Our goal is to discover drugs that will make menopausal hormone therapy (MHT) safe for long-term treatment of chronic conditions associated with menopause. Due to the increasing longevity of women, menopause has become a critical issue in Women's Health. Life expectancy for women is now 81.2 years. Unlike just a century ago, most women will reach menopause and live approximately one-third of their life after menopause. There are currently 36 million menopausal women in the U.S. and the number is projected to soar to about 50 million in 25 years. Unfortunately, menopause is associated with an increase in the incidence of osteoporosis, obesity, diabetes and metabolic syndrome. Long term exposure to MHT decreases the risk of these conditions. MHT is approved for short-term treatment of hot flashes and vaginal/vulvar symptoms, since long-term treatment with MHT is associated with an increased risk of breast cancer, cardiovascular risks and Alzheimer's disease. A major breakthrough in primary prevention for Women's Health would occur if safer MHT regimens could be developed for long-term treatment. We discovered compounds termed ERα coligands that reprogram the effects of estradiol on gene expression and cell proliferation. Our data indicate that the ERα coligand binds to the surface of ERα, at a separate binding site than estrogens, leading to an increase in binding of E2 to its binding site. The binding of both ligands simultaneously to ERα produces a change in conformation as demonstrated by an alteration in the melting temperature of ERα. These studies indicate that the conformation of the E2-ERα-ER coligand complex is distinct from the E2-ERα complex leading to the reprogramming of the E2 transcriptional and cellular effects. In fact, we found that the E2/ERα coligand combination reprograms E2 to regulate over 800 unique genes in U2OS cells. These genes are not regulated by E2 or the ERα coligand alone. It is well established that E2 stimulates the proliferation of MCF-7 breast cancer cells by binding to ERα resulting in the activation of oncogenes, such as c-MYC. We found that the ERα coligand reprograms ERα so E2 no longer causes cell proliferation, nor does it stimulate c-MYC production. The ERα coligand also blocked E2 stimulation of uterine growth in mice. Based on these findings, we hypothesize that ERα coligands can be combined with existing estrogens, used in MHT, to block the adverse proliferative action of E2 to allow the ERα coligand/estrogen combination to be used safely for long-term MHT treatment. The aim of this phase I proposal is to select a lead ERα coligand/estrogen combination that has the best safety profile in cultured cells and animals prior to advancing it to Pharmacokinetic/Pharmacodynamic and other pre-clinical testing in a phase II proposal. These studies have the potential to facilitate the early development of a new type of MHT, that can be used for long-term administration, to prevent chronic diseases associated with menopause, such as osteoporosis, obesity, diabetes and metabolic syndrome.
Public Health Relevance Statement: Public Health Relevance: Estrogen Receptor α Coligand Reprogramming of Menopausal Hormone Therapy
Project narrative: Menopause is associated with chronic conditions, such as osteoporosis, obesity, and diabetes. While studies indicate that estrogens in menopausal hormone therapy (MHT) can prevent these conditions in postmenopausal women, current MHT regimens are not approved for these indications, because long-term MHT can result in life threatening adverse events. The objective of this proposal is to determine if an estrogen receptor α coligand can reprogram estrogen's effect in cancer cells and mice to block adverse proliferative effects. These studies could facilitate the development of new, safer MHT regimens that can be used for long-term therapy to prevent chronic conditions associated with menopause.
Project Terms: Abdomen; Adverse event; Alzheimer's Disease; Animals; base; Binding; Binding Sites; Blood; bone; bone cell; Breast; Breast Cancer Cell; cancer cell; cancer risk; cardiovascular risk factor; Cell Count; Cell Culture Techniques; Cell Line; Cell Proliferation; Cells; Chronic; Chronic Disease; Clinical Research; Combined Modality Therapy; Complex; Cultured Cells; Data; Development; Diabetes Mellitus; diabetes risk; Drug Combinations; Drug Kinetics; Endometrial Carcinoma; Estradiol; Estriol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Estrone; Ethinyl Estradiol; Event; Exposure to; Fatty acid glycerol esters; Female; Flow Cytometry; Fracture; Gene Expression; Genes; Goals; Growth; Health; hormone therapy; Hot flushes; improved; in vivo; Incidence; inflammatory marker; innovation; interest; Lead; Life; Life Expectancy; Ligands; Longevity; malignant breast neoplasm; Mammary gland; MCF7 cell; Measures; Mediating; melting; Menopause; Metabolic; Metabolic syndrome; Molecular Conformation; molecular modeling; Molecular Models; Mus; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; novel; Obesity; Oncogene Activation; Osteitis; Osteoporosis; Osteoporosis prevention; Pharmaceutical Preparations; Pharmacodynamics; Phase; Ploidies; Postmenopause; prevent; Prevention; Primary Prevention; Production; Proliferation Marker; public health relevance; Raloxifene; Regimen; research clinical testing; Risk; Safety; Selective Estrogen Receptor Modulators; Serum Markers; stroke; Surface; Symptoms; Temperature; Testing; Tissues; Uterus; Vagina; Vulva; Weight; Weight Gain; Wo
