Western University BiologyWestern Science

John Wiebe, PhD

Hormonal Regulatory Mechanisms


John Wiebe 2013 Position:
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Professor
Biological & Geological Sciences 3030
Biological & Geological Sciences 3029
519 661-3131
519 661-3935
jwiebe@uwo.ca

Role of progesterone metabolites in breast cancer

For the majority of breast cancers there has been no adequate hormone-based explanation and therapy. The only hormone-based therapies for breast cancer involve suppressing the body’s estrogen levels and actions. Unfortunately, these therapies are effective in only a portion (about 1/3) of breast cancer patients and only for a limited time. We have identified two new types of steroid hormones, produced in breast tissue from progesterone (progesterone metabolites), that appear to have the ability to regulate all forms of breast cancer. One hormone, 5a-pregnane-3,20-dione (5aP), is cancer-promoting, since it stimulates cells to proliferate (tumor growth) and to detach (metastasis). The other hormone, 3a-hydroxy-4-pregnen-20-one (3aHP), is cancer-inhibiting since it suppresses cell proliferation and detachment. Our in vitro studies, conducted on 5 different human breast cell lines, have shown that both 5aP and 3aHP act on estrogen-responsive and estrogen non-responsive cells, as well as on tumorigenic and non-tumorigenic cells. The results strongly suggest that 5aP and 3aHP may have the capacity to regulate all forms of breast cancer, the final result depending on the ratio of the two hormones in the breast tissue microenvironment. New detection assays and new hormone-based treatment for breast cancer are suggested by our findings.

Our findings to date

We propose to determine if 5aP and 3aHP actually regulate induction, growth and regression of mammary tumors by testing the effects of the hormones in vivo (in a living organism).

Hypothesis. The hypothesis is that 5aP 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 5aP formation (with the inhibitor, dutasteride) and/or treatment with 3aHP will suppress tumor formation, growth and metastasis and/or cause regression of established tumors.

Current grant funded research objectives

  1. To determine what factors in the body (particularly in the breast tissue) cause the changes in progesterone metabolizing enzyme expression and activity that lead to higher 5aP and lower 3aHP production and tumor development.
  2. To determine the in vivo effects of the progesterone metabolites on induction, growth and regression on mammary tumors.
  3. To identify the molecular structures of 5aP and 3aHP membrane receptors.
  4. To identify cellular and molecular mechanisms and cell signaling pathways of 5aP and 3aHP actions.

Recent Publications