三阴性乳腺癌亚型中基于通路的放射敏感性与治疗靶向

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous disease with subtypes that differ in therapy response and radiosensitivity. Experimental models suggest that pathway-level modulation may provide more actionable insights into resistance mechanisms. Using syngeneic, aggressive murine models of breast cancer (4T1), 60 female Balb/c mice were randomized after palpable tumor formation to six treatment arms: ad libitum feeding (AL), radiation alone (8 Gy), caloric restriction (CR, 30% reduction in intake), CR+RT, curcumin alone, and curcumin+RT. CR evoked a marked delay in tumor growth, with AL mice reaching a 1 cm³ tumor volume at ~24 days post-injection, while CR mice reached this threshold at ~37 days. CR also increased overall survival and markedly reduced pulmonary metastases: at 35 days post-injection, the total metastatic burden was 1360 mm³ in AL-fed mice compared to 150 mm³ in CR mice. Transcriptome profiling of CR-treated tumors revealed 18 dysregulated pathways, including downregulation of c-MYC, PIK3CA, and androgen receptor, suggesting a mechanistic basis for radiosensitization. Tumor volume trajectories in curcumin-treated groups revealed non-monotonic growth patterns, while curcumin combined with a 3-dose 2 Gy radiation regimen between days 6-10 resulted in a flatter post-radiation trajectory. During the radiation window, curcumin alone tumors expanded by +815 mm³, whereas curcumin + RT increased by +568 mm³, representing a ~30% smaller rise. Over the full 20-day study, curcumin + RT showed a 28% lower cumulative volume increase (1026 vs 1434 mm³) and a reduced daily growth rate (51 vs 72 mm³/day). These trends suggest that curcumin may modulate stress adaptation and survival signaling under radiation exposure. Mouse weights remained stable across all arms, supporting tolerability. In conclusion, pathway-level interventions such as caloric restriction and curcumin demonstrate potential to enhance radiosensitivity in preclinical TNBC models. Therefore, interventions such as caloric restriction and curcumin may enhance radiosensitivity by modulating pathways relevant to established radioresistant BL2 and M TNBC subtypes. Ongoing cell line studies in HCC1806 (BL2) and MDA-MB-231 (Mesenchymal) can test whether these mechanisms observed in vivo are recapitulated in defined subtype models. By refining these strategies and integrating pathway biology into subtype classification, translational radiosensitization approaches may be improved.