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    Role of Retinoid X Receptor and its Ligand in Breast Cancer

    Scientific Abstract:
    Epidemiological, animal and in vitro studies have suggested that the level of fats in the diet, and more important the identity of the fatty acid (FA) constituents, modulate breast cancer risk and progression. However, little is known about the molecular pathways by which various FAs exert their effects on the prevention and promotion of breast cancer development and progression. Recent studies show that certain essential dietary FAs bind to the retinoid X receptor (RXR), a member of the steroid/thyroid/retinoid nuclear receptor superfamily of transcriptional factors, suggesting that RXR plays a role in mediating the activities of dietary FAs in breast cells. We previously reported that orphan nuclear receptor TR3 migrates from the nucleus to mitochondria to trigger cytochrome c release and apoptosis. In studying how TR3 translocates from the nucleus to mitochondria, we recently observed that RXRa is essential through its unique heterodimerization with TR3. This finding indicates that the TR3-dependent apoptosis is subject to regulation by RXR ligands. We hypothesize that certain dietary FAs modulate breast cancer cell growth and apoptosis through their RXRa binding that regulates the mitochondrial targeting of the RXRa./TR3 heterodimer. In the proposed studies, we will evaluate a panel of dietary FAs for their ability to bind RXRa. We will then study the contribution of the RXR-binding to their effect on the growth and apoptosis of breast cancer cells. We will also determine their effects on subcellular localization and the expression of the tumor suppressor retinoic acid receptor b in the nucleus as well as mitochondrial targeting by the RXRa/TR3 heterodimer. Finally, the role of RXRa in mediating the biological activities of dietary FAs will be evaluated in nude mice. Together, these studies will yield important information regarding the molecular mechanisms by which dietary FAs regulate the growth of breast cancer cells and provide a better guidance for using dietary intervention for treating and preventing breast cancer.

    Lay Abstract:
    The high prevalence of breast cancer and the limited options for treatment provide a strong rationale for identifying new and selective molecular targets that can be nutritionally or pharmacologically modulated. Epidemiological, animal and cell culture studies have suggested that fatty acid (FA) composition of the diet modulates the development and progression of breast cancer. High-fat diet rich in polyunsaturated omega-6 FAs stimulate mammary carcinogenesis and tumor progression, while the long-chain omega-3 FAs present at high concentration in some fish oils exert inhibitory effects. However, the molecular mechanisms by which FAs prevent and promote breast cancer development remain unknown. Recent studies demonstrate that certain essential dietary FAs bind to a vitamin A receptor called retinoid X receptor (RXR), which belongs to the steroid/thyroid/retinoid receptor superfamily of transcriptional factors. These observations suggest that RXR may be an important molecular target mediating FAs action. Recently, we discovered that TR3, another member of the nuclear receptor superfamily, migrates from the nucleus to mitochondria in cells to induce apoptosis, a programmed cell death, in cancer cells. Furthermore, we found that RXR is essential for this death process through its interaction with TR3. Since induction of cell death is an effective way to restrict cancer development and progression, we propose that dietary FAs modulate breast cancer cell growth and death through their RXR binding that regulates subcellular localization of RXR. In studies proposed in this application, we will first evaluate a panel of dietary FAs for their ability to bind RXR. We will then determine whether and to what degree that the binding contributes to their effects on growth and death of breast cancer cells. Dietary FAs that bind RXR will be further studied for their modulation of the migration of RXR and TR3 in breast cancer cells. We will also investigate the effect of the dietary FAs in the nucleus to induce expression retinoic acid receptor beta, a potent growth inhibitor, and in the cytoplasm to modulate the mitochondrial targeting of RXR/TR3 complex. Finally, the regulatory pathway and biological activities of FAs will be evaluated in animal. Together, results from these studies will explain how dietary FAs regulate the growth of breast cancer cells and provide a better guidance for using dietary intervention for treating and preventing breast cancer. The results may also provide a molecular basis for developing novel therapies for breast cancer.