Effects of Estrogen Receptors Alpha and Beta on R-Loops, DNA Damage, and Suppression of Triple-Negative Breast Tumors
Abstract
Overarching challenges? The immediate challenge is to identify determinants of breast cancer initiation, risk, and susceptibility. Estrogen is a critical driver of breast cancer and contributes to the burden of breast cancer affecting up to one in eight women during their lifetimes. So how does estrogen drive breast cancer? Equally important is why seven out of eight women never develop breast cancer despite exposure to estrogen from puberty to menopause. These questions are intertwined with the paradoxical roles of estrogen in contributing to both risk and resistance to breast cancer. The mechanisms mediating these opposing effects of estrogens will be studied in strains of mice that differ in the fidelity of DNA repair and immune function and that render one strain susceptible to breast tumors while another strain is resistant. These studies will provide insights into why estrogen exposures can be pathogenic and result in breast cancer in a minority of women (1/8) while the majority of women are unaffected (7/8). Who will be helped? There is an immediate need for more accurate estimation of risk for women with high mammographic density or diagnosed with premalignant breast lesions. More than 15% of women have “extremely dense breasts,” which is associated with a four- to six-fold increase in breast cancer risk. However, chemoprevention is not presently an option for most of these women. Therefore, the present approach is anxiety without options. Similarly, approximately 50,000 women are diagnosed annually with premalignant breast lesions, which is also associated with an increased risk of breast cancer of approximately four-fold. Tamoxifen reduces the risk of subsequent tumors in these women by ~60%, but the remainder progress in spite of treatment. The proposed experiments will identify mechanisms affecting susceptibility to breast cancer and identify biomarkers to accurately determine individual risk. Therapeutic options for women with triple-negative breast cancers (TNBCs) remain a challenge, but administration of estrogen-suppressed growth of invasive mammary tumors in mice. High-dose estrogen therapies were shown to be effective in the 1970s in clinical trials. These data emphasize the complex actions of estrogens and that these can be used to identify the mechanisms that mediate the tumor-suppressive effect of estrogen in women with TNBCs. What are the potential clinical applications, benefits, and risks? For women with dense breasts or a diagnosed with premalignant breast lesions, the biomarkers to be developed will provide guidance for patients and clinicians struggling with whether prophylactic therapies such as Tamoxifen would be beneficial. The biomarkers can be analyzed in routine biopsies of tissues or in analyses of cells in blood (lymphocytes). The experiments use strains of mice that also differ in the balance of their immune responses. With the growing recognition that the immune system can be targeted therapeutically to treat, and in some cases cure, cancers, the experiments will test whether the estrogens can tip the balance of the immune system toward elimination of cancer cells in some individuals. How long will it take to achieve patient-related outcomes? Biomarkers to stratify patients can have an immediate impact on women faced with the dilemma of whether Tamoxifen or other prophylactic therapies may be beneficial. Estrogen as a therapeutic for TNBCs could be implemented immediately given the clinical evidence from trials in the 1970s along with the availability of formulations that are already in use. The critical hurdle is the need to clearly discriminate women for whom estrogen intervention is likely beneficial. The mechanistic studies will fill this void. If ERß proves to enhance immunosurveillance, selective agonists targeting this receptor that have been in clinical trials for other indications can be quickly repurposed for use in the treatment of breast canc
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910372
Entities
People
- Donald Jerry
Organizations
- United States Army
- University of Massachusetts Amherst