Physiological and pathological aspects of the ligand-activated transcription factors: AhR and ERβ
Ligand-activated transcription factors are a diverse group of proteins that are involved a variety of physiological processes. The purpose of these studies was to investigate the aryl hydrocarbon receptor (AhR) knockout mouse and the effects of hormone replacement therapy on the postmenopausal breast in order to better understand the functions of the ligand-activated transcription factors AhR and estrogen receptor β (ERβ). In the first part of these studies, we investigated the AhR knockout mouse in order to further elucidate the physiological functions of AhR. These mice developed stones in their urinary bladders composed of 100% uric acid while the serum uric acid levels remained normal. We determined these stones were formed by the breakdown of DNA into uric acid from a large number of dying cells. These mice also develop fibrosis of their ventral prostates and a phenotype in the immune system similar to chronic myeloid leukemia. The second part of these studies was to investigate the effects of hormone replacement therapy on the histology and expression of various ligand-activated transcription factors in the postmenopausal breast. We treated postmenopausal women with estrogen or estrogen-progesterone therapy for 3 months and took biopsies of the breasts before and after treatment. Expression of several proteins including AhR, ERα, and ERβ were unchanged after treatment while expression of progesterone receptors was increased. Proliferation and breast density were unchanged by treatment in these breasts; however, we show possible mechanisms leading to proliferation and development of density in non-cancerous breast tissue. In conclusion, these studies revealed a role for AhR in prostatic development, uric acid formation, and leukemia, and have provided new information on the safety of short-term use of HRT.