Radiation-Induced Reprogramming of Pre-Senescent Mammary Epithelial Cells Enriches Putative CD44(+)/CD24(-/low) Stem...

Area of Science:

• * Cell biology
• * Cancer research
• * Radiation oncology

Background:

• * Ionizing radiation (IR) enriches CD44(+)/CD24(-/low) breast stem cells, attributed to radioresistance and symmetric division.
• * Radiation-induced phenotypic reprogramming, where non-stem cells adopt the stem cell phenotype, is a potential enrichment mechanism.
• * The relative contribution of stem cell survival versus induced reprogramming to enrichment remains unclear.

Purpose of the Study:

• * To investigate the mechanistic basis of CD44(+)/CD24(-/low) stem cell enrichment after IR exposure.
• * To differentiate between stem cell survival and phenotypic reprogramming as drivers of enrichment.
• * To compare enrichment mechanisms in non-tumorigenic (MCF-10A) and cancerous (MCF-7) breast cells.

Main Methods:

• * Combined cellular automata modeling with in vitro experimental data.
• * Utilized MCF-10A non-tumorigenic human mammary epithelial cells and MCF-7 breast cancer cells.
• * Analyzed cells in the context of radiation-induced cellular senescence.

Main Results:

• * Quantitative modeling indicated incomplete phenotypic reprogramming of pre-senescent non-stem cells contributes to CD44(+)/CD24(-/low) subpopulation enrichment.
• * MCF-7 cells exhibited earlier, more persistent stem cell enrichment at lower IR doses compared to MCF-10A cells.
• * Phenotypic plasticity appears less regulated in breast cancer cells.

Conclusions:

• * Reprogramming of pre-senescent non-stem cells is a significant mechanism for stem cell enrichment post-IR in both normal and cancerous mammary epithelial cells.
• * Differences in enrichment dynamics between MCF-7 and MCF-10A cells highlight reduced regulation of phenotypic plasticity in cancer.
• * Findings have implications for optimizing radiation therapy and understanding radiation carcinogenesis.