Abstract: Compared to other subtypes of breast cancers, triple negative breast cancers (TNBC) present poorer clinical outcome and prognosis due to their resistance to therapeutic radiation and undefined molecular signature. The current study investigated the mechanism underlying radiation-resistance of TNBC through a newly discovered BCCIP/53BP1 pathway. An automatic high throughput metaphase screening and analyzing system was used to detect the influence of radiation induced chromosomal aberration in BCCIP deficient mouse breast cancer cells by the absence of 53BP1. Immunofluorescent staining and Western blot were then performed to detect the effect of 53BP1 depletion on the repair efficiency of DNA double-strand breaks in BCCIP deficient breast cancer cells. The 53BP1 silencing induced alteration of homologous recombination repair efficiency in BCCIP deficient mouse breast cancer cells were further tested by both DR-GFP report system and sister chromatid exchange assay. Finally, colony formation assay was applied to detect the cell survival rate in 53BP1/BCCIP co-depleted breast cancer cells after radiation exposure. The results showed that the enhanced chromosomal aberration rate in radiation exposed BCCIP deficient mouse breast cancer cells was suppressed by 53BP1 depletion. The level and foci number of DNA double-strand break marker γH2AX in 53BP1/BCCIP co-depleted breast cancer cells were both lower than BCCIP solo-depleted cells. The homologous recombination repair efficiency was significantly recovered in 53BP1 additionally depleted BCCIP null breast cancer cells in response to radiation. The radiation resistant capacity was enhanced by 53BP1 co-deletion in BCCIP deficient cells. Collectively, these results suggested that the DNA double-strand break repair efficiency was reinforced in BCCIP deficient breast cancer cells by removing the inhibition to homologous recombination through 53BP1 simultaneous depletion, and therefore, enhanced cell radiation resistant capacity. These findings will give new insights in the anti-radiation feature of TNBC, and provide potential biomarkers for its radiotherapeutic intervention.
Key words: radiotherapy; radiosensitivity; breast cancer; BCCIP; 53BP1
（Acta Laser Biology Sinica, 2021, 30(3): 207-216）