THE INFLUENCE OF ESTROGEN RECEPTORS ON THE EFFECTIVENESS AND PROGNOSIS OF HORMONE THERAPY FOR BREAST CANCER

Breast cancer (BC) is the most common cancer among women in the world and in Ukraine.In 2022, 2.3 million new cases were registered in the world, of which 670 thousand resulted in death.It is known that approximately 70-75% of BC cases are estrogen receptor-positive (ER +), which makes endocrine therapy (ET) the basis of systemic treatment.ET includes aromatase inhibitors (IA), selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs).However, despite the initial effectiveness, approximately 40% of patients with metastatic ER+ BC subsequently develop acquired resistance to ET. Resistance to ET, depending on the timing of development, can be primary and secondary (acquired).The development of resistance to ET in breast cancer can be due to many reasons, namely: a decrease in the content of ER, a violation of the balance between ER activator and suppressor proteins, ligand-independent activation of ER, stimulation of the EGFR, PI3K, NF-kB signaling pathways that bypass estrogen receptors, the spread of hormone resistance in a paracrine manner or through intercellular contacts.When studying the causes of hormone resistance in breast cancer patients, a huge role is played by the study of the structure of the gene and, accordingly, the ER protein.According to researchers, the breast cancer group (ERβ+/ERα+) accounts for more than half of cases of primary breast cancer, while the expression of the ERβ group (ERβ+/ERα -) occurs in approximately 20% of cases.The ERgroup of tumors is characterized by a more aggressive course and a low frequency of response to hormone therapy, including the second group of ERβ-expressing neoplasms.The proportion of such ER-breast cancer with the ERβ +/ERα -phenotype is 50-80%.However, it must be recognized that the ERβ+/ERαbreast cancer group is only in the stage of study.In cases of ET breast cancer, resistance is often associated with changes in the ERα structure, the main principle of which is the occurrence of changes that allow it to remain active regardless of the ligand or in the presence of antiestrogens.The most significant structural mechanism of acquired resistance, especially after IA therapy, is the occurrence of point mutations in the ESR1 gene.These mutations are more common in metastatic breast cancer.Point mutations in the LBD (ESR1) and aberrant posttranslational modifications are key mechanisms that lead to constitutive (ligandindependent) receptor activation.Understanding the mechanisms and consequences of mutations and posttranslational modifications (PTMs) of ER has led to the development of new therapeutic approaches aimed at overcoming these structural defects.Recently developed oral SERDs, such as Imlunestrant and Elacestrant, have demonstrated highly efficient degradation of mutant ERα with LBD mutations and a significant clinical advantage over older SERDs and IAs.The use of combination therapy (e.g., CDK4/6 inhibitors) to prevent hyperactivation of ERα through phosphorylation is already almost standard practice and demonstrates high efficacy.Журнал «Перспективи та інновації науки» № 12(58) 2025 2038 Given the above, further study of the structural biology of ER is a pressing problem in oncology and medicine.