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    Research Grants Awarded

    Immune system contribution to the progression of mammary tumors towards hormone-independent behavior.

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    Breast carcinoma is one of the most common carcinomas in pregnant women and show significantly reduced relapse-free and cancer-free survival rates. As most of pregnancy associated breast cancers do not express either estrogen or progesterone receptors (ER-PR-), it could be speculated that high estrogen and progesterone circulating levels during pregnancy could be relevant only during the pre-clinical stages. Then, ER-PR- cancer cells somehow prevail after parturition and detected pregnancy-associated tumors are mostly hormone independent (HI) and very aggressive cancers. Besides, strong evidence sustains that NFkB activation would be relevant for ER-PR- cell survival, specially in human inflammatory breast cancer. Breast cancer is an immunogenic tumor; however this response is not sufficient to block tumor growth. Recruitment of regulatory T cells (Tregs) have been suggested as a tumor tool to evade immune response suppressing effectors T cells and professional antigen presenting cells, promoting tumor immune escape. However, it is unclear whether this association plays a relevant role in breast cancer progression itself. Interestingly, recent reports indicate that estrogen modulates the suppressive function of Treg activating Foxp3+ gene expression. Our group has reported that MMTV virus strain induces pregnancy-dependent mammary tumors in BALB/c mice, which express high levels of estrogen and progesterone receptors. These lesions eventually progress to a hormone-independent behavior when transplanted into virgin hosts, losing the expression of estrogen and progesterone receptors. These tumors also show strong mononuclear infiltration and high expression of Foxp3 gene. Therefore, this model provides a very useful tool to study the role of Treg cells in the rise of pregnancy associated HI breast cancer. Up to date there are no publications addressing the role of Treg in progression of breast cancer towards hormone-independence. The aim of this project is to investigate the role of inflammation and Treg cells in the rise of pregnancy associated breast cancer. Our specific aims are: 1) analyze inflammatory component, Treg presence and NFkB activation in HD and HI tumors; and determine the relevance of hormonal status on these parameters. 2) Explore the association and participation of inflammation, NFkB and Treg activation in loss of mammary tumor hormone regulation. And 3) investigate whether the depletion of Tregs affects growth and progression of pregnancy-dependent mammary tumors. Therefore, our final goal is to determine whether altering the immune response to breast cancer could modify its behavior and then the outcome of the illness.

    Lay Abstract:
    Breast carcinoma is one of the most common tumors that appear in women during the first year after parturition. Unfortunately, these patients commonly show low relapse-free and cancer-free survival rates. This kind of breast cancer usually does not express estrogen and progesterone receptors, does not respond to anti-hormone therapy and, therefore, it is considered hormone-independent (HI). In addition, these tumors frequently show activation of certain intra-cellular signaling cascades, like activated NFkB, pathway, which facilitate cancer cell survival and proliferation. Although breast cancers activate an anti-tumor immune response, it is weak and ineffective to control tumor growth and metastasis development. During the last years a new immune cell was discovered, the regulatory T cell (Treg), which is able to inhibit the immune response. However, it is still unclear whether Tregs play a relevant role in breast cancer progression. Interestingly, recent reports indicate that estrogen modulates the suppressive function of Treg. Our group has developed a model in which the mouse mammary tumor virus (MMTV) induces pregnancy-dependent tumors. We have found that these lesions require a high level of circulating estrogen for their development. This hormone can be supplied by pregnancy itself or by external treatment. Therefore, they are considered hormone-dependent (HD) tumors. However, upon transplantation these tumors frequently loss the expression of estrogen and progesterone receptors and become HI. Interestingly, we have found that MMTV-induced tumors commonly show lymphocyte infiltrates that include Treg cells. However, up to date, there are no publications addressing the role of these cells in the evolution of breast cancer towards hormone-independence. Therefore, this model provides a very useful tool to study the role of Treg cells in the rise and progression of pregnancy-associated breast cancer. Specifically, this project propose to: 1) analyze inflammatory component, Treg presence and NFkB activation in mouse HD and HI tumors, and determine the relevance of hormonal status on these parameters; 2) explore the association and participation of inflammation, NFkB and Treg activation in the loss of mammary tumor hormone regulation; and 3) investigate whether the elimination of Tregs affects growth and progression of pregnancy-dependent mammary tumors. Therefore, our final goal is to determine whether altering the immuno-suppressive response to breast cancer could modify its behavior and then the outcome of the illness