Mammary carcinogenesis is accelerated in a dose-dependent manner by feeding increasing amounts of dietary iron. Under these conditions mammary gland iron increased in proportion to body iron stores. These observations apply to a range of iron intake that is relevant to human nutrition in the United States. We propose to investigate athe mechanism(s) that accounts for these effects. Our approach will test three hypotheses stated in the following aims.
Aim 1. Ho: Oxidative cellular events that can result in mutations in mammary gland DNA are increased with increasing iron. Two indicators of oxidative cellular events will be assessed. They are lipid peroxidation which will be measured as tissue malondialdehyde by HPLC, and 8-hydroxydeoxyguanosine (8-OHdG), which also will be measured by HPLC using electrochemical detection. If cellular oxidation is observed, we will determine if it can be suppressed via dietary antioxidant supplementation and whether suppression of oxidation blocks the promotional effect of increasing amounts of iron on the carcinogenic process. We will also determine if mutations predicted to be associated with athe specific type off DNA damage to be measured occur with increased frequency with increasing iron.
Aim 2. Ho: Increased iron alters clonal expansion via affecting cell proliferation and/or cell death during pre-malignant and malignant stages of the disease process. We have recently developed a model of mammary carcinogenesis in which morphologically identifiable pre- malignant and malignant lesions (intraductal proliferations, ductal carcinoma in situ, and invasive carcinoma) resembling those that are found in the human disease can be identified and studied. The effects of iron will be evaluated: on the frequency of occurrence of these lesions, on changes in cell proliferation and cell death rates in these lesions, and on pathogenetic characteristic of these lesions.
Aim 3. Ho: The process of chemically-induced tumor initiation in the mammary gland will be enhances with increasing iron. We propose to investigate the effect of iron status on the process of tumor initiation induced by a carcinogen that requires metabolic activation. It is hypothesized that the iron status of the host will influence primary and/or secondary metabolism of a proximate carcinogen and/or alter the sensitivity of the mammary gland to carcinogenic insult. If an effect of iron status is observed, additional studies would evaluate for effects on formation of DMBA-DNA adducts, and enzymes that are involved in xenobiotic metabolism. The proposed mechanistic studies may contribute significantly to our understanding of the role of iron in modifying events causally related to the genesis of cancer, and ultimately lead to changes in public health recommendations for cancer prevention.
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