Breast cancer (BC) continues to be a significant challenge in oncology, primarily due to the emergence of drug resistance, which severely limits treatment efficacy and adversely affects patient outcomes. This review aims to elucidate the mechanisms underlying drug resistance in BC, focusing on the roles of the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) signaling pathways. It identifies advanced therapeutic strategies that effectively target and overcome resistance by analyzing these pathways. This review integrates a comprehensive selection of clinical data and cell lines with known resistance profiles, encompassing both clinical and laboratory settings. It employs cutting-edge techniques such as highthroughput sequencing, proteomics, and advanced imaging. Key measurements include receptor expression levels, pathway activation states, and drug response data, analyzed using bioinformatics tools for genetic and proteomic insights and statistical models to determine the clinical significance of the findings. The review identifies specific mutations and alterations in the ER and HER2 pathways that contribute to drug resistance. Notably, it highlights novel biomarkers and resistance mechanisms, including the upregulation of alternative signaling cascades and mutations in downstream effectors. It also emphasizes promising targeted therapeutic strategies, such as combination therapies and next-generation inhibitors, which have demonstrated encouraging results in preclinical models. In conclusion, this review provides critical insights into the intricate mechanisms of drug resistance in BC, underscoring the pivotal roles of the ER and HER2 signaling pathways. It identifies unique resistance mechanisms and potential therapeutic targets, paving the way for the development of advanced strategies to improve treatment outcomes.
Kuttiappan et al. (2026) studied this question.