Abstract: Background Targeted drugs for the AXL/Gas6 signaling pathway have become a new focus in current cancer drug research. However，there is significant controversy over the expression and role of Gas6 in breast cancer.Objective To investigate the expression of Gas6 and AXL in breast cancer and to explore the correlation of GAS6 with clinicopathological features and prognosis. Methods A total of 60 patients with invasive breast cancer who were treated at the Breast Surgery Department of Fujian Medical University Affiliated Mindong Hospital from October 2019 to February 2022 were included. Surgical resection specimens of cancerous and adjacent tissues were collected from these patients. The expressions of Gas6 and AXL were detected using immunohistochemical staining（IHC） and real-time fluorescence quantitative PCR. Spearman correlation analysis was employed to assess the correlation between the two factors and the relationship between Gas6 and clinical pathological features. Additionally，gene expression data for Gas6 and AXL in breast cancer and normal breast tissues were collected from the GEPIA2.0，UALCAN，and METABRIC databases for supplementary validation. Survival data for different breast cancer subtypes were collected from the METABRIC dataset and KM Plotter database. Kaplan-Meier survival curve analysis was conducted to evaluate the correlation between Gas6 and breast cancer prognosis. Results IHC and RT-qPCR detection results show that the relative expression levels of Gas6 protein and mRNA in breast cancer tissues are lower than those in adjacent non-cancerous tissues，with statistical significance（P<0.001）. In contrast，the relative expression levels of AXL protein and mRNA in breast cancer tissues are higher than those in adjacent non-cancerous tissues，also with statistical significance（P<0.001）. Bioinformatics analysis reveals that there was a positive correlation between Gas6 and AXL mRNA expression in the total breast cancer population and four subtypes of patients（rs=0.460，P<0.001）. Moreover，statistically significant differences（P<0.05） were observed in Gas6 mRNA expression levels among patients with different breast cancer molecular subtypes，primary tumor stages，histological grades，chemotherapy treatments and regional lymph node stages.Kaplan-Meier survival curve analysis indicates that in the overall breast cancer population and among patients with Luminal A subtype，the group with high Gas6 mRNA expression in cancerous tissues has a longer overall survival and disease-free survival compared to the low expression group. Additionally，for Luminal B subtype patients，the disease-free survival of the high Gas6 mRNA expression group in cancerous tissues is also longer than that of the low expression group，with these differences being statistically significant（P<0.05）.Conclusion High expression of tumor cell-derived Gas6 is a favorable prognostic factor for invasive breast cancer. Targeting Gas6 and its receptor in breast cancer represents a promising therapeutic approach，particularly when combined with immunotherapy.

Key words: Breast cancer, Gas6, AXL, Prognosis, Spearman correlation analysis

摘要： 背景 AXL/Gas6信号通路靶向药物是目前肿瘤药物研究的新热点，但Gas6在乳腺癌中的表达及其作用尚存在争议。目的 探讨Gas6和AXL在乳腺癌中的表达及GAS6与临床病理特征和预后的相关性。方法 纳入2019年10月—2022年2月就诊于福建医科大学附属闽东医院乳腺外科的60例浸润性乳腺癌患者为研究对象，收集患者手术切除癌组织及癌旁组织标本，使用免疫组织化学染色（IHC）和RT-qPCR检测Gas6及AXL的表达情况，采用Spearman相关性分析二者及Gas6与临床病理特征的相关性。收集GEPIA2.0、UALCAN、METABRIC数据库中乳腺癌和正常乳腺组织Gas6和AXL基因表达数据进行补充验证；收集METABRIC数据集和KMPlotter数据库中不同乳腺癌亚型患者的生存数据，采用Kaplan-Meier生存曲线分析Gas6与乳腺癌预后的相关性。结果 IHC结果和RT-qPCR检测结果显示，乳腺癌组织中Gas6蛋白和mRNA的相对表达量均低于癌旁组织，差异有统计学意义（P<0.001）；乳腺癌组织中AXL蛋白和mRNA的相对表达量均高于癌旁组织，差异有统计学意义（P<0.001）。生物信息学分析结果显示，在乳腺癌总人群和4种亚型患者中Gas6和AXLmRNA表达呈正相关（rs=0.460，P<0.001），且不同乳腺癌分子分型、原发肿瘤分期、组织学分级、化疗、区域淋巴结分期患者Gas6mRNA表达水平比较，差异具有统计学意义（P<0.05）；Kaplan-Meier生存曲线分析结果显示，乳腺癌总人群及LuminalA亚型患者的癌组织Gas6mRNA高表达组的总生存期和无复发生存期均高于低表达组，且LuminalB亚型患者的癌组织Gas6mRNA高表达组无复发生存期高于低表达组，差异均有统计学意义（P<0.05）。结论 肿瘤细胞来源的Gas6高表达是浸润性乳腺癌有利的预后因素，在乳腺癌中靶向Gas6及其受体是一种有前途的治疗方法，尤其是针对与免疫疗法结合使用时具有更高的临床价值。

关键词: 乳腺癌, Gas6, AXL, 预后, Spearman 相关性分析