The applicant's long term goal is to understand the role of the vitamin A signaling pathway in normal breast development and the role of inactivation of this pathway in breast cancer development. Vitamin A is essential in mammalian embryogenesis and the maintenance of tissue differentiation. Cellular response to vitamin A, or retinol, is mediated by a family of nuclear receptors for retinoic acid, i.e., cells must import, store and oxidize retinol, forming retinoic acid (RA) or other RAR ligands in order to evoke a response. The cellular retinol binding protein I (CRBP) was recently shown to be essential for vitamin A homeostasis due to its role in retinol storage. Once formed, RA binds to nuclear RA receptors (RAR-alpha, -beta, -gamma), which act as ligand dependent transcription factors to regulate target gene transcription. RAR-beta2 is a growth suppressor that is inactivated in human breast cancer. The applicant has shown that CRBP expression is also inactivated in human breast cancer and that CRBP suppresses the malignant transformation of SV40 large T-immortalized human breast epithelial cells. These and other observations provide a strong rationale for the thus far untested hypothesis that underexpression of these and other retinoid signaling genes promote mammary carcinogenesis. He will now address this hypothesis using two animal models: CRBP and RAR knockout mice (Aim 1) and MMTV-dominant negative RAR (DNRAR) transgenic mice (Aim 2). The susceptibility of these animals to DMBA-induced carcinogenesis and the ability of functional RAR inactivation to synergize with the neu oncogene (bitransgenic animals) will be studied. Biomarker assays will identify the cellular process accounting for observed changes in tumor incidence.
In Aim 3 the applicant will define the mechanism of tumor suppression by CRBP, focusing on the hypothesis, based on preliminary data, that CRBP increases retinol storage and RA availability and downregulates the expression of invasion and metastasis genes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA054273-10
Application #
6375900
Study Section
Special Emphasis Panel (ZRG1-ET-2 (03))
Project Start
1991-04-01
Project End
2005-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
10
Fiscal Year
2001
Total Cost
$322,050
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
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Cohn, Ellen; Ossowski, Liliana; Bertran, Silvina et al. (2010) RAR?1 control of mammary gland ductal morphogenesis and wnt1-tumorigenesis. Breast Cancer Res 12:R79
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