Simulated Galactic Cosmic Radiation Exposure-Induced Mammary Tumorigenesis in ApcMin/+ Mice Coincides with Activation of ERα-ERRα-SPP1 Signaling Axis

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.

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.

This study aimed to investigate the role of the estrogen-induced ERα-ERRα-SPP1 signaling axis in relation to mammary tumorigenesis in female ApcMin/+ mice exposed to simulated GCR (GCRsim) at 100-110 days post-exposure.

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 gene Esrra, which encodes ERRα, was also upregulated along with its oncogenic target gene Spp1, 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.