Silencing the estrogen receptor promoter using DIF‐1, a naturally occurring differentiation molecule of the cellular slime mold Dictyostelium discoideum

Abstract

Drugs and environmental chemicals exhibit estrogenic activities by various signaling pathways. Recently, we have shown that pesticides like DDT activate cell signals involved in estrogen receptor (ERα) coregulator recruitment. We have also shown that plant compounds extracted from soy are potent antiestrogens. In the present study we employ a naturally occurring compound secreted by the slime mold Dictyostelium discoideum to probe the basis of estrogenicity. Differentiation inducing factor 1 (DIF‐1) is a morphogen and mitogen in the slime mold. Our objective was to determine the estrogenic activity or lack thereof of DIF‐1 in a model system (ERα (+) breast cancer cell line MCF‐7). Using colony assays, we showed DIF‐1 blocks MCF‐7 cell growth. ERE‐luciferase assays showed DIF‐1 inhibited ERα activity. Quantitative PCR revealed DIF‐1 inhibited the transcription of the ERα regulated genes stromal derived factor 1 (SDF‐1) and progesterone receptor (PR), and Western blot analysis showed DIF‐1 downregulated total ER. Finally, an ER promoter assay was used to show DIF‐1 partially blocks transcription of ERα. This represents a novel mechanism for anti‐estrogenic action in mammalian cells. Our results present DIF‐1 as a novel ER antagonist which will shed light on the mechanism of action of estrogenic compounds. This work was supported by the Office of Naval Research, grant number N00014‐06‐1136.