Cancer Genetics and Epigenetics, 2025, Vol.13, No.3, 117-125 http://medscipublisher.com/index.php/cge 117 Research Insights Open Access Mechanisms and Therapeutic Strategies for Endocrine Resistance in Breast Cancer Xiaohong Yang, Liting Wang Hainan Institute of Biotechnology, Haikou, 570206, Hainan, China Corresponding author: liting.wang@hibio.org Cancer Genetics and Epigenetics, 2025, Vol.13, No.3 doi: 10.5376/cge.2025.13.0012 Received: 21 Mar., 2025 Accepted: 29 Apr., 2025 Published: 13 May, 2025 Copyright © 2025 Yang and Wang, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Yang X.H., and Wang L.T., 2025, Mechanisms and therapeutic strategies for endocrine resistance in breast cancer, Cancer Genetics and Epigenetics, 13(3): 117-125 (doi: 10.5376/cge.2025.13.0012) Abstract This study conducts a detailed analysis of the causes of endocrine resistance in breast cancer, such as abnormal estrogen receptor signaling, activation of signaling pathways like PI3K/AKT/mTOR, and changes in the surrounding environment of the tumor. This study also explored existing and emerging treatment approaches for drug resistance, such as the use of CDK4/6, PI3K and mTOR inhibitors, the development of second-generation serd and PROTACs drugs, and the formulation of personalized treatment plans by detecting biomarkers. In the future treatment of endocrine-resistant breast cancer, personalized treatment plans need to be adopted, the research results of multiple omics should be integrated, and collaborative research among different disciplines should be strengthened. Only in this way can new therapeutic targets be found and more appropriate treatments be provided for patients. Keywords Endocrine resistance; Estrogen receptor-positive breast cancer; Targeted therapy; PI3K/AKT/mTOR pathway; Precision medicine 1 Introduction Breast cancer is the most common cancer among women worldwide. Among them, cases of estrogen receptor-positive (ER+) breast cancer account for approximately 70%~80% of all breast cancer patients (Hanker et al., 2020; Nicolini et al., 2025). Breast cancer of type ER+is very important because it is usually sensitive to hormone-related treatment methods. Through this type of treatment, the recurrence rate and mortality rate of cancer in patients can be significantly reduced, and the treatment effect can be improved. However, even if the treatment is effective at the beginning, many ER+breast cancer patients will eventually develop resistance to endocrine therapy, which brings great difficulties to clinical treatment (Murphy and Dickler, 2016; Hanker et al., 2020; Sahin et al., 2021; Nicolini et al., 2025). Whether it is early or advanced ER+breast cancer, endocrine therapy is the main treatment approach (Ramaswamy and Zhao, 2014). Commonly used drugs include selective estrogen receptor modulators (SERMs), such as tamoxifen, aromatase inhibitors (AIs), and selective estrogen receptor degraders (SERDs), such as fulvestine (Perrone et al., 2005; Fan et al., 2015). These drugs work by inhibiting estrogen, which is crucial for the growth and survival of ER+breast cancer cells (Hanker et al., 2020; Sahin et al., 2021; Nicolini et al., 2025). After the advent of these drugs, the time without disease progression and the overall survival time of patients with hormone receptor-positive breast cancer were significantly prolonged. However, some patients have no response to treatment at the beginning, and some patients develop drug resistance after a period of treatment. This remains a major problem for long-term disease control (Murphy and Dickler, 2016; Hartkopf et al., 2020). This study will conduct an in-depth analysis of the causes of endocrine resistance in estrogen receptor-positive breast cancer and sort out the current and emerging treatment methods, with the aim of solving the problem of drug resistance. This study will also summarize the new findings of drug resistance-related research, evaluate the therapeutic effect of new combination therapies, and hope to find better treatment plans for patients with endocrine-resistant breast cancer and improve treatment outcomes.
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