Abstract P5-03-14: Low dose ionising radiation effects in normal breast progenitor sub-populations

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Abstract The human breast is a radiosensitive tissue and radiation exposure is proposed to contribute to mammary gland carcinogenesis through changes to stem and progenitor cells that result in aberrant proliferation, differentiation and genome instability. However, little is known about the low dose radiation response (LD IR) under conditions of relevance to environmental and occupational and medical imaging exposures. This study utilises 2-D and 3-D breast models derived from two normal breast cell lines (MCF10A and HME1) and primary human mammary epithelial cells from reduction mammoplasty surgery, to investigate the mechanisms underpinning sensitivity of normal breast to LD IR and elucidate its role in breast cancer initiation and progression. We have shown that DNA damage can be detected in both cell lines after doses <50 mGy and that an increased level of DNA damage foci at 1 h post LD IR is observed in a subpopulation of cells. Using antibodies to cell surface markers suggested to be putative breast stem cell markers, we have performed Fluoresence Activated Cell Sorting (FACS) to isolate subpopulations from the MCF10A cell line. CD49fhi, EpCAM-, MUC1- cells thought to be progenitor like cells were found to be more resistant to LD IR than the EpCAM+, MUC1+ population. As the pathways that govern survival/proliferation of stem and progenitor cells versus differentiation are interconnected, we have investigated if radiation resistance is also correlated with changes to breast cell differentiation. It was observed that LD IR modulated breast cell lineage markers in 2D cultures of both cell lines. We subsequently found that radiation induces a decrease in MUC1 mRNA expression levels which coincides with increased Lef1 expression. Lef1 has been shown to promote Mre11 expression thereby conferring elevated DNA repair and radiation resistance in tumour cells. Based on our findings, we hypothesize that progenitor cell populations within normal breast cell lines may be more efficient at detecting DNA DSBs resulting from LD IR leading to a pro-survival response. We are currently investigating these effects in primary mammary epithelial cell samples, using FACS to isolate progenitor subpopulations. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-03-14.