Progression and regression of mammary preneoplasia

乳腺肿瘤前期的进展和消退

• 批准号: 7740957
• 负责人: Priscilla A. Furth
• 金额: $ 8.9万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-23 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740957
• 关键词: Adenocarcinoma; Affect; Age-Months; BRCA1 gene; Breast; Cell Cycle; Chemoprevention; Cyclin D1; Data; Development; Disease; Disease regression; Ductal; Engineering; Epithelial; Epithelial Cells; Epithelial-Stromal Communication; Estrogen Antagonists; Estrogen Therapy; Estrogens; Functional disorder; Gene Expression; Genetic; Green Fluorescent Proteins; Growth; Growth and Development function; Hormonal; Hormones; Human; Image; Interruption; Intraductal Hyperplasia; Length; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Measures; Modeling; Molecular; Mutation; NCOA3 gene; Neonatal; Noninfiltrating Intraductal Carcinoma; Nuclear; Nutritional; Organ Culture Techniques; Pattern; Principal Investigator; Protein Isoforms; Proteins; Research Design; Role; Signal Pathway; Signal Transduction; Stromal Cells; Structure; Techniques; Technology; Testing; Time; Tissues; Transgenic Mice; Transplantation; Tumor Suppressor Genes; Ultrasonography; Variant; animal tissue; base; cancer initiation; human disease; in vivo; malignant breast neoplasm; mouse model; novel; pre-clinical; programs; research study; response; time use

_ROVIDED. Long term aims: Understand how ERa driven breast cancers originate, develop more effective and less toxic approaches for chemoprevention, and determine if/how environmental and nutritional factors impact disease. This proposal will determine the role of three specific genetic factors in the development of breast preneoplasia and establish if they block regression of disease following hormone-based therapies. A novel conditional mouse model of mammary specific deregulated ERa expression that develops ductal hyperplasia and DCIS by 4 months of age will be used. The study will test if co-activators AIB1 and A3AIB1, cell cycle regulator Cyclin D1, or loss of tumor suppressor gene Brcal collaborate with ERa and/or compromise the response of preneoplasia and DCIS to anti-estrogen therapies. The hypothesis is that gain of AIB1, A3AIB1, or Cyclin D1 function or loss of Brcal function collaborate with ERa to promote mammary cancer initiation and progressionand impair the response to anti-estrogen-based chemoprevention. Specific aims are: i. Determine how gain of AIB1 or A3AIB1 or loss of AIB1 alters hormonal signaling patterns, development of ERa initiated preneoplasia and cancer or response to anti-estrogens, ii. Find out how gain or loss of Cyclin D1 alters development of ERa initiated preneoplasia and cancer and determine if changes in Cyclin D1 expression levels alter the response of preneoplasia to anti-estrogens, iii. Define how loss of full- length Brcal alters development of ERa initiated preneoplasia and cancer and test if loss of full-length Brcal compromises the response to anti-estrogens. The combination of genetically engineered whole mouse models, mammary gland transplants and mammary gland organ cultures will be used to identify specific pathophysiological mechanisms including changes in hormone responsiveness, variations in gene expression and activity, and altered epithelial-stromal interactions. Pathophysiological changes will be followed in vivo in real-time using ultrasonography and green flourescent protein-based technology.

_ROVIDED。