Cancer Genetics and Epigenetics, 2025, Vol.13, No.3, 117-125 http://medscipublisher.com/index.php/cge 120 standards, primary drug resistance refers to recurrence in patients within the first two years of receiving adjuvant endocrine therapy, or deterioration of the condition in patients with advanced breast cancer within the first six months of receiving first-line endocrine therapy. Acquired drug resistance refers to recurrence in patients two years after the start of adjuvant therapy, recurrence within 12 months after the completion of adjuvant therapy, or deterioration of the condition in patients with advanced breast cancer after 6 months of endocrine therapy (Hartkopf et al., 2020; Lambertini et al., 2023). These judgment criteria can help doctors decide how to treat patients, determine whether patients can participate in clinical trials, and can also be used to evaluate the treatment effect and prognosis of patients (Guo and Wu, 2024). Studies have found that compared with patients with acquired drug resistance or sensitivity to endocrine therapy, patients with primary drug resistance have poorer therapeutic effects. This also indicates that accurately distinguishing the types of drug resistance is very important for formulating better treatment plans (Lambertini et al., 2023). 4 Molecular Mechanisms of Endocrine Resistance 4.1 Abnormal ER signaling pathways Problems with the estrogen receptor (ER) signaling channel are the main cause of resistance to endocrine therapy in breast cancer. Mutations in the ESR1 gene encoding ERα can keep estrogen receptors in an active state all the time. In this way, even without estrogen or with endocrine therapy drugs, tumor cells can still continue to grow (Hartkopf et al., 2020). In addition, a decrease or even disappearance of estrogen receptor expression levels, as well as changes in the related activators and inhibitors, will all lead to a deterioration of the therapeutic effect targeting this signal channel (Grzybowska et al., 2018; Sahin et al., 2021). These molecular-level changes enable tumor cells to transmit signals without relying on estrogen, thereby developing resistance to drugs such as selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and selective estrogen receptor degraders (SERDs). If ESR1 gene mutations or down-regulation of estrogen receptor expression are detected, it often indicates a poor prognosis for the patient and a poor response to conventional endocrine therapy (Grzybowska et al., 2018; Hartkopf et al., 2020; Sahin et al., 2021). 4.2 Activation of kinase pathways The activation of other signal channels that promote tumor growth and survival, especially the two signal channels PI3K/AKT/mTOR and MAPK, is another key factor for endocrine resistance in breast cancer (Wetsel et al., 2011). When key substances on signal channels such as PIK3CA and AKT1 mutations, tumor cells can grow independently without relying on estrogen receptor signals, greatly reducing the effect of endocrine therapy (Araki and Miyoshi, 2018; Hartkopf et al., 2020; Sahin et al., 2021). These kinase signaling channels become active due to genetic alterations or interactions with growth factor receptors (such as EGFR and HER2), further facilitating the proliferation and survival of tumor cells (Wetsel et al., 2011). The combination of targeted therapy that inhibits PI3K, mTOR or CDK4/6 and endocrine therapy has a certain effect in overcoming the problem of drug resistance, which also indicates the importance of these signaling channels in the process of drug resistance (Araki and Miyoshi, 2018; Hartkopf et al., 2020; Sahin et al., 2021). 4.3 Tumor microenvironment and cell phenotypic changes The environment around the tumor has a significant impact on the formation and development of endocrine resistance in breast cancer. Cytokines with pro-inflammatory effects and immune cells invading tumor tissues can activate estrogen receptor signals in some ways that do not require the participation of estrogen, such as phosphorylating ERα, enabling tumors to continue growing after endocrine therapy (Nwachukwu et al., 2017; Sahin et al., 2021). Changes in the characteristics of tumor cells, such as epithelial cells transforming into mesenchymal cells (EMT), and the emergence of cell populations similar to cancer stem cells, can also lead to drug resistance. These changes make tumor cells more flexible, more likely to invade surrounding tissues, and have stronger survival ability,
RkJQdWJsaXNoZXIy MjQ4ODYzNA==