Retinoids are promising chemopreventive agents in animals and in humans. However, because currently available retinoids are relatively toxic, retinoids are not generally used for cancer prevention. The long-term goal of our studies is to elucidate the mechanisms by which retinoids inhibit carcinogenesis in order to develop more effective and less toxic chemopreventive agents. Our preliminary studies demonstrate that 9cRA suppresses mammary tumor development in transgenic mice, but that is also induces significant toxicity. We have also shown that pathway- selective retinoids, which may be less toxic than naturally occurring broad spectrum retinoids, can inhibit the proliferation of normal and malignant breast cells. We now propose to test the hypotheses that pathway-specific retinoids will efficiently prevent breast carcinogenesis with reduced toxicity. Firstly, we will determine whether the ability of retinoids to suppress breast tumorigenesis is dependent on the specific oncogenic pathway. We will compare the chemopreventive efficacy of 9-cis retinoic acid (9cRA) in different animal models which develop breast tumors through distinct mechanisms, such as by overexpression of the c-myc or Her2/neu genes, or by chronic estrogen exposure. We will also determine whether this broad-spectrum retinoid interferes with the progression of premalignant to malignant breast tumors in these models. Secondly, we will determine which pathway-selective retinoids are able to suppress carcinogenesis in vivo. We will compare the chemopreventive efficacy and toxicity of RAR-, RXR-, and anti-AP-1-selective retinoids with that of 9cRA in animals in which 9cRA prevents breast carcinogenesis. Thirdly, we will determine whether changes in the expression of retinoid-regulated genes involved in growth regulation are associated with successful chemoprevention by retinoids. We will investigate the retinoid-induced changes in the expression of RARbeta, E-cadherin and matrix metalloproteinase-9, all of which are involved in regulating the growth and invasiveness of breast cells. We will then determine whether changes in the expression of these markers are associated with decreased proliferation, increased apoptosis, or decreased invasiveness. Through these studies we plan to identify pathway-selective retinoids which effectively prevent mammary tumorigenesis with minimal toxicity. Such investigations will provide the foundation for the development of more specific preventive retinoids and the justification for testing such agents in clinical chemoprevention trials in humans.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078480-04
Application #
6350310
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1999-04-06
Project End
2004-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
4
Fiscal Year
2001
Total Cost
$351,034
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
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Li, Yuxin; Shen, Qiang; Kim, Hee-Tae et al. (2011) The rexinoid bexarotene represses cyclin D1 transcription by inducing the DEC2 transcriptional repressor. Breast Cancer Res Treat 128:667-77
Uray, Iván P; Brown, Powel H (2011) Chemoprevention of hormone receptor-negative breast cancer: new approaches needed. Recent Results Cancer Res 188:147-62
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Uray, Iván P; Shen, Qiang; Seo, Hye-Sook et al. (2009) Rexinoid-induced expression of IGFBP-6 requires RARbeta-dependent permissive cooperation of retinoid receptors and AP-1. J Biol Chem 284:345-53
Li, Y; Zhang, Y; Hill, J et al. (2008) The rexinoid, bexarotene, prevents the development of premalignant lesions in MMTV-erbB2 mice. Br J Cancer 98:1380-8

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