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    Orphan Nuclear Receptor PXR in Estrogen Deprivation and Breast Cancer

    Scientific Abstract:
    Background: Breast cancer results from the abnormal overgrowth of the mammary epithelial cells. Estrogen (E2) is required for mammary epithelial proliferation and is a prerequisite for breast cancer formation. So an understanding of the metabolism and homeostasis of E2 is clinically important. Estrogen can be deactivated by sulfation, a conjugation reaction that is catalyzed by the estrogen sulfotransferase (EST). The sulfonated E2 is inactive since it cannot bind to the estrogen receptor. Therefore, EST may act as a switch to deactivate E2 at both systemic and local levels. EST is expressed in normal mammary epithelial cells but not in many breast cancer cell lines, suggesting it may play a role in E2 homeostasis and breast cancer. Pregnane X receptor (PXR) functions as a xenobiotic receptor to regulate the expression of many xenobiotic enzymes, including the sulfotransferases. PXR is expressed in both liver and mammary gland, two tissues primarily responsible for E2 catabolism. Our preliminary results show that the hepatic EST activity was increased in PXR activating transgenic mice. Moreover, mice treated with PXR agonist dexamethasone showed an elevated hepatic EST expression. Hypothesis/Objective: We hypothesize that EST is a transcriptional target of PXR. Activation of PXR in normal or cancerous mammary epithelia induces the expression of EST and promotes the deprivation of E2, resulting in the inhibition of E2-dependent cell growth and tumorigenesis. The overall objective is to establish EST as a PXR target gene and to determine the implication of this gene regulation in estrogen homeostasis and breast cancer. Specific Aims and Study Design: (1) To determine whether activation of PXR can increase E2 sulfonation and inhibit E2-dependent cell growth in PXR-expressing MCF-7 cells; (2) To determine whether activation of PXR in the liver or mammary gland of transgenic mice causes systemic and mammary local increase in E2 sulfonation and inhibits E2 activity in vivo. The effects of PXR activation on both mammary gland development and chemical-induced carcinogenesis will be evaluated. (4) To examine whether EST is a direct transcriptional target of PXR by cloning and characterization of the EST gene promoter. It is anticipated that elucidation of the molecular pathways by which PXR regulate EST expression, estrogen deprivation, and cell growth may be used to develop novel preventions and therapies for breast cancer.

    Lay Abstract:
    Background: Breast cancer, which arises from the uncontrolled overgrowth of breast cells, is the leading cause of death in American women. Estrogen stimulates growth of breast cells, and is a prerequisite for breast cancer formation. So an understanding of the metabolism and homeostasis of estrogen is clinically important. Estrogen can be deactivated by sulfation and this process is carried out by the estrogen sulfotransferase (EST). The sulfonated estrogen is inactive because it cannot bind to the estrogen receptor. Therefore, EST may act as a switch to deactivate estrogen and to limit breast cancer growth. In fact, decreased EST production has been linked to breast cancer formation. Pregnane X receptor (PXR) is a so-called “xenobiotic receptor” that controls the production of sulfotransferases. PXR is expressed in both liver and mammary gland, two organs that are primarily responsible for estrogen deactivation. Our preliminary results show that the EST production was increased in PXR transgenic mice. Moreover, treatment with dexamethasone, a PXR activating agent, induced EST production. Hypothesis/Objective: We hypothesize that PXR can induce EST production and increase estrogen deactivation. We predict increased estrogen deactivation will lead to inhibition of estrogen-dependent breast cancer growth. Specific Aims and Study Design: (1) To determine whether PXR can induce EST production and inhibit estrogen-dependent breast cancer cell growth in cell cultures; (2) To determine whether an increased production of PXR in the liver or breast of transgenic mice can inhibit estrogen activity in whole animals. The effects of PXR on both breast development and breast cancer formation will be determined. (3) To examine whether the production of EST is under the direct control of PXR by cloning and characterization of the EST gene promoter. It is anticipated that the mechanisms by which PXR regulate EST production, estrogen deactivation, and breast caner cell growth may be used to develop novel preventions and therapies for breast cancer.