By Lynn Yarris
Chemical compounds found in vegetables such as Brussels sprouts, cabbage, and cauliflower, along with a number of Asian herbs, show promise for stopping the spread of breast cancer. A Berkeley Lab scientist is now testing a theory as to how these compounds work.
Many of the different forms of breast cancer tumors, including those that spread the fastest, depend upon the hormone estrogen for growth and development. Tests have shown that naturally-occurring antiestrogen compounds can be effective treatments. These antiestrogens are quite varied in chemical structure and may act through a cellular receptor normally used to detect toxins in the cell. If
the mechanism by which antiestrogens prevent cancer growth can be identified, it might be possible to synthesize safer and even more effective versions.
James Bartholomew, a biophysicist with Berkeley Lab's Structural Biology Division, working in collaboration with Leonard Bjeldanes, of the Depart- ment of Nutrition at the University of California at Berkeley, is now in the process of examining approximately 100 antiestrogen compounds, many of which were imported from Asia where successful herbal treatments of breast cancer have been reported.
Bartholomew believes that the tumor suppressing activity of the antiestrogens is controlled by a protein called AhR. This protein is a receptor inside the cell that binds with a drug or other type of chemical in order to induce the enzymes that metabolize it.
"Little attention has been focused on the possible mitigating role of widely occurring natural antiestrogens in breast cancer," says Bartholomew. "Certain indole derivatives, such as indolo carbazole (ICZ), which are produced from dietary vegetables and by bacterial metabolism in the gastrointestinal tract, show potent antiestrogenic activity in model systems and may be useful as cancer preventative agents." Bartholomew and Bjeldanes are employing standard biochemical and immunological assays in combination with a series of special molecular biology techniques to assess the effects of AhR on the expression of estrogen-regulating genes that have been linked to breast tumor growth. AhR is known to bind to TCDD, the environmental toxin contained in Agent Orange, and experiments by Bjeldanes and others have shown that it also binds to ICZ.
"Our theory is that when AhR binds to ICZ or to TCDD or other antiestrogens, the effect is to suppress the growth of breast cancer tumors," says Bartholomew. "We think these complexes inhibit the expression of genes in the cells which are necessary for growth."
In the next round of experiments, he and Bjeldanes will work with a special set of cell lines that lack the AhR receptor. These cell lines, which were developed at Berkeley Lab for studies of the notorious breast carcinogen benzo[a]pyrene, will be used to study the role AhR plays in enabling ICZ to inhibit estrogen-dependent tumors.
"If we can identify the mechanism by which ICZ and other antiestrogen compounds suppress breast cancer tumors, we should be able to predict which of these compounds will work best," says Bartholomew. "An important element in this puzzle is undoubtedly the structure of these receptors when they have a bound chemical (called a ligand). It is probably this structural detail that determines whether the receptor-ligand complex controls one set of genes or another."
Another argument for understanding this mechanism is safety. Antiestrogens, like TCDD, induce the activity of P-450, a cytochrome in the liver that metabolizes chemicals into carcinogenic derivatives.
"You would not, for example, want to be a smoker and be on an anti-estrogen therapy," says Bartholomew.
"If you know the mechanism by which antiestrogens suppress tumors, it opens up the possibility that you can design a dietary regime which would inhibit the growth of new tumor cells without affecting the chemicals used to kill existing tumors."