Effects of Radiation Therapy on Breast Epithelial Cells in BRCA1/2 Mutation Carriers

Abstract

Women carrying BRCA1 and BRCA2 mutations have significantly elevated risk of developing breast and ovarian cancers. BRCA1-associated breast cancer likely originates from progenitors of the luminal epithelial lineage. Recent studies indicate that radiation therapy (RT) for BRCA1 cancer patients is associated with lower incidence of developing subsequent ipsilateral breast cancer. In the current study, we analyzed tumor-free breast tissue procured via prophylactic bilateral mastectomy from three BRCA1 and one BRCA2 mutation carriers, who had been previously treated with RT for unilateral breast cancers. Freshly isolated breast cells from the irradiated and nonirradiated breast tissue of the same individuals were subjected to flow cytometry, using established cell-surface markers. Two out of the three BRCA1 carriers and one BRCA2 carrier exhibited significantly diminished luminal cell population in the irradiated breast versus the nonirradiated side. There was also RT-associated reduction in the colony-forming ability of the breast epithelial cells. Our finding suggests that prior RT could result in the depletion of the luminal epithelial compartment and thus reduced incidence of BRCA1/2-associated breast cancer.

Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis

“…2a and Supplementary Fig. 2)29. Four distinct cell populations were acquired: stromal cells, basal epithelial cells, luminal progenitor (LP) cells and mature luminal epithelial (ML) cells.…”

Nonsurgical Options for Risk Reduction of Contralateral Breast Cancer in BRCA Mutation Carriers With Early-Stage Breast Cancer

“…42 Several mechanisms may contribute to risk reduction by mammary irradiation (Fig 1), including elimination of cells that may have already transformed to malignant cells, radiation induced arrest of mammary epithelial cells proliferation leading to decreased accumulation of transmissible genetic aberrations, and reduction of the luminal epithelial compartment. 43 An indirect indicator for these effects is reduction of breast density after adjuvant irradiation. 44 The state of Israel has a relatively large cohort of BRCA mutation carriers, and nearly 20% of young Israeli patients with BC are mutation carriers.…”