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Estrogen Receptor Modulators and Dendritic Cell Function

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Regimens for prevention or treatment of breast cancer involve partial blockade of systemic estrogen responses via selective estrogen receptor modulators (SERM). The study of tamoxifen and raloxifene (STAR) is a current NCI breast cancer prevention trial involving treatment of women at high risk for breast cancer with these two SERM. Immune cells express estrogen receptors (ER); however, the potential effects of SERM on human or murine antigen-specific immune responses to pathogens or tumors are largely undocumented. Antigen specific T cell responses are dependent on the function of dendritic cells (DC) during the initiation of both innate and adaptive immunity. Activated DC promote innate immune responses by responding to pathogen associated molecules and secretion of inflammatory cytokines. DC also display high levels of MHC-bound antigens and costimulatory molecules, leading to the activation and differentiation of naive T cells. In a murine ex vivo culture system, we have shown that estradiol is required during DC differentiation from bone marrow precursors, while tamoxifen and raloxifene inhibit DC differentiation. Our initial in vitro studies show that the few DC that do differentiate in the presence of SERM exhibit decreased surface expression of MHCII and CD86 after LPS activation. Thus, we hypothesize that the consequences of systemic SERM treatment on the immune system might be: 1) reduced numbers of DC in lymphoid organs; and 2) impaired antigen presenting function in those DC that do develop. Experiments proposed here will examine DC numbers and function, and resulting CD4+ T cell responses, in intact and ovariectomized mice after in vivo exposure to SERM. Aim 1: Determine the effects of SERM on DC numbers and phenotype in vivo. Aim 2: Investigate the capacity of SERM treated DC to stimulate naive CD4+ T cells in vivo. Aim 3: Determine T helper cell polarization by SERM exposed DC in vivo. Knowledge of the effects of SERM on DC function will be important during evaluation of the efficacy of these drugs in breast cancer risk reduction.
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