Iron is an essential nutrient utilized in metabolic processes and in cell proliferation. In addition, mammary epithelial cells have a unique requirement for iron, because they synthesize iron-lactoferrin complex as an iron source of mother's milk to meet the iron needs of the newborn. Our hypothesis is that the chronic ingestion of diets containing high iron concentrations overloads the iron storage and utilization capacity of mammary cells and in concert with estrogen induces mammary tumors. The excess iron may cause toxicities such as lipid peroxidation and free radical-mediated DNA and protein damage. Cells damaged by these processes and at the same time responding to estrogen stimulation of growth may be transformed and develop into mammary tumors. Dr. Liehr will examine this hypothesis by addressing the following questions. 1. a) Does iron accumulate in kidney of hamsters or mammary tissue of Noble (Nb) rats (animal models for estrogen-induced carcinogenesis) in response to estrogen treatment? b) Is this iron accumulation an estrogen receptor-dependent process? c) Does iron continue to accumulate in these rodent organs under conditions of chronic treatment with estradiol implants and cause toxicity at excess tissue iron concentrations? d)Does iron redistribute to organs of estrogen-induced carcinogenesis in estrogen-treated animals receiving a low iron-containing diet? 2. Does a low iron diet (3.5 ppm Fe) prevent estrogen-induced carcinogenesis? 3. Does iron accumulate in """"""""normal"""""""" tissue surrounding tumors of breast cancer patients compared to controls? 4. What are the cellular mechanisms of action and interaction between iron and estrogens in MCF-10A immortal human mammary epithelial cells and in MCF-7 breast cancer cells? His studies will determine whether dietary iron accumulation causes breast cancer. In future experiments he will extend his findings to understanding the interactions of vitamins A and D with estrogens and iron in the etiology of breast cancer, and extend his hypothesis to prostate cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Chemical Pathology Study Section (CPA)
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Yang, Shen K
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Stehlin Foundation for Cancer Research
United States
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Liehr, J G; Jones, J S (2001) Role of iron in estrogen-induced cancer. Curr Med Chem 8:839-49
Liehr, J G (2001) Genotoxicity of the steroidal oestrogens oestrone and oestradiol: possible mechanism of uterine and mammary cancer development. Hum Reprod Update 7:273-81
Liehr, J G (2000) Is estradiol a genotoxic mutagenic carcinogen? Endocr Rev 21:40-54
Newbold, R R; Liehr, J G (2000) Induction of uterine adenocarcinoma in CD-1 mice by catechol estrogens. Cancer Res 60:235-7
Liehr, J G (2000) Role of DNA adducts in hormonal carcinogenesis. Regul Toxicol Pharmacol 32:276-82
Jefcoate, C R; Liehr, J G; Santen, R J et al. (2000) Tissue-specific synthesis and oxidative metabolism of estrogens. J Natl Cancer Inst Monogr :95-112
Wyllie, S; Liehr, J G (1998) Enhancement of estrogen-induced renal tumorigenesis in hamsters by dietary iron. Carcinogenesis 19:1285-90