The Role of Metalloid/Metal Anions in Progesterone-Independent Activation of Progesterone Receptor

Abstract

Progesterone and progesterone receptor play a central role in hormone responsive tissue. Although there is increasing evidence that disruption of the progesterone pathway is associated with an increased risk of developing breast cancer, there are few known environmental compounds with progesterone-like activity. Previous studies from our laboratory and others show that metalloestrogens including metal/metalloid anions and bivalent cations have estradiol-like activity in breast cancer cell lines that leads to estradiol-independent activation of estrogen receptor alpha. Estrogen receptor alpha and progesterone receptor (PR) have similar protein structures. This study addresses the role of the oxyanions arsenite and nitrite in progesterone independent activation of progesterone receptor (PR). Treatment with arsenite or nitrite induced the expression of the PR responsive genes BIRC3, FKBP5, and STAT5A in T47D-co breast cancer cells that constitutively express PR and in HEK293-T cells that transiently express PRB. Treatment with the pure antiprogesterone EC317 blocked the induction of the expression of the PR responsive genes BIRC3, FKBP5, and STAT5A in T47D-co breast cancer cells in response to arsenite or nitrite treatment. In HEK293T cells transiently transfected with PRB, treatment with arsenite or nitrite recruited PRB to the progesterone response element in the promoters of BIRC3, FKPB5A, and STAT5A. Treatment with the oxyanions also recruited the steroid receptor co-activator 1 (SRC1) and RNA polymerase II (POLII) to the promoters of BIRC3, FKBP5, and STAT5A. In the ligand-binding domain of the PRB, the amino acids that are important for arsenite or nitrite induction of the progesterone responsive genes BIRC3, FKBP5 and STAT5A were S754, H881 and K919. Furthermore, H888 and R899 were important sites for arsenite or nitrite induction of FKBP5 and STAT5A mRNAs. Together, these results suggest that the oxyanions arsenite and nitrite activate PR.