The development of breast cancer can be modulated by the actions of the immune system. Reciprocally, mammary tumors appear to cause profound alterations on the immunologically relevant cells, either directly, via tumor cell derived factors, or in an indirect manner. We propose to continue our studies to elucidate the interactions between the growing neoplasms and the immune effector cells using two well characterized mammary tumor systems. These tumors, which are syngeneic to BALB/c mice, allow the study of the effects of exogenous mammary tumor virus (MMTV) and its superantigen properties, and of other neoantigens appearing on mammary tumor cells of either viral etiology or chemically induced. We will specifically focus on the alterations observed in the lymphocytic compartment of these tumor bearing mice that have been detected in our ongoing studies. Specifically, we will (1) elucidate the molecular causes of the constitutive production of TNF-alpha by B cells from tumor bearing mice and the biological significance to the host of the overexpression of this pleiotropic cytokine; (2) we will investigate the role that MMTV plays in the downregulation of immune responses that occur during mammary tumor progression; (3) determine the mechanisms underlying the thymic involution observed in mammary tumor bearing mice; and (4) analyze the reasons for the altered cytokine expression in peripheral T cells from tumor bearing mice. An understanding of the causes for the immune deviations occurring during mammary tumorigenesis at the cellular and molecular levels, will help devise rational new therapeutic approaches for the eventual control of breast cancer.

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National Cancer Institute (NCI)
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Experimental Immunology Study Section (EI)
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University of Miami School of Medicine
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Ilkovitch, Dan; Carrio, Roberto; Lopez, Diana M (2012) uPA and uPA-receptor are involved in cancer-associated myeloid-derived suppressor cell accumulation. Anticancer Res 32:4263-70
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Carrio, Roberto; Altman, Norman H; Lopez, Diana M (2009) Downregulation of interleukin-7 and hepatocyte growth factor in the thymic microenvironment is associated with thymus involution in tumor-bearing mice. Cancer Immunol Immunother 58:2059-72
Torroella-Kouri, Marta; Silvera, Risset; Rodriguez, Dayron et al. (2009) Identification of a subpopulation of macrophages in mammary tumor-bearing mice that are neither M1 nor M2 and are less differentiated. Cancer Res 69:4800-9
Carrio, Roberto; Lopez, Diana M (2009) Impaired thymopoiesis occurring during the thymic involution of tumor-bearing mice is associated with a down-regulation of the antiapoptotic proteins Bcl-XL and A1. Int J Mol Med 23:89-98
Ilkovitch, Dan; Lopez, Diana M (2009) Urokinase-mediated recruitment of myeloid-derived suppressor cells and their suppressive mechanisms are blocked by MUC1/sec. Blood 113:4729-39
Ilkovitch, Dan; Lopez, Diana M (2009) The liver is a site for tumor-induced myeloid-derived suppressor cell accumulation and immunosuppression. Cancer Res 69:5514-21
Handel-Fernandez, Mary Ellen; Ilkovitch, Dan; Iragavarapu-Charyulu, Vijaya et al. (2009) Decreased levels of both Stat1 and Stat3 in T lymphocytes from mice bearing mammary tumors. Anticancer Res 29:2051-8
Calderon, Cesar L; Torroella-Kouri, Marta; Dinapoli, Michael R et al. (2008) Involvement of protein kinase C and not of NF kappa B in the modulation of macrophage nitric oxide synthase by tumor-derived phosphatidyl serine. Int J Oncol 32:713-21

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