Intervention models for thyroid proliferative disease using diet derived antiestrogen

Raj Tiwari PhD, Jan Geleibter Phd, Stim Schantz MD, Edward Shin, MD

Two hundred million people worldwide are affected by thyroid proliferating diseases (TPD) including goiter. Women are three times more susceptible than men and overall the incidence of thyroid dysfunction occurring in one in eight women is a sizable health issue  and compares to breast cancer risk. The focus of our research is to define the regulatory link of the estrogen mediated cellular and growth regulating signal transduction aberration in TPD using cell culture, animal model and human clinical specimen and explore relevant intervention strategies.

We and others have observed that thyroid cells (transformed and non-transformed) are estradiol (E2)-responsive; can metabolize estradiol; express the estrogen receptor (ER); estrogen mobilizes Bone Marrow-Endothelial Cells  to induce neovascularization in response to injury. Intervention studies in the laboratory and clinical trials initiated by us suggest that the diet derived bioactive food component the antiestrogen, DIM down regulates the Akt pathway and modulated estrogen metabolism in cells; a  fourteen day supplementation (150 X4 mg) in patients results in detectable levels in biological fluids (blood and urine) and thyroid tissues. Coupled with these observations in our laboratory and the report that DIM inhibits angiogenesis,  we are testing the following hypothesis  “inhibitors of estrogen mediated angiogenesis by BM-EC and Akt-estrogen crosstalk signaling pathway in goiter are clinically utilizable intervention points for TPD management”.  Thus, we are currently:

  1. Examining the estrogen mediated genomic and non-genomic signaling pathway in BM-EC and goiter cells and identify the biochemical and molecular intervention targets of DIM in the downstream of Akt and Akt-estrogen cross talk pathway.
  2. Validating the significance of estrogen mediated neovasculature and Akt-estrogen crosstalk pathway using  a xenograft animal model with implantation of FTC-133 and HTh74 goiter cells lines in ± ovariectomized Balb/c/nu/nu mice ± DIM incorporated in the diet

In the next three years we will focus our attention on two aspects of our program:

  1. A clinical trial to determine if oral administration of an absorption-enhanced formulation of DIM (Bioresponse DIM) achieves adequate thyroid tissue bioavailability and estradiol metabolites in blood and urine
  2. Defining the profile of DIM induced molecular changes and correlate pathway changes in goiter using FNA and thyroidectomy samples using transcriptome analysis, correlated by a proteomic analysis using MALDI-MS and detection of chromosomal changes using comparative genomic hybridization (CGH).

Future studies and the subject of grant proposals will be designing small molecular weight inhibitors of the estrogen-activated pathways for the management of TPD.


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