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Abstract

Grant Number:	5R01CA112176-03
Project Title:	Progression and regression of mammary preneoplasia

PI Information:	Name	Email	Title
	FURTH, PRISCILLA A.	paf3@georgetown.edu	PROFESSOR

Abstract: DESCRIPTION (provided by applicant): 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 ?3AIB1, cell cycle regulator Cyclin D1, or loss of tumor suppressor gene Brca1 collaborate with ERa and/or compromise the response of preneoplasia and DCIS to anti-estrogen therapies. The hypothesis is that gain of AIB1, ?3AIB1, or Cyclin D1 function or loss of Brca1 function collaborate with ERa to promote mammary cancer initiation and progression and impair the response to anti-estrogen-based chemoprevention. Specific aims are: i. Determine how gain of AIB1 or ?3AIB1 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 Brca1 alters development of ERa initiated preneoplasia and cancer and test if loss of full-length Brca1 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.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
breast neoplasm, carcinogenesis, gene expression, neoplasm /cancer genetics, neoplastic process, preneoplastic state
biological signal transduction, brca gene, chemoprevention, cyclin, green fluorescent protein, growth factor, growth factor receptor, neoplasm /cancer remission /regression, ultrasonography
athymic mouse, immunocytochemistry, polymerase chain reaction, terminal nick end labeling, western blotting

Institution:	GEORGETOWN UNIVERSITY
	37TH AND O STS NW
	WASHINGTON, DC 20057
Fiscal Year:	2007
Department:	ONCOLOGY
Project Start:	23-DEC-2004
Project End:	30-NOV-2009
ICD:	NATIONAL CANCER INSTITUTE
IRG:	TCB

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