Context-dependent modulation of epithelial-mesenchymal transition-associated markers and migration behavior by mammography-equivalent low-dose radiation in established breast cell lines.

PURPOSE: Mammography is an essential breast cancer screening tool that uses low doses of ionizing radiation. Determining whether such exposures modulate cellular processes associated with epithelial plasticity remains important. This preliminary study investigated whether clinically relevant radiation doses (≈2.14 mGy per exposure) influence epithelial-mesenchymal transition (EMT)-associated markers and motility in breast cell lines.

MATERIALS AND

METHODS

Human breast cell lines MCF-10A (non-tumorigenic), MCF-7 (luminal, ER+), and MDA-MB-231 (triple-negative) were exposed to single (2.14 mGy) or repeated (2.14 + 2.14 mGy) doses. Exposure was defined using a Monte Carlo-estimated glandular-equivalent dose derived from a breast-equivalent phantom under mammographic conditions. EMT-associated markers (E-cadherin, fibronectin, vimentin), collective migration, extracellular matrix invasion, MMP-2/9 activity, and transendothelial migration were assessed.

RESULTS

Low-dose irradiation induced cell-specific modulation of EMT-associated markers and motility (p-values correspond to single and repeated exposures, respectively). In MCF-10A cells, E-cadherin expression decreased (p = 0.0025; p = 0.028). A fibronectin degradation pattern was observed under both regimens; however, total band quantification (220 kDa subunit plus smaller fragments) was unchanged. Collective migration increased modestly (p < 0.05), while invasion through a basement membrane matrix increased markedly (p < 0.0001), and MMP-9 activity decreased (p < 0.0001). In MCF-7 cells, irradiation increased fibronectin (p = 0.05, repeated doses), enhanced collective migration (p < 0.05; p < 0.001), abolished MMP-2 activity in controls (in both treatments), and reduced MMP-9 activity (p < 0.0001), without altering invasion. In MDA-MB-231 cells, vimentin expression was upregulated after repeated exposures (p = 0.0067), while fibronectin expression decreased (p = 0.035; p = 0.046). Matrix invasion increased after single and repeated exposures (p < 0.05; p < 0.0001), MMP-9 activity increased after single exposure (p < 0.0001), and transendothelial migration decreased after single and repeated exposures (p < 0.01; p < 0.0001), without changes in collective migration. MMP-2 activity was undetectable in MCF-10A and MDA-MB-231 cells.

CONCLUSION

Mammography-equivalent radiation doses were associated with lineage-dependent modulation of EMT-associated markers and cellular motility in vitro, indicating context-dependent phenotypic effects of clinically relevant low-dose radiation.