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Estrogen Receptor Beta in Relation to Breast Cancer Proliferation
Tumor Cell Biology II
Background: Estrogen stimulates epithelial cell proliferation in both normal and malignant breast. ER alpha is well documented to stimulate proliferation. Its presence in a breast tumor is the indication for patients to receive tamoxifen as adjuvant endocrine therapy. This routine presented clinicians with two major puzzles: 1) some ER alpha-positive patients do not respond to tamoxifen; and 2) many patients develop recurrence after receiving 5 years of treatment. The second estrogen receptor, ERbeta, and its splice variant ERbeta cx, are also expressed in both normal breast and breast cancer. However, their value in guiding breast cancer treatment is yet unclear. It is known that: 1) The binding affinity of ER alpha and ERbeta is similar for estradiol, but quite different for some SERMs (selective estrogen receptor modulators). This has led to development by many pharmaceutical companies of highly selective ERalpha and ERbeta agonists. 2) ERbeta cx does not bind to estradiol. But both ERbeta and ER beta cx are repressors of ER alpha when they are expressed the same cell; 3 ) In the breast, ER alpha is expressed in the luminal epithelium, but ERbeta is expressed in all cellular compartments; 4 ) ERalpha but not ERbeta is down regulated by estradiol; 5 ) ERbeta, but not ER alpha, is expressed in the proliferating cells; 6 ) ERbeta is essential for the terminal differentiation of the breast epithelium; 7) In many primary breast cancers, ER alpha is up-regulated while ERbeta is down-regulated. Hypothesis/Objective: ERbeta agonists would be of benefit in treatment of breast cancer because they would inhibit proliferation and enhance differentiation of breast epithelium. Specific Aims: To understand the role of ERbeta in controlling proliferation of breast cancer. Study design: (1) By transfecting ERbeta or ER betacx to ER alpha positive breast cancer MCF7 cell and treating with agonist to ER alpha or ER beta, the effect on proliferation and differentiation will be evaluated. (2) The model of DMBA induced mammary carcinogenesis in ERbeta knockout mice and their littermates will be used to evaluate the effect of loss of ERbeta expression on tumor development and the effect of ERbeta agonist in preventing tumor growth. Potential Outcomes and Benefits of the Research: This study will help us to understand the role of ERbeta in controlling the cell proliferation in breast and to develop special agonist for ERbeta for improving the treatment of breast cancer.
Breast cancer is one of the leading causes of death in women. Recent studies show that hormone replacement therapy (HRT) after the menopause increases the risk of breast cancer. Estradiol, the most potent estrogen in the body, has multiple functions in the breast. Under some conditions it can increase proliferation but under other conditions it can stop proliferation and induce the cells to become more differentiated. A well-differentiated cancer is much milder than a poorly differentiated cancer. In the past 10 years a new development has occurred in our understanding of how estradiol carries out its functions. We now know that there are two receptors which are activated by estradiol but which give the cell completely different signals. When estradiol binds to estrogen receptor alpha, the signal is for the cell to proliferate and for ducts to grow. When it binds to ERbeta, the cell is instructed to stop proliferating and to begin to differentiate. If a woman has ER alpha in her breast cancer she is given an estrogen receptor blocker, tamoxifen, and this stops proliferation. The two major problems with this treatment are (1) some ERalpha-positive patients do not respond to tamoxifen treatment and (2) many patients develop recurrence after receiving 5 years of treatment. ERbeta and its splice variant ERbetacx are also expressed in both normal breast and breast cancer, but their significance in guiding breast cancer treatment is yet unclear. We think that the antiproliferative, pro-differentiative effects mediated by ERbeta can be utilized in the treatment of breast cancer. This project aims at understanding the role of ERbeta in controlling breast cancer growth. We will introduce ERbeta and ERbetacx gene into ERalpha-positive breast cancer cell line, MCF7, and evaluate the changes of growth rate and differentiation. In addition, we will use a mouse model of cancer to evaluate the role of ERbeta and ERbeta-selective agonists in the development, progression of a chemically induced breast cancer. Mice in which the ERbeta gene has been knockout and their wild type littermates will be given a chemical carcinogen, DMBA. Some of these mice will be treated with selective ERbeta agonists for various periods during the development and growth of the cancer. If ERbeta can inhibit breast cancer development and growth in this mouse model, it will provide the incentive for development of special ERbeta agonists to improve the treatment of breast cancer patients.