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LRH-1 Antagonism: Impact on Estrogen-dependent Breast Cancer

LRH-1 拮抗剂：对雌激素依赖性乳腺癌的影响

基本信息

批准号：
8442839
负责人：
MARCIA I. DAWSON
金额：
$ 38.03万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-12 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8442839
关键词：
Ablation Adipose tissue Adjuvant Adjuvant Therapy Adrenal Glands Adverse effects Adverse event Androgens Androstenedione Aromatase Aromatase Inhibitors Attenuated Binding Biological Assay Breast Breast Cancer Cell Cancer Patient Cancer cell line Cancerous Cell Line Cell Proliferation Cellular biology Computer Analysis Coupled Cyclin D1 Diagnosis Disease Elements Engineering Enzymes Estrogen Antagonists Estrogen Nuclear Receptor Estrogen Receptors Estrogens Genes Genetic Transcription Human Immunodeficient Mouse In Vitro Indium Lead Ligand Binding Ligand Binding Domain Ligands Malignant Neoplasms Mammary Gland Parenchyma Memory Loss Menopause Methods Molecular Biology Mus Mutagenesis Nuclear Orphan Receptor Nuclear Receptor Gene Ovary Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Postmenopause Production Proteins Recurrence Relapse Reporter Reporter Genes Resistance Role Signal Pathway Spectrometry Synthesis Chemistry Therapeutic Tissues Validation Woman Xenograft Model base bone loss cancer cell computer studies design human NR5A2 protein improved in vivo interdisciplinary approach malignant breast neoplasm multidisciplinary overexpression pharmacophore prevent promoter scaffold small heterodimer partner protein small molecule transcription factor treatment duration

项目摘要

DESCRIPTION (provided by applicant): Using NMR spectrometry and reporter assays we identified liver receptor homolog 1 (LRH-1) transcriptional antagonists. We hypothesize that LRH-1-selective antagonists would be useful for treating or preventing recurrence of estrogen-dependent breast cancer in postmenopausal women. We base this hypothesis on the following findings: After menopause, estrogen is produced locally in breast tissue rather than coming from the ovary. In the postmenopausal cancerous breast, expression of the enzyme synthesizing estrogen (aromatase) becomes elevated, as do estrogen and the estrogen nuclear receptor (ER). Moreover, compared to other tissues, aromatase is expressed by activation of a different promoter that is responsive to binding by LRH-1, an orphan nuclear receptor. LRH-1 is also overexpressed in the postmenopausal cancerous breast. There, the major producer of estrogen is the preadipocyte followed by the cancer cell. Thus, treatment with an LRH-1 antagonist would locally reduce estrogen levels compared to adjuvant therapeutics such as estrogen antagonists and aromatase inhibitors and, thereby, attenuate the adverse systemic effects caused by whole-body estrogen ablation. Use of a dual therapeutic approach may also extend the treatment period for adjuvant therapy until relapse occurs. LRH-1 also activates the ER gene promoter to induce the expression of the ER, which in the presence of estrogen is activated to drive breast cancer cell proliferation. LRH-1 also has independent roles in cell proliferation and invasion that are related to its ability to induce the expression of other genes such as cyclin D1 and c-Myc. Therefore, treatment with an LRH-1 antagonist could block estrogen-dependent breast cancer cell proliferation and invasion. We propose a three-year multidisciplinary project involving three Specific Aims: (1) LRH-1 antagonist design and synthesis based on direct design and SAR approaches. The lead antagonist was first found to interact with another orphan nuclear receptor, small heterodimer partner. On the basis of computational analysis, we hypothesize that appropriate scaffold substitutions will selectively enhance interaction with the LRH-1 ligand-binding domain and improve antagonism of transcriptional activity. (2) Bioevaluation in preadipocyte and estrogen-dependent cell lines coupled with mutagenesis studies will enable us to identify an LRH-1 pharmacophore and ligand-binding pose in the human LRH-1 ligand-binding pocket to optimize activity. The antagonists will also permit us to investigate LRH-1 signaling pathways in breast cancer cells and preadipocytes. (3) In vivo validation in an estrogen-dependent breast cancer xenograft model in ovariectomized immunodeficient mice inoculated with engineered cancer cells stably expressing LRH-1 and treated with the estrogen precursor androstenedione.

描述（由申请人提供）：