Progesterone stimulates proliferation of a long-lived epithelial cell population in rat mammary gland.

Abstract

Long-lived somatic cells such as stem/progenitor cells may progressively accumulate oncogenic mutations and cause cancer. Some evidence suggests that pre-menopausal administration of progesterone confers a long-term increased risk of breast cancer. To clarify the effect of progesterone on long-lived mammary epithelial cells in rats. Female Sprague- Dawley rats (3 and 7 weeks of age) were implanted sc with 14-day slow-release pellets of 5-bromo-2'-deoxyuridine (BrdU) and were sacrificed every 2 weeks between 0 and 10 weeks after the release period. Some rats at 7 weeks of age were also implanted with progesterone and sacrificed 0 or 10 weeks after the release period. Mammary glands were examined by immunohistochemistry and immunofluorescence for BrdU, proliferative cell nuclear antigen (PCNA) and progesterone receptor (PR). After BrdU labeling of 3- and 7-week-old rats, the BrdU index decreased gradually over 10 weeks and resulted in small fractions (1-3%) of label-retaining epithelial cells (LREC) 10 weeks after BrdU labeling in both mammary lobules and ducts. Treatment with progesterone during labeling significantly increased the fraction of long-lived LREC in lobules and ducts by 9- and 4-fold, respectively. The long-lived LREC population in the ducts was enriched for PCNA- and PR-positive cells, but the percentage of positive cells was not affected by progesterone in either lobules or ducts. Progesterone stimulates proliferation of a long-lived epithelial cell population in the mammary lobules and ducts of rats. Such cells in the duct are characterized by a high proliferation rate and PR expression.