Novel Technologies to Identify Tissue-Selective Estrogens

Institution: University of California, San Francisco
Investigator(s): Fred Schaufele, Ph.D. -
Award Cycle: 2001 (Cycle VII) Grant #: 7IB-0024 Award: $75,000
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure



Initial Award Abstract (2001)
Breast tumors are broadly classified into one of two categories, those that contain, or do not contain, a specific protein that binds estrogen (the "estrogen receptor"). In estrogen receptor-containing tumors, estrogen binding to the estrogen receptor causes tumor growth. Growth of these tumors is counteracted by the drug tamoxifen that, when bound to the estrogen receptor, prevents estrogen binding. As such, tamoxifen is very effective in treating these tumors. However, the tamoxifen-bound receptor behaves like the estrogen-bound receptor in some other organs, particularly the uterus, in which tamoxifen weakly promotes the growth of uterine tumors.

A goal of modern medicine is to prevent disease before it occurs. Blockage of estrogen action would prevent the development of estrogen-dependent tumors, but long-term treatment would block the highly beneficial effects of estrogens in most organs. Preventative therapy requires the identification of drugs that act like estrogen in most organs but that block estrogen in the breast and uterus. We aim to develop methods to speed the identification of cheap drugs with organ-specific actions ideal for wide-spread breast cancer prevention and improved therapy.

For estrogens to have different actions in different organs, something other the estrogen receptor must be different in each organ. Different proteins interact with the estrogen receptor bound to estrogen, tamoxifen, or other breast cancer drugs. There also are two different estrogen receptors and differences between them may account for organ-specific actions. We will determine which proteins interact with which estrogen receptor bound by estrogens and existing breast cancer drugs. These interactions will be compared with the interactions regulated by novel compounds to identify new drugs with potentially new organ-selective actions.

Most current studies of the interactions of estrogen receptor with other proteins are conducted in test tubes. To determine the organ-selective actions of breast cancer drugs, it would be far superior to study the interactions in living cells representing the estrogen-responsive tissues. We have developed unique techniques that allow these interactions to be precisely measured in living cells. These innovative methods are so sensitive that they detect even minor variations in the direction in which two molecules interact with each other. This huge advance will be very important for discerning differences in the way that existing and novel breast cancer drugs affect those interactions and will permit the identification of drugs that selectively regulate different interactions.


Final Report (2003)
Breast tumors are broadly classified into one of two categories, those that contain, or do not contain, a specific protein that binds estrogen (the "estrogen receptor"). In estrogen receptor-containing tumors, estrogen binding to the estrogen receptor causes tumor growth. Growth of these tumors is counteracted by the drug tamoxifen that, when bound to the estrogen receptor, prevents estrogen binding. As such, tamoxifen is very effective in treating these tumors. However, the tamoxifen-bound receptor behaves like the estrogen-bound receptor in some other organs, particularly the uterus, in which tamoxifen weakly promotes the growth of uterine tumors.

A goal of modern medicine is to prevent disease before it occurs. Blockage of estrogen action would prevent the development of estrogen-dependent tumors, but long-term treatment would block the highly beneficial effects of estrogens in most organs. Preventative therapy requires the identification of drugs that act like estrogen in most organs but that block estrogen in the breast and uterus. We aim to develop methods to speed the identification of cheap drugs with organ-specific actions ideal for wide-spread breast cancer prevention and improved therapy.

For each estrogen or estrogen-like compound to have different actions in different organs, the estrogen receptor must behave differently when bound to each compound. Those ligands differentially affect, in each organ, the estrogen receptor, or estrogen receptor interaction with other proteins. Most current studies of the interactions of estrogen receptor with other proteins are conducted in test tubes and therefore provide little information about organ-specific effects.

To determine the organ-selective actions of breast cancer drugs, we have studied their effects on estrogen receptor interactions in living cells representing estrogen-responsive tissues. We have developed unique "fluorescence resonance energy transfer" techniques that allow these interactions to be precisely measured in living cells. These innovative methods are so sensitive that they detect even minor variations in the direction in which two molecules interact with each other. This huge advance will be very important for discerning differences in the way that existing and novel breast cancer drugs affect those interactions. This will permit the identification of drugs that selectively regulate different interactions. We already identified one such drug in our studies. This new compound has some similarities to tamoxifen and other similarities to genistein, an estrogenic compound found in soy. Our goal is to compare the interactions regulated by these compounds in different tissues, leading to the identification of new drugs with potentially new organ-selective actions.

These highly powerful techniques are currently quite time-consuming. We also attempted to develop "high-throughput" techniques that would allow the rapid screening of multiple interactions regulated by breast cancer drugs. We achieved the initial goals of this project. We are currently poised to realize this high-throughput goal, pending the development of some computer software. Once realized, we would be able to examine many more compounds in many different cell types than we currently are able to. This ultimately will allow us to detect a few pharmaceuticals, amongst many, that have unique properties that could improve breast cancer treatment and prevention.