Mammary and endometrial cancer are among the leading causes of premature death in North American women. Approximately one in nine women in this country will develop breast cancer during their lifetime and the incidence of mammary cancer has been increasing. Over 150,000 new cases of endometrial cancer are diagnosed worldwide each year. Epidemiology studies have clearly demonstrated that both mammary and endometrial cancer share a common set of risk factors including: early age at menarche, late age at menopause, obesity, parity and increased exposure to unopposed estrogen. A high percentage of early stage mammary tumors are estrogen receptor positive (ER+), and many of these patients respond to antiestrogen or endocrine therapy with drugs such as tamoxifen which has now been successfully used for treatment of several million women with breast cancer. Unfortunately, resistance to tamoxifen can develop in some patients and there is now increasing concern that long term use of this drug increases the risk for endometrial cancer. Therefore, it is imperative to develop new drugs which can be used alone or in combination therapy (e.g. with tamoxifen) for treatment of hormone-dependent tumors. Our studies have identified alternate-substituted alkyl PCDFs as a new mechanism-based class of antiestrogens which block estrogen-induced mammary and endometrial cell/tumor growth via crosstalk between the ER and Ah receptor signaling pathways. Based on results of previous studies, the antitumorigenic activities of selected alkyl PCDFs will be thoroughly investigated in the DMBA-induced rat mammary tumor model (Aim 1) and athymic nude mice bearing breast cancer cell xenografts (Aim 2).
Aim 3 will focus on their inhibition of endometrial cancer growth in rodent models and Aim 4 will determine the important interaction of tamoxifen and alkyl PCDFs in both mammary and endometrial cancer models. These studies will also determine tissue-specific inhibition of tamoxifen-induced estrogenic responses in the uterus, bone and on serum cholesterol levels by alkyl PCDFs. Preliminary studies indicate that alkyl PCDFs block the effects of tamoxifen only in the uterus. Thus the proposed studies will define a new mechanism-based class of antiestrogens that can be used alone or in combination with tamoxifen for treatment of breast and endometrial cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA064081-04A1
Application #
2843979
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Forry, Suzanne L
Project Start
1995-04-14
Project End
2002-05-31
Budget Start
1999-06-01
Budget End
2000-05-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Texas A&M University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047006379
City
College Station
State
TX
Country
United States
Zip Code
77845
Safe, Stephen; McDougal, Andrew (2002) Mechanism of action and development of selective aryl hydrocarbon receptor modulators for treatment of hormone-dependent cancers (Review). Int J Oncol 20:1123-8
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McDougal, A; Gupta, M S; Morrow, D et al. (2001) Methyl-substituted diindolylmethanes as inhibitors of estrogen-induced growth of T47D cells and mammary tumors in rats. Breast Cancer Res Treat 66:147-57
Safe, S (2001) Molecular biology of the Ah receptor and its role in carcinogenesis. Toxicol Lett 120:1-7
Wormke, M; Castro-Rivera, E; Chen, I et al. (2000) Estrogen and aryl hydrocarbon receptor expression and crosstalk in human Ishikawa endometrial cancer cells. J Steroid Biochem Mol Biol 72:197-207
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Fernandez, P; Wilson, C; Hoivik, D et al. (1998) Altered phenotypic characteristics of T47d human breast cancer cells after prolonged growth in estrogen-deficient medium. Cell Biol Int 22:623-33
Wang, W; Smith 3rd, R; Safe, S (1998) Aryl hydrocarbon receptor-mediated antiestrogenicity in MCF-7 cells: modulation of hormone-induced cell cycle enzymes. Arch Biochem Biophys 356:239-48
Wang, W L; Porter, W; Burghardt, R et al. (1997) Mechanism of inhibition of MDA-MB-468 breast cancer cell growth by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Carcinogenesis 18:925-33
Sun, G; Safe, S (1997) Antiestrogenic activities of alternate-substituted polychlorinated dibenzofurans in MCF-7 human breast cancer cells. Cancer Chemother Pharmacol 40:239-44

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