Protons Show Greater Relative Biological Effectiveness for Mammary Tumorigenesis with Higher ERα- and HER2-Positive Tumors Relative to γ-rays in APC Mice.

PURPOSE

Exposure to ionizing radiation increases risk of breast cancer. Although proton radiation is encountered in outer space and in medicine, we do not fully understand breast cancer risks from protons owing to limited in vivo data. The purpose of this study was to comparatively assess the effects of γ-rays and protons on mammary tumorigenesis in APC mice.

METHODS AND MATERIALS

Female APC mice were exposed to 1 GeV protons (1.88 or 4.71 Gy) and Cs γ-rays (2 or 5 Gy). Mice were euthanized 100 to 110 days after irradiation, at which point mammary tumors were scored, tumor grades were assessed, and relative biological effectiveness was calculated. Molecular phenotypes were determined by assessing estrogen receptor α (ERα) and human epidermal growth factor receptor 2 (HER2) status. ERα downstream signaling was assessed by immunohistochemistry.

RESULTS

Exposure to proton radiation led to increased mammary tumor frequency at both proton radiation doses compared with γ-rays. The calculated relative biological effectiveness for proton radiation-induced mammary tumorigenesis was 3.11 for all tumors and >5 for malignant tumors relative to γ-rays. Tumor frequency per unit of radiation was higher at the lower dose, suggesting a saturation effect at the higher dose. Protons induced more adenocarcinomas relative to γ-rays, and proton-induced tumors show greater ERα and HER2 positivity and higher activation of the ERα downstream PI3K/Akt and cyclin D1 pathways relative to γ-rays.

CONCLUSIONS

Our data demonstrate that protons pose a higher risk of mammary tumorigenesis relative to γ-rays. We also show that proton radiation-induced tumors in APC mice are ERα- and HER2-positive, which is consistent with our previous data on radiation-induced estrogenic response in wild-type mice. Although this study establishes APC as a model with adequate signal-to-noise ratio for space radiation-induced mammary tumorigenesis, further studies will be required to address the uncertainties in space radiation-induced breast cancer risk estimation.