-5p) and complemented by miR-18a-5p, miR-155-5p, miR-9-5p, miR-146b-5p. Enrichment analysis yielded a four-axis intervention map: 1. Apoptosis (intrinsic/BCL2 axis). Over-representation of the BAD–BCL2 complex and checkpoint regulators indicates that enforcing pro-apoptotic bias—via the miR-15/16 family and BCL2-family targeting—should amplify tumor cell kill. 2. Migration/EMT/angiogenesis. Significant enrichment for positive regulation of cell migration/locomotion points to EMT and pro-angiogenic circuits under hub-miRNA control (miR-9-5p, miR-18a-5p), with FGF2, cytoskeletal, and adhesion genes populating the leading edge. 3. Xenobiotic response/drug transport. Enrichment of ABCB1/ABCG2/ABCC1 suggests a route to resensitize chemotherapy by convergently modulating efflux and oxidative buffering. 4. Metabolism and pH homeostasis. Over-representation of one-carbon metabolism and pH regulation (carbonic-anhydrase and ion-transport nodes) proposes a metabolic flank to undermine adaptation. The 14-gene intersection set sits at the crossroads of these axes, providing a compact panel for experimental prioritization (e.g., BCL2/BCL-xL, FGF2, ABCB1, MYLK, ADORA3). Notably, ADORA3 was under multi-miRNA control across hubs, aligning with inflammation/adenosine signaling and microenvironmental crosstalk. Discussion/Impact From this map, three combination archetypes emerge: Apoptosis-first: Pair DNA-damage or BCL2-axis therapies with interventions that restore miR-15/16 family function (or mimic their effects) and add saffron bioactives to further tip the balance toward death (shared convergence on BCL2-family and checkpoints). Anti-metastatic overlay: Combine an EMT/migration brake (targeting miR-9/miR-18a pathways and FGF/adhesion genes) with apoptosis-inducing therapy; saffron contributes by dampening invasion-linked targets already present in the network. Resistance-breaking flank: Co-target xenobiotic transport and oxidative stress (ABCs/redox) to lower effective chemotherapy doses; saffron’s network footprint overlaps these nodes, offering a tolerable way to weaken drug-efflux circuits. Because the network is compact and the enriched terms are high-confidence with broad miRNA coverage, these strategies are experiment-ready: each can be tested by measuring apoptosis (BCL2 axis), migration/EMT markers (VIM, E-cadherin), and efflux activity (ABCB1) under combination conditions. The same architecture suggests patient-level personalization: tumors with high oncomiR (miR-9/miR-18a/miR-155) signatures may benefit most from combinations that add saffron bioactives to blunt these circuits while standard therapy targets proliferation.
  • Conclusion: Integrating miRNA regulation with saffron target genes reveals actionable synergy points spanning apoptosis, invasion, drug resistance, and metabolism/pH control. The data support kaempferol/crocin-anchored adjuvant strategies layered onto standard therapies, with hub-miRNA–aware design to collapse compensatory pathways. This network-pathway framework is concise, mechanistically transparent, and primed for oral presentation and experimental follow-up.
  • Keywords: network synergy; microRNA-gene integration; saffron adjuvant; apoptosis–EMT axis; drug resistance

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