Association of radiotherapy with preferential depletion of luminal epithelial cells in a BRCA1 mutation carrier

Women who carry cancer-predisposing germ-line mutations in BRCA1 have up to 80% chance of developing breast cancer in their lifetime [1,2]. Narod and coworkers recently reported that radiation therapy (RT) was associated with a significant reduction in the risk of ipsilateral breast cancer among BRCA1 mutation carriers [3]. Although the exact mechanism by which radiation affects breast cancer recurrence is not clear, it has traditionally been thought to be due to killing of residual tumor cells left behind after excision of the primary tumor [4,5].BRCA1-associated tumors usually have the “basal-like” features and therefore had been presumed to originate from basal stem cells. Surprisingly, recent work from several laboratories suggests that BRCA1 tumors likely originate from luminal progenitor cells [6-8]. Given the well-documented role of BRCA1 in double-strand break repair and radiation sensitivity [9,10], selective elimination of the cell of origin for BRCA1-associated tumors could be an additional or alternative mechanism by which RT reduces incidence of ipsilateral breast cancer in BRCA1 mutation carriers.In the current study, we analyzed the abundance and activity of luminal epithelial cells from irradiated and non-irradiated breast tissue of a BRCA1 mutation carrier who underwent bilateral prophylactic mastectomy. Our result supports the notion that precancerous luminal progenitor cells of BRCA1 mutation carriers are particularly sensitive to radiation. The potential lineage-specific radiosensitivity of cells from BRCA1 mutation carriers could be exploited to develop novel prophylactic measures for this select group of at-risk women.Human breast tissue from mastectomy was dissociated enzymatically with collagenase and hyaluronidase per published procedure [11].According to a previously published protocol [6], mammary cell suspension was pre-blocked and then labeled with an allophycocyanin-conjugated rat antibody to CD49f and FITC-conjugated mouse antibody to