Understanding Tamoxifen - A Drug for Breast Cancer

Institution: University of California, San Francisco
Investigator(s): Paul Webb, Ph.D. -
Award Cycle: 1995 (Cycle I) Grant #: 1KB-0188 Award: $225,000
Award Type: New Investigator Awards
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

Initial Award Abstract (1995)
Tamoxifen is a widely used drug that is known to prevent breast cancer growth. When breast cancer first arises the cancer cells often continue to require estrogen to grow, just as their normal counterparts do. The requirement for estrogen provides an unparalleled opportunity to control the growth of the cancer. Tamoxifen acts by opposing the action of estrogens, and is therefore termed an antiestrogen. This property means that tamoxifen will arrest estrogen-dependent breast cancer growth while other treatments, such as surgery and chemotherapy, can be tried. Tamoxifen treatment for breast cancer has proven very successful. It is even presently proposed that tamoxifen should be given to healthy women to prevent formation of breast cancer. Unfortunately, this is not without risks. Instead of opposing estrogen action, tamoxifen can sometimes act just like estrogen. In women who take tamoxifen, this can result in stimulation of the growth of later stage breast tumors and increases in the risk of cancer of the uterus. Our goal is to understand how tamoxifen causes these estrogen-like effects and to use this knowledge to design better cancer blocking drugs. Estrogen acts by binding to a specific protein, called the estrogen receptor that, in turn, stimulates cell growth. Tamoxifen binds to the estrogen receptor protein, and dislodges estrogen from the estrogen binding pocket on the receptor. We recently showed that tamoxifen, when attached to the estrogen receptor protein, stimulates the activity of certain proteins (AP-1) that are normally involved in cell growth and may be important in cancer development.

In this project we will study tamoxifen activity on AP-1 in cell culture models that are easy to manipulate. We will then use genetic and biochemical approaches to understand how tamoxifen stimulates AP-1 activity and how the estrogen-like effects of tamoxifen on cancer growth might arise. We hope to use this work to develop screening systems that will tell us whether new breast cancer drugs might have similar harmful effects, and to identify new strategies for preventive drug design. New antiestrogens with more desirable properties have the potential to reduce the human and economic costs of breast cancer in California.

Final Report (1998)
Estrogens are natural female hormones that are needed for breast cells to grow. Breast cancer cells often resemble healthy breast cells and also require estrogens to grow. Interfering with estrogen action or estrogen production is therefore an important way to block tumor growth. The most popular strategy to block estrogen action is to use a type of drug called antiestrogens which oppose the action of estrogen. These include tamoxifen (Nolvadex), which is the often the first line treatment for breast cancer and raloxifene (Evista) which is presently in clinical trials to see whether it might be able to prevent breast cancer. However, antiestrogens often show estrogen-like side effects. In some tissues they block estrogen action, in other tissues they act like estrogen. The estrogen-like side effects of tamoxifen are thought to be responsible for increased cancer of the uterus in breast cancer patients. Even more disturbingly, tamoxifen blocks breast tumor growth initially, but the tumor often adapts and its growth becomes stimulated by tamoxifen. We wish to understand the source of these estrogen-like effects. We hope to use this knowledge to design better antiestrogens and to understand the events in breast cancer progression. This project is relevant to BCRP priority “Primary Prevention.” New antiestrogens could reduce the costs of breast cancer in California.

Estrogen acts by binding to proteins, called estrogen receptors, that stimulate cell growth. Tamoxifen dislodges estrogen from the estrogen binding pocket on the receptor. The estrogen receptor increases or decreases production of other proteins. These changes cause the cells to grow. We wanted to understand how the receptor can change the level of different proteins in the cell. We have found that one way that the receptor changes cellular protein levels is to stimulate the activity of certain proteins (AP1). These are implicated in cell growth and cancer and act as switches for cellular protein production. AP1 activity is stimulated very strongly by antiestrogens. We have mapped the regions of estrogen receptor that are needed to stimulate AP1 activity and found that the receptor stimulates AP1 activity in two ways, one regulated by estrogens, the other regulated by antiestrogens. The antiestrogen pathway is mediated by a class of proteins called corepressors. Understanding how the receptor interacts with corepressors will help us understand how antiestrogens work.

Differential transactivation properties for the two estrogen receptors (ERalpha and ERbeta)
Index Medicus: Science
Authors: Paesch K, Webb P, Kuiper GJM, Nilsson S. Gustafsson JA, and Scanlan TS et al
Yr: 1997 Vol: 277 Nbr: 5331 Abs: Pg:1508-1510

Estrogen receptor activation function 1 works by binding p160 coactivator proteins
Periodical:Molecular Endocrinology
Index Medicus: Mol Endocrinol
Authors: Webb P, Nguyen P, Shinsako JS, Anderson CM, Feng WJ, and Nguyen MP, et al
Yr: 1998 Vol: 12 Nbr: 10 Abs: Pg:1605-1618

Transcriptional activities of estrogen and glucocorticoid receptors are functionally integrated at the AP-1 response element
Index Medicus: Endocrinology
Authors: Uht RM, Anderson CM, Webb P, Kushner PJ
Yr: 1997 Vol: 138 Nbr: 7 Abs: Pg:2900-2908