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    Awarded Grants
    Role of Nitrites/Nitrates in the Etiology of Breast Cancer

    Scientific Abstract:
    Background: Epidemiological studies show that endocrine status is an important underlying factor in the prediction of risk for breast cancer due to the hormonal control of breast cell proliferation. The prominence of estrogens in the etiology of the disease suggests that environmental exposures that mimic the effects of estrogens may be potential risk factors for breast cancer. Preliminary data presented in this grant show that nitrites and nitrates have estrogen like effects in breast cancer cells. Similar to estradiol, nitrites and nitrates induced the growth of the breast cancer cells MCF-7, induced the estrogen regulated gene progesterone receptor, and activate estrogen receptor (ER- in transient transfection experiments. The ability of nitrites and nitrates to mimic the functions of estradiol was blocked by an antiestrogen suggesting that their effects were mediated by ER- Hypothesis: This proposal will test the hypothesis that nitrites and nitrates play a role in the both the etiology and progression of breast cancer, in part, due to their ability to activate the estrogen receptor. Specific Aims: Aim 1 will determine whether nitrites and nitrates have estrogen like activity in breast cancer cells and aim 2 will determine whether these compounds have estrogen like activity in vivo. More specifically, aim 1 will: 1, determine whether dietary and environmentally relevant amounts of nitrites and nitrates activate ER- in breast cancer cells; 2, determine the mechanism by which these compounds activate the receptor; and 3, determine whether growth factors and cytokines activate ER- through a pathway mediated by nitric oxide synthase. Aim 2 will determine whether nitrites and nitrates have estrogen like effects in the uterus, mammary gland, hypothalamus, and pituitary of ovariectomized animals. Potential Outcomes and Benefits of Research: If the results of these studies demonstrate that low doses of nitrites and nitrates activate the estrogen receptor, than environmental as well as occupational exposures to these compounds would be an important target for prevention efforts. Understanding the mechanism by which nitrites and nitrates influence the progression of breast cancer will also allow us to design appropriate treatment strategies that block their actions.

    Lay Abstract:
    Background: Epidemiological studies show that endocrine status is an important underlying factor in the prediction of risk for breast cancer due to the hormonal control of breast cell proliferation. The prominence of estrogens in the etiology of the disease suggests that environmental exposures that mimic the effects of estrogens may be potential risk factors for breast cancer. Preliminary data presented in this grant show that nitrites and nitrates have estrogen like effects in breast cancer cells. Similar to estradiol, nitrites and nitrates activate estrogen receptor (ER-increase the growth of the breast cancer cells MCF-7, and increase the expression of the estrogen regulated gene progesterone receptor. The ability of nitrites and nitrates to mimic the functions of estradiol was blocked by an antiestrogen suggesting that their effects were mediated by ER- Hypothesis: This proposal will test the hypothesis that nitrites and nitrates play a role in the both the etiology and progression of breast cancer, in part, due to their ability to activate the estrogen receptor. Specific Aims: Aim 1 will determine whether nitrites and nitrates have estrogen like activity in breast cancer cells and aim 2 will determine whether these compounds have estrogen like activity in animals. More specifically, aim 1 will: 1, determine whether dietary and environmentally relevant amounts of nitrites and nitrates activate ER- in breast cancer cells; 2, determine the mechanism by which these compounds activate the receptor; and 3, determine whether growth factors and inflammatory cytokines activate ER- through a pathway mediated by nitric oxide synthase. Aim 2 will determine whether nitrites and nitrates have estrogen like effects in the uterus, mammary gland, hypothalamus, and pituitary of ovariectomized animals. Potential Outcomes and Benefits of Research: If the results of these studies demonstrate that low doses of nitrites and nitrates activate the estrogen receptor, than environmental as well as occupational exposures to these compounds would be an important target for prevention efforts. Understanding the mechanism by which nitrites and nitrates influence the progression of breast cancer will also allow us to design appropriate treatment strategies that block their actions.