Modelling anti-estrogen resistance in estrogen receptor-positive breast cancer: molecular mechanisms and emerging therapeutic strategies

Abstract Endocrine therapy continues to be a fundamental treatment for estrogen receptor-positive (ER+) breast cancer; however, its long-term effectiveness is often hindered by the development of acquired resistance. This resistance poses a significant challenge in clinical management, limiting the durability of treatment responses. Recently, new clinical data have emerged showing promise with combination therapies that integrate endocrine agents and pathway inhibitors, offering renewed hope for patients. Nevertheless, resistance to these combination therapies still occurs, emphasizing the urgent need for further investigation into the underlying mechanisms. Preclinical models, including cell lines and animal studies, play a crucial role in advancing this research. Various in vitro models have been developed to mimic resistance to different endocrine therapies, such as long-term estrogen deprivation models that simulate aromatase inhibitor treatment, as well as models resistant to tamoxifen and selective estrogen receptor degraders like fulvestrant. This review systematically examines these preclinical models used to study the multifactorial mechanisms that drive antiestrogen resistance, highlighting their relevance and utility in improving therapeutic strategies. Understanding resistance pathways through these models is essential to developing more effective interventions for overcoming endocrine therapy resistance in ER+ breast cancer.