Selective Activation of p53 and Genome Surveillance Pathways by Estrogen Receptor Beta
Abstract
Overarching challenges? Prevention of breast cancer is the overarching challenge. To be successful, it will be necessary to identify the signals within the breast that, when disrupted, allow cancer to take root. Estrogenic compounds found within the environment can promote breast cancer; however, administration of estrogens to mimic the levels found during pregnancy, confers a long-lasting reduction in mammary tumors. This protective effect of estrogens is observed even when rodents are challenged with carcinogens or inherited mutations in breast cancer susceptibility genes. Our preliminary studies suggest that these paradoxical actions of estrogens may be mediated by two distinct estrogen receptors (ERalpha and ERbeta) and that selective stimulation of ERbeta can be harnessed to identify new therapies to prevent and treat breast cancer. Who will be helped and what are the potential clinical applications? The studies are focused on developing new strategies for chemoprevention. Present therapies selectively block ERalpha in breast tissue to prevent progression of premalignant lesions (atypical hyperplasias) and preinvasive cancers (ductal carcinoma in situ). Loss of estrogen suspends the growth, but is less effective in eliminating the rogue cells. By selectively engaging the ERbeta receptor, we show that it is possible to enhance surveillance pathways in tissue and eliminate cells with damaged DNA without causing proliferation. The studies will assess the efficacy of drugs that selectively activate ERbeta and identify critical downstream pathways that offer even more specific targets for therapies. Triple-negative breast cancers are formidable challenges presently. Although lacking ERalpha, a substantial fraction of triple-negative breast cancers (TNBCs) retain expression of ERbeta. Therefore, we will explore the use of selective ligands for ERbeta or the downstream targets to (i) inhibit growth and (ii) render the cells more sensitive to therapies such as ionizing radiation. These mechanisms will also provide insights that will improve predictions of clinical prognosis. Approaches and limitations? Mouse models will be treated with drugs that selectively activate ERbeta in Aim 1. This will define the signals that regulate genome surveillance and stem cells and test whether these pathways are sufficient to prevent tumors. We have selected a set of surrogate biomarkers for assessing responses, but the tissues collected can be used for genome-wide evaluation of gene expression if a more comprehensive evaluation of signaling networks is required. However, the analyses are limited to one strain of mice and are unlikely to represent the variation in responses likely to be observed among women. Therefore, we also evaluate responses in primary breast explants and tumors from women in Aim 2. These tissues allow both the doses of drugs targeting ERbeta and the range of responses among patients to be determined along with the potential for undesired proliferation. Biomarkers can be developed to select the subset of patients who will respond favorably. The efficacy of drugs targeting ERbeta in suppressing growth or sensitizing to radiation therapy will be tested in a subset of TNBCs maintained as xenografts grown in immunodeficient mice. The use of these patient-derived xenograft models has not been used extensively in drug testing but offers the potential for greater reliability in predicting clinically relevant drugs and is supported by the Avatar Institute at the University of Massachusetts Medical Center. Time required for patient-related outcomes and impact on ending breast cancer? The studies have the potential for immediate impact on how environmental estrogens are assessed for safety. It is not simply whether a compound can initiate a proliferative response, but also whether in may block ERbeta and the protective responses it mediates. Although drug development has a protracted timeline, our app
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510217
Entities
People
- D. Jerry
Organizations
- United States Army
- University of Massachusetts Amherst