Effect of Estrogen on Mutagenesis in Human Mammary Epithelial Cells

摘要

Epidemiology studies have linked estrogen to breast carcinogenesis. However, the question of how estrogen acts as a carcinogen is basically unanswered. We hypothesized that estrogen signaling through the estrogen receptor alpha (ERalpha) may induce a mutator phenotype by suppressing DNA repair activity in ERalpha positive mammary epithelial cells. To determine the effect of estrogen and/or ERalpha on DNA repair activity in the ERalpha positive human breast cancer cells, we have developed a method to measure DNA repair activity and DNA mutation rate in live cells. Measurements of DNA repair efficiency showed that ERalpha positive cells had significantly lower DNA repair activity than ERalpha negative cells. Ectopic expression of ERalpha in ERalpha negative breast cancer cells reduced DNA repair activity. Treatment of ERalpha positive breast cancer cells with estrogen inhibited DNA repair and increased mutation rate. Our results suggest that estrogen/ER may induce genetic instability by suppressing DNA repair activity resulting in an increased DNA mutation rate.