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    Research Grants Awarded

    The Role Of Dietary Antioxidants And Expression Of Nm23-H1 In Breast Cancer Skeletal Metastasis

    Study Section:
    Tumor Cell Biology IV

    Scientific Abstract:
    Although breast cancer progression is associated with increased metastasis to bone, current understanding of the molecular basis of bone metastasis is very limited and the role for diet-gene interactions in the control of bone metastasis remains largely unexplored. Recognizing this, we initiated a series of studies to identify novel diet-sensitive intrinsic therapeutic targets to prevent and treat breast cancer progression. Breast cancer cells compared to normal cells in the mammary gland intrinsically generate increased levels of reactive oxygen species (ROS) that should link treatment modalities to molecular pathways capable of controlling tumor progression and metastasis. Breast cancer metastasis is influenced by the expression of a limited set of known metastasis suppressor genes, including Nm23-H1. However, there is no therapeutic modality in place for inducing cancer cell-targeted expression of Nm23-H1. We discovered that decreased mammary tumor metastasis to the lungs correlated with increased tumor-targeted generation of ROS and expression of Nm23-H1 in MMTVPyVT transgenic mice fed a diet depleted of vitamin E and vitamin A. Importantly, we discovered that increased intracellular generation of ROS resulted in increased expression of Nm23-H1 in bone metastasis-competent human breast cancer cells. We hypothesize that increased expression of Nm23-H1 mechanistically links tumor-targeted increased generation of ROS to modulation of cell signaling pathways that result in inhibition of breast cancer metastasis to bone . The first aim of this study is to determine whether stable expression or silencing of Nm23-H1 complements or interferes with inhibition cancer cell growth and induction of cancer cell death by increased generation of ROS. The second aim of these studies is to determine whether stable expression or silencing of Nm23-H1 complements or interferes with ROS-induced inhibition of breast cancer cell motility and invasion. The third aim of these studies is to determine whether stable expression or silencing of Nm23-H1 in bone metastasis-competent breast cancer cells complements or interferes with the inhibition of bone metastasis in nude mice fed a diet depleted of antioxidant vitamins A and E. The long term goal of these studies is to identify the mechanistic links between Nm23-H1 and diet-induced tumor-targeted generation of ROS and the control of breast cancer progression and bone metastasis.

    Lay Abstract:
    Although breast cancer progression is associated with distant spread of the primary tumor to bone, current understanding of the biological basis for the spread of breast cancer cells to bone is very limited and the role for diet-gene interactions in the control of tumor spread to bone remains largely unexplored. Breast cancer cells compared to normal cells in the mammary gland are inherently more likely to generate increased levels of oxygen free radicals that should link therapeutic approaches to cascades of biological events capable of controlling breast cancer growth and spread to distant body sites. Breast cancer growth and spread to distant body sites are linked to genetic alterations in the cancer. We discovered that feeding a diet depleted of vitamin E and vitamin A to mice that spontaneously develop breast cancer resulted in decreased cancer growth and spread to the lungs that correlated with increased cancer cell generation of oxygen free radicals and expression of Nm23-H1, a gene that suppresses the spread of cancer to distant body sites. Importantly, in human breast cancer cells capable of spreading to bone, increased expression of Nm23-H1 occurred when cells were induced to generate oxygen free radicals. Thus, we hypothesize that increased expression of Nm23-H1 mechanistically links cancer cell-targeted increased generation of oxygen free radicals to biological signaling cascades that result in inhibition of the spread of breast cancer to bone . The first aim of this study is to determine whether stable expression or silencing of Nm23-H1 plays a role in the inhibition of cancer cell growth and induction of cancer cell death by increased generation of oxygen free radicals. The second aim of these studies is to determine whether stable expression or silencing of Nm23-H1 is involved in oxygen free radical-induced inhibition of breast cancer cell motility and invasion. The third aim of these studies is to determine whether stable expression or silencing of Nm23-H1 in bone metastasis-competent breast cancer cells complements or interferes with the inhibition of bone metastasis in nude mice fed a diet depleted of antioxidant vitamins A and E. In summary, the long term goal of these studies is to determine the mechanistic role for the gene Nm23-H1 in the control of breast cancer progression and metastasis by diet-induced tumor-targeted increased generation of oxygen free radicals.