Cancer Genetics and Epigenetics, 2025, Vol.13, No.1, 21-31 http://medscipublisher.com/index.php/cge 23 3 Androgen Receptor (AR) Signal Regulatory Network 3.1 The mechanism of ARgene variations and splicing variants Genetic alterations of androgen receptor genes are important factors promoting the deterioration of diseases. In untreated primary prostate cancer, the incidence of AR gene mutations is relatively low, but it significantly increases during the castration resistance stage. These mutations often affect the receptor-ligand binding regions, enabling them to be activated by non-androgen substances or even anti-androgen drugs (Koochekpour, 2010). Furthermore, approximately 30%~50% of drug-resistant tumors exhibit copy number amplification of the ARgene, resulting in excessive expression of the receptor and enabling the tumor to continuously proliferate in a low androgen environment. Studies have found that patients carrying AR amplification have a relatively prolonged survival period after recurrence, suggesting that this variation endows tumors with selective growth advantages (Koivisto et al., 2021). The discovery of the splicing variant AR-V7 reveals a new drug resistance mechanism. This type of variant lacks ligand-binding domains and has the characteristic of continuous activation, exerting resistance to traditional treatments (Zhang et al., 2020; Jacob et al., 2021). Clinical data show that patients with AR-V7 positive have a poor prognosis when receiving targeted therapy because they do not rely on androgens to drive tumor progression. The AR-V7 detection technology based on circulating tumor cells has become an important tool for predicting therapeutic responses. 3.2 The core role of AR signal networks in the progression of the disease course This signaling pathway is regulated throughout the entire disease process. During the hormone-sensitive period, tumor proliferation mainly relies on the classical androgen-mediated pathway, which enables hormone blockade therapy to show significant efficacy (Jacob et al., 2021). However, when the disease enters the castration resistance stage, cancer cells maintain AR activity through means such as gene amplification and structural variation to ensure survival in a low androgen microenvironment (Aurilio et al., 2020; Pisano et al., 2021). The continuously activated AR signal becomes the key for tumors to maintain a malignant phenotype (Nelson, 2012). The interaction between AR signals and other molecular networks increases the complexity of treatment. For example, its synergistic activation with the PI3K/AKT/mTOR pathway can replace androgen deficiency and maintain tumor growth. It is notable that some cases presented neuroendocrine differentiation characteristics, showing weakened AR dependence, which suggests the need to adopt a multi-dimensional treatment strategy (Bluemn et al., 2017; Pisano et al., 2021). 3.3 Clinical application and limitations of AR targeted therapy AR signal suppression remains a core treatment approach. Novel inhibitors such as enzalutamide significantly prolong the survival period of patients by blocking receptor activation and nuclear transport (Jacob et al., 2021; Chung and Abboud, 2022). These drugs exert therapeutic effects by interfering with the transcription of target genes. However, the phenomenon of therapeutic resistance is widespread, mainly due to the generation of splicing variants and the activation of bypass signals. Current research focuses on breaking through the bottleneck of drug resistance, including developing combination regimens that can simultaneously inhibit multiple pathways, and using biomarkers such as AR-V7 to guide precise medication (Zhang et al., 2020; Jamroze et al., 2021). The new generation of AR inhibitors have demonstrated better anti-tumor activity by optimizing their binding characteristics (Nelson, 2012; Chung and Abboud, 2022). However, how to formulate the optimal treatment sequence and combination plan still requires in-depth research to balance efficacy and safety (Chung and Abboud, 2022). 4 Analysis of the Core Signal Transmission Mechanisms 4.1 Abnormal activation mechanism of the PI3K/AKT/mTOR pathway The PI3K/AKT/mTOR signaling axis, as a core regulatory network, plays a key role in the evolution of prostate cancer. This pathway shows an abnormally activated state in most cases, promoting tumorigenesis and development and triggering treatment resistance (Gao et al., 2020; Shorning et al., 2020). Its abnormal activation
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