Plasma Proteomic Analysis Reveals Complement System Changes in Irradiated Female BALB/c Mice during Mammary Carcinogenesis

The risk of breast cancer increases decades after ionizing radiation exposure, thereby linking aging intrinsically to the evolution of cancer. We hypothesized that radiation accelerates aging and carcinogenesis through similar pathways, specifically low-grade systemic inflammation. In this study, we used the radiation-genetic mammary chimera model to examine the differential expression of 532 plasma proteins in BALB/c female mice between radiation exposure and experiment termination at 18 months. Mice were sham irradiated or irradiated with 50 cGy prior to being orthotopically transplanted with syngeneic Trp53-null mammary epithelium and half were treated for 6 months with anti-inflammatory low-dose aspirin. Plasma was collected at 4, 8, and 18 months from non-tumor-bearing mice and from those that had developed tumors between 12 and 18 months. Plasma quantitative proteomic analysis identified significant alterations in proteins involved in the inflammatory response in irradiated mice as a function of age. Levels of C4b-binding protein were decreased at 4 months in irradiated mice compared with controls, which was blocked in aspirin-treated irradiated mice. Notable differences in the expression of proteins associated with the inflammation were evident in tumor-bearing versus similarly aged mice. Complement components C1qA, C1qB, and C1qC were significantly increased in tumor-bearing mice that had been irradiated, whereas similarly aged mice without tumors displayed a decline in complement system activity. The specific changes in the complement system, which mediates adaptive immune function, following radiation exposure may contribute to cancer progression as a function of age. SIGNIFICANCE: Women treated with radiotherapy as children or young adults bear an increased breast cancer risk, which is more likely to be aggressive, hormone receptor negative, and immune poor. Understanding radiation effects that could be modified after exposure may lead to prevention strategies. Consistent with our hypothesis that systemic inflammation contributes to risk, the plasma proteome from mice undergoing mammary carcinogenesis demonstrates changes in the complement system.