RT is associated with reduced recurrence of sporadic [15
] as well as BRCA1
-associated breast cancer [3
]. In fact, whole-breast low-dose RT has been proposed as an alternative to prophylactic mastectomy [17
]. Historically, RT was thought to primarily target residual tumor cells left behind after excision of the primary tumor, despite histologically cancer-free margins [4
]. While this remains a viable hypothesis, our finding that RT is associated with a dramatically reduced luminal compartment and diminished progenitor cell activity provides an additional possible mechanism by which RT could reduce incidence of cancer recurrence. Our observation is consistent with the notion that radiation reduces the number of non-cancerous luminal progenitor cells, the likely cell of origin for BRCA1
-associated tumors, thus leading to reduced cancer incidence.
There are several limitations in the current study. First, while our data indicate a relatively larger fraction of basal/myoepithelial cells in the irradiated breast, it is unclear whether this was due to an absolute increase in their number or a relative effect due to the decrease in luminal progenitor cells. However, the similarity in the abundance of the stromal proportion in both breasts argues that there were absolute changes in number of both epithelial compartments. Second, whether the changes observed in our study are unique to breast epithelial cells from BRCA1 mutation carriers needs to be determined. In addition, it is important to validate these results when more samples of BRCA1 patients with similarly uncommon confluence of events become available. However, since these results are consistent across disparate technological and methodological platforms, including FACS, IHC, and the cell-based functional assay, it is unlikely that they are due to chance alone. Lastly, we do not know the long-term effects of RT on the breast cancer incidence for the particular individual involved in the study.
The generality of the BRCA1 function in double-strand break repair, as demonstrated in numerous in vitro systems, is in stark contrast to its highly tissue-specific nature as a tumor suppressor. Consistent with this, there are no reports of excessive radiosensitivity in skin or connective tissue of BRCA1 mutation carriers who receive RT. Likewise, we did not observe any significant difference between the stromal cell populations of the irradiated and non-irradiated breast samples. Therefore, radiosensitivity of cells from BRCA1 mutation carriers may depend on their tissue location, differentiation lineage, and developmental stage. As our study was conducted two years after RT, the observed difference is most likely long-term, not acute, effects of radiation. This is an especially important consideration when exploring a radiation-based preventive approach.
In conclusion, our study reveals an interesting association between RT and reduced luminal epithelial population in the breast tissue of a BRCA1 mutation carrier. The potential vulnerability of luminal epithelial cells to RT could be the “Achilles’ heel” for the cell of origin of BRCA1-associated tumors, exploitation of which may guide the development of novel preventive options for this very select patient population.