The role of genetics and epigenetics in breast cancer: A comprehensive review of metastasis, risk factors, and future perspectives

This literature review investigates the mechanisms of resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapies in HER2⁺ breast cancer, a subtype that accounts for approximately 20% of breast cancer cases. Despite the effectiveness of treatments such as trastuzumab and lapatinib, many patients experience either primary or acquired resistance, leading to treatment failure. The review systematically categorizes various resistance mechanisms, including the role of receptor activator of nuclear factor kappaΒ (RANK) expression, which has been shown to activate the nuclear factor kappaB (NF-κB) pathway, promoting cell survival and contributing to resistance. Other mechanisms include the activation of alternative signaling pathways, such as the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway, and the involvement of tumor-associated fibroblasts, which can drive resistance through receptor tyrosine kinase (RTK) activation. Additionally, the review highlights the importance of understanding these mechanisms to inform the development of novel therapeutic strategies. By identifying potential biomarkers and therapeutic targets, the review suggests that combining HER2 inhibitors with agents that target resistance pathways may enhance treatment efficacy and improve patient outcomes. Overall, this review underscores the complexity of HER2⁺ breast cancer treatment and the need for continued research to overcome resistance challenges.