Neamah Abbas S, Lafta Fadhel M, Wadan Al-Hassan Soliman
Department of Biology College of Sciences, University of Baghdad, Baghdad, Iraq.
Oral Biology Department, Faculty of Dentistry, Galala University (15888), Suez, Egypt.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Aug 20. doi: 10.1007/s00210-025-04487-z.
Breast cancer remains a leading cause of cancer-related morbidity in women worldwide, with hormone receptor-positive (HR +) subtypes comprising approximately 70% of cases. Despite advances in endocrine therapies, the development of hormone resistance poses a major challenge, often leading to treatment failure and disease progression. This review addresses the central problem of resistance in HR + breast cancer (HR + BC), focusing on key mechanisms such as mutations in the estrogen receptor (ER), activation of alternative survival pathways including the PI3K/Akt/mTOR axis, and the inherent heterogeneity of tumors. Emerging therapies aim to overcome these barriers by combining hormone treatments with targeted inhibitors. Special emphasis is placed on novel approaches involving mitochondrial disruption, epigenetic modulation, and manipulation of the tumor microenvironment. These strategies reflect a shift toward personalized medicine, where molecular profiling and biomarker identification guide individualized treatment plans. Understanding and targeting the multifactorial nature of resistance in HR + BC is essential to improving therapeutic outcomes. A multidisciplinary, mechanism-based approach offers the most promise for restoring treatment sensitivity and enhancing long-term survival.
乳腺癌仍然是全球女性癌症相关发病的主要原因，其中激素受体阳性（HR+）亚型约占病例的70%。尽管内分泌治疗取得了进展，但激素抵抗的出现构成了重大挑战，常常导致治疗失败和疾病进展。本综述探讨了HR+乳腺癌（HR+BC）耐药的核心问题，重点关注关键机制，如雌激素受体（ER）突变、包括PI3K/Akt/mTOR轴在内的替代生存途径的激活以及肿瘤的内在异质性。新兴疗法旨在通过将激素治疗与靶向抑制剂相结合来克服这些障碍。特别强调了涉及线粒体破坏、表观遗传调控和肿瘤微环境操纵的新方法。这些策略反映了向个性化医疗的转变，即分子谱分析和生物标志物鉴定指导个体化治疗方案。了解并针对HR+BC耐药的多因素性质对于改善治疗结果至关重要。基于机制的多学科方法最有希望恢复治疗敏感性并提高长期生存率。
