Breast Cancer Prevention by Inhibition of Estrogen Action

Institution: Cedars-Sinai Medical Center
Investigator(s): Vicki Davis, Ph.D. -
Award Cycle: 1999 (Cycle V) Grant #: 5JB-0118 Award: $302,983
Award Type: IDEAS II
Research Priorities
Etiology and Prevention>Prevention and Risk Reduction: ending the danger of breast cancer

Initial Award Abstract (1999)
Breast cancer is a highly prevalent disease that destroys the lives of women from their reproductive years through postmenopausal ages. Tamoxifen therapy, which was shown in a recent study to lessen the risk of breast cancer, reduces estrogen activity in the breast. However, this therapy also modifies the ability of other tissues to respond to estrogen, tissues which benefit from estrogen action, causing adverse effects on reproduction, cardiovascular fitness, menopausal symptoms, and uterine cancer risk. Therefore, to circumvent these problems, we will test a novel means of breast cancer prevention that inhibits estrogen action in the breast, but not in other tissues that benefit from the actions of this hormone.

In the breast and other tissues that respond to estrogens, estrogen acts by interacting with a protein known as the estrogen receptor. The presence of this receptor in breast cancer is used by physicians to determine treatment strategies for the patient. Our design involves interfering with the normal actions of the estrogen receptor in order to modify the tissue's ability to respond to estrogen. As shown with tamoxifen, interfering with estrogen's ability to stimulate the growth of breast cells can reduce the risk of breast cancer. In this study, we propose to investigate the ability to inhibit estrogen receptor action, in the presence of estrogen, to prevent breast cancer in mice. These mice develop mammary cancer that frequently spreads to the lungs. We will determine whether the mice remain tumor-free for longer periods and if the number of tumors that develop and that invade the lung are reduced in mice that have the modified receptor compared to mice that do not, as is suggested by our preliminary results.

Demonstrating in our mouse model that estrogen action can be suppressed in the breast in the presence of estrogen would provide the evidence to guide the development of new breast cancer prevention therapies for pre- and post-menopausal women. By devising a therapy that can simultaneously protect organs that need estrogen and protect the breast from estrogen, the benefits to women's health and life span would be immense. Development of this novel method to defeat estrogen effects on breast cancer would substantially reduce the impact of the disease without adversely affecting mammary gland function. In addition, the benefits would include an improved quality of life, especially for women in their reproductive years or at high risk for other life threatening diseases associated with loss of estrogen, such as osteoporosis and heart disease.

Final Report (2002)
Breast cancer treatment and prevention has been targeted at inhibiting estrogen action in breast tissue. Although inhibiting estrogen action is beneficial for reducing breast cancer risk, reduced estrogen action has been associated with risks for disease in other tissues, including heart disease and osteoporosis. Our goal in this project was to test a novel means to inhibit estrogen action in the breast, while leaving estrogen available to other tissues that benefit from its actions. Our studies were done using a mouse model that develops mammary cancer caused by the most common cancer gene in breast cancer (neu, HER2/neu, or erbB2). Two groups of female mice were tested, the control group, with normal estrogen action, and the test group, with estrogen action inhibited. Tumor development was assessed for the age which tumors are first found and the number of females that get tumors. The results indicate that the test group had fewer females with tumors compared to the control group, but this is likely due to the tumor starting at later ages. The later age for tumor onset indicates a beneficial effect in the test group, since a comparable delay in women would them to remain tumor-free for many more years of their life.

Female mice in the control and test groups were also tested for tumor development after treatment with tamoxifen (equivalent to 20 mg/day dose for women) and soy isoflavones (>300 mg/day for women). Tamoxifen has been shown in women to be effective for breast cancer prevention. Soy products, containing the estrogenic isoflavone compounds, have also been proposed to be beneficial for breast cancer prevention. However, in research studies with soy isoflavones, there is evidence of both diminished and augmented growth of breast tumors, leaving questions regarding its effects on breast cancer unresolved. In our study, at the dose of isoflavones tested (which is around 3 times higher than generally recommended for postmenopausal women, 100 mg/day or less), no protection from mammary tumors was found for either the control or test groups. In contrast, tamoxifen provided strong protection against tumor development in both groups. This protection was enhanced substantially in the test group, with only 1 female getting a tumor.

To reduce breast cancer development in the presence of estrogen would allow women to reduce breast cancer risk without increasing the risk of other diseases that diminish their quality of life and life expectancy. This means of therapy could not only reduce the costs in human life and economic resources from breast cancer, but also from other prevalent, estrogen-dependent diseases, such as heart disease and osteoporosis. With renewed concerns about estrogen replacement therapy increasing breast cancer risk, our concept to protect the breast and other estrogen responsive tissues in the presence of estrogen provides a timely and potentially safe alternative for women.