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    Research Grants Awarded

    Regulation of Breast Cancer by Progesterone Metabolites

    Study Section:
    Tumor Cell Biology IV

    Scientific Abstract:
    Background . The current hormone-based therapies for breast cancer involve suppression of estrogen levels and actions. These therapies are effective in only a portion (about 1/3) of breast cancer patients and only for a limited time. Thus for the majority there is currently no hormone-based therapy. We have shown that breast tissues and cell lines produce two classes of progesterone metabolites (5 a -pregnanes and 4-pregnenes) that have powerful pro- and anti-cancer actions in a variety of breast cell types. Most of the studies, performed on cells in culture ( in vitro ), have been on the 5 a -pregnane, 5 a P, and the 4-pregnene, 3 a HP. Studies on 5 different breast cell lines have shown that 5 a P stimulates cell proliferation (mitogenesis) and metastasis, whereas 3 a HP suppresses cell proliferation and metastasis. The results, showing that 5 a P and 3 a HP act on estrogen-responsive and estrogen non-responsive as well as tumorigenic and non-tumorigenic cell lines, strongly suggest that 5 a P and 3 a HP may have the capacity to regulate various forms of breast cancer. We propose to determine if 5 a P and 3 a HP actually regulate mammary tumor formation and growth by testing their effects in vivo in mouse models. Hypothesis . The general hypothesis is that progesterone metabolites, produced in breast cells/tissues, are hormones with the capacity to either promote or suppress various forms of breast cancer. The specific hypothesis is that 5 a P will stimulate cells injected into mice in the same way that it stimulates cells in culture dishes, resulting in formation, growth and metastasis of tumors; conversely, blocking 5 a P formation (with the inhibitor, dutasteride) and/or treatment with 3 a HP will suppress tumor formation, growth and metastasis and/or cause regression of established tumors. Study Design . Mouse mammary cells (model A) and human breast cells (model B) will be inoculated into strains of mice and the effects of treating with 5 a P, 3 a HP, and dutasteride on tumor formation, growth, metastasis and regression will be determined. Potential Benefits of the Research. If 5 a P and 3 a HP can be shown to promote/regress tumors in mice, the results will provide the first in vivo evidence that progesterone metabolites are cancer regulating hormones. More importantly, the results should encourage exploration of new breast cancer therapies in which 5 a P synthesis (or action) is blocked and 3 a HP is administered.

    Lay Abstract:
    Background . The current hormone-based therapies for breast cancer involve suppression of estrogen levels and actions. These therapies are effective in only a portion (about 1/3) of breast cancer patients and only for a limited time. Thus for the majority there is currently no hormone-based therapy. We have identified two new types of steroid hormones, produced in breast tissue from progesterone (progesterone metabolites), that appear to have the ability to promote or suppress breast cancer. One hormone, 5alphaP, is cancer-promoting, since it stimulates cells to multiply (proliferation) and to spread to other sites (metastasis). The other hormone, 3alphaHP, is cancer-inhibiting, since it suppresses proliferation and metastasis. Studies on 5 different breast cell lines grown in culture dishes ( in vitro ), have shown that 5alphaP and 3alphaHP act on estrogen responsive and unresponsive cells, as well as on normal and tumor forming cells. These in vitro results strongly suggest that 5alphaP and 3alphaHP may have the capacity to regulate various forms of breast cancer. We propose to determine if 5alphaP and 3alphaHP actually regulate tumor formation and growth by testing their effects in vivo (in living organisms). Hypothesis . The general hypothesis is that progesterone metabolites, produced in breast cells/tissues, are hormones with the capacity to either promote or suppress various forms of breast cancer. The specific hypothesis is that 5alphaP will stimulate cells injected into mice in the same way that it stimulates cells in culture dishes, resulting in formation, growth and metastasis of tumors; conversely, blocking 5alphaP formation (with the inhibitor, dutasteride) and/or treatment with 3alphaHP will suppress tumor formation, growth and metastasis and/or cause regression of established tumors. Study Design . Mouse mammary cells (model A) and human breast cells (model B) will be inoculated into strains of mice and the effects of treating with 5alphaP, 3alphaHP, and dutasteride on tumor formation, growth, metastasis and regression will be determined. Potential Benefits of the Research. If 5alphaP and 3alphaHP can be shown to promote/regress tumors in mice, the results will provide the first in vivo evidence that progesterone metabolites are cancer regulating hormones. More importantly, the results should encourage exploration of new breast cancer therapies in which 5alphaP production is inhibited and 3alphaHP is administered.