_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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA112176-05S1
Application #
7740957
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Ogunbiyi, Peter
Project Start
2004-12-23
Project End
2010-11-30
Budget Start
2008-12-01
Budget End
2010-11-30
Support Year
5
Fiscal Year
2009
Total Cost
$88,950
Indirect Cost
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
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Assefnia, Shahin; Kang, Keunsoo; Groeneveld, Svenja et al. (2014) Trp63 is regulated by STAT5 in mammary tissue and subject to differentiation in cancer. Endocr Relat Cancer 21:443-57
Mahmoodzadeh, Shokoufeh; Leber, Joachim; Zhang, Xiang et al. (2014) Cardiomyocyte-specific Estrogen Receptor Alpha Increases Angiogenesis, Lymphangiogenesis and Reduces Fibrosis in the Female Mouse Heart Post-Myocardial Infarction. J Cell Sci Ther 5:153
Dabydeen, Sarah A; Furth, Priscilla A (2014) Genetically engineered ER?-positive breast cancer mouse models. Endocr Relat Cancer 21:R195-208

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