The estrogen receptor (ER) pathway is crucial in breast cancer development and progression. Endocrine therapy targeting this pathway is effective but often faces resistance due to intrinsic or acquired mechanisms. Key resistance factors include ER pathway deregulation, altered cell cycle and survival signals, and activation of alternative pathways. Growth factor receptor pathways, especially EGFR/HER2, are strongly linked to endocrine resistance. Combining ER and growth factor receptor therapies has shown promise in preclinical models. Clinical studies support this approach but highlight the need for better patient selection. ER is a major driver in most breast cancers, with expression correlating with patient age, tumor grade, and prognosis. ER+ tumors vary in resistance to endocrine therapy, with some being more resistant despite ER expression. Tumors with high ER and PR levels, low HER2 amplification, and slow proliferation are more likely to benefit from endocrine therapy. ER+ tumors that are more aggressive are less responsive. Recent molecular studies have classified ER+ tumors into luminal A and B subtypes, with luminal B tumors being more resistant. ER signaling involves both genomic and non-genomic activities. Genomic activity regulates gene expression, while non-genomic activity involves membrane-bound ER and can rapidly influence signaling pathways. ER can interact with other transcription factors and coregulators, which modulate its activity. Overexpression of ER coactivators like AIB1 is associated with tamoxifen resistance. ER signaling is also regulated by membrane tyrosine kinases, including EGFR, HER2, and IGF1-R, which can activate ER through various mechanisms. Endocrine therapies include SERMs like tamoxifen, which can have agonist effects on certain genes, and estrogen deprivation using aromatase inhibitors. Fulvestrant, an ER downregulator, is more potent than tamoxifen. Resistance can be de novo or acquired, with some tumors losing ER expression or developing alternative survival pathways. PR loss is more common and is associated with worse outcomes. Multiple pathways contribute to endocrine resistance, including cell cycle signaling, growth factor receptor pathways, and tumor microenvironment factors. These pathways can be modulated by genetic or epigenetic changes, affecting drug response. The tumor microenvironment, including stromal cells and extracellular matrix components, also plays a role in resistance. Integrins and other adhesion molecules are involved in signaling that can influence ER function. Combining ER-targeted therapies with growth factor pathway inhibitors has shown promise in clinical trials. Trials involving HER2-positive tumors and ER-positive tumors have demonstrated benefits from such combinations. However, resistance can develop, and the effectiveness of these strategies varies among patients. Further research is needed to identify patients most likely to benefit from these approaches. Understanding the mechanisms of resistance is crucial for developing more effective treatments.The estrogen receptor (ER) pathway is crucial in breast cancer development and progression. Endocrine therapy targeting this pathway is effective but often faces resistance due to intrinsic or acquired mechanisms. Key resistance factors include ER pathway deregulation, altered cell cycle and survival signals, and activation of alternative pathways. Growth factor receptor pathways, especially EGFR/HER2, are strongly linked to endocrine resistance. Combining ER and growth factor receptor therapies has shown promise in preclinical models. Clinical studies support this approach but highlight the need for better patient selection. ER is a major driver in most breast cancers, with expression correlating with patient age, tumor grade, and prognosis. ER+ tumors vary in resistance to endocrine therapy, with some being more resistant despite ER expression. Tumors with high ER and PR levels, low HER2 amplification, and slow proliferation are more likely to benefit from endocrine therapy. ER+ tumors that are more aggressive are less responsive. Recent molecular studies have classified ER+ tumors into luminal A and B subtypes, with luminal B tumors being more resistant. ER signaling involves both genomic and non-genomic activities. Genomic activity regulates gene expression, while non-genomic activity involves membrane-bound ER and can rapidly influence signaling pathways. ER can interact with other transcription factors and coregulators, which modulate its activity. Overexpression of ER coactivators like AIB1 is associated with tamoxifen resistance. ER signaling is also regulated by membrane tyrosine kinases, including EGFR, HER2, and IGF1-R, which can activate ER through various mechanisms. Endocrine therapies include SERMs like tamoxifen, which can have agonist effects on certain genes, and estrogen deprivation using aromatase inhibitors. Fulvestrant, an ER downregulator, is more potent than tamoxifen. Resistance can be de novo or acquired, with some tumors losing ER expression or developing alternative survival pathways. PR loss is more common and is associated with worse outcomes. Multiple pathways contribute to endocrine resistance, including cell cycle signaling, growth factor receptor pathways, and tumor microenvironment factors. These pathways can be modulated by genetic or epigenetic changes, affecting drug response. The tumor microenvironment, including stromal cells and extracellular matrix components, also plays a role in resistance. Integrins and other adhesion molecules are involved in signaling that can influence ER function. Combining ER-targeted therapies with growth factor pathway inhibitors has shown promise in clinical trials. Trials involving HER2-positive tumors and ER-positive tumors have demonstrated benefits from such combinations. However, resistance can develop, and the effectiveness of these strategies varies among patients. Further research is needed to identify patients most likely to benefit from these approaches. Understanding the mechanisms of resistance is crucial for developing more effective treatments.