Background: Exposure to galactic cosmic radiation (GCR) is a breast cancer risk factor for female astronauts on deep-space missions. However, the specific signaling mechanisms driving GCR-induced breast cancer have not yet been determined. Methods: This study aimed to investigate the role of the estrogen-induced ERα-ERRα-SPP1 signaling axis in relation to mammary tumorigenesis in femaleApcMin/+mice exposed to simulated GCR (GCRsim) at 100–110 days post-exposure. Results: In GCRsim-exposed mice, we observed marked elevations in serum estradiol, increased ductal overgrowth, ERα activation, and upregulation of ERα target genes with pro-tumorigenic functions in mammary tissues that was coupled with a higher mammary tumorigenesis, relative to control. Additionally, the ERα target geneEsrra, which encodes ERRα, was also upregulated along with its oncogenic target geneSpp1, indicating the activation of the ERα-ERRα-SPP1 axis in mouse mammary tissues after GCRsim exposure. Using a human tissue microarray and human breast cancer gene expression analysis, we also highlighted the conserved nature of the ERα-ERRα-SPP1 signaling in human breast cancer development. Conclusions: We identified the ERα-ERRα-SPP1 signaling axis as a potential key mediator in GCR-induced breast cancer with conserved activation in human breast cancer. These findings suggest that targeting this pathway could serve as a potential target for therapeutic intervention to safeguard female astronauts during and after a prolonged outer space mission.
背景：银河宇宙辐射暴露是执行深空任务的女宇航员面临的乳腺癌风险因素。然而，驱动GCR诱发乳腺癌的具体信号传导机制尚未明确。方法：本研究旨在探讨雌激素诱导的ERα-ERRα-SPP1信号轴在暴露于模拟银河宇宙辐射的雌性ApcMin/+小鼠乳腺肿瘤发生中的作用，观察时间为暴露后100-110天。结果：与对照组相比，GCR模拟暴露组小鼠血清雌二醇水平显著升高，乳腺导管过度增生明显，ERα活性增强，同时乳腺组织中具有促肿瘤功能的ERα靶基因表达上调，这些变化与更高的乳腺肿瘤发生率相关。此外，编码ERRα的ERα靶基因Esrra及其致癌靶基因Spp1表达均上调，表明GCR模拟暴露后小鼠乳腺组织中ERα-ERRα-SPP1信号轴被激活。通过人类组织微阵列和乳腺癌基因表达分析，我们进一步揭示了ERα-ERRα-SPP1信号通路在人类乳腺癌发展中的保守性。结论：我们确定ERα-ERRα-SPP1信号轴是GCR诱发乳腺癌的潜在关键介质，且在人类乳腺癌中具有保守的激活特性。这些发现提示，靶向该通路可能成为保护长期外太空任务期间及之后女宇航员的潜在治疗干预靶点。
肿瘤(癌症)患者之家