TARGETING BREAST CANCER COMPLEXITY: MOLECULAR SIGNALLING, MICROENVIRONMENT AND NEXT-GENERATION THERAPEUTIC STRATEGIES

Abstract

Breast cancer is a leading global health concern characterized by molecular heterogeneity and complex pathogenesis, fueled by intricate signaling pathways that trigger its genesis, progression and therapeutic resistance. This assessment delves into the elucidation of intricate molecular pathways navigating oncogenic cascades, including hormone receptor signaling driven by estrogen and progesterone, HER2-mediated cascades, PI3K/AKT/mTOR, RAS/MAPK, Wnt/β-catenin, JAK/STAT and Notch signaling pathways, alongside their influence on tumor behavior through interplay with metabolic reprogramming notably the Warburg effect and epigenetic modifications, including DNA methylation and histone alterations. The tumor microenvironment, comprising anti-inflammatory macrophages, tumor-infiltrating lymphocytes, cancer-associated fibroblasts and the extracellular matrix, further governs immune evasion, angiogenesis and metastasis. This review underscores advancements in therapies targeting these pathways, including endocrine therapies (selective estrogen receptor modulators, aromatase inhibitors, selective estrogen receptor degraders), immune checkpoint inhibitors (pembrolizumab, atezolizumab), HER2-targeted agents (trastuzumab, T-DXd), CDK4/6 inhibitors (palbociclib, ribociclib) and PARP inhibitors (olaparib, talazoparib). It also emphasizes emerging cutting-edge strategies, such as antibody-drug conjugates, PROTACs and RNA-based therapies (siRNAs, antisense oligonucleotides) to overcome drug resistance and enhance personalized therapies. Despite significant advancements, challenges such as tumor heterogeneity, pathway crosstalk, clonal evolution, immune suppression and acquired resistance reinforce the need for biomarker-driven combination therapies. By integrating multi-omics and AI-driven technologies into drug development, future treatment prospects aim to achieve personalized, durable and sustained responses to improve patient outcomes.