Novel Pro-Inflammatory Progesterone Receptor/STAT5 Gene Programs in Breast Cancer
Abstract
Breast cancer is the most common cancer in women. Despite advances in understanding how breast cancer develops, this has not translated into better therapies. The majority of breast cancers are positive for hormone receptors, such as the estrogen and progesterone receptor (PR), and are dependent on these receptors and their hormone ligands (estrogen and progesterone) for growth. However, as tumors progress, they become hormone-independent, meaning they grow in the absence of hormones normally required for cell growth, perhaps due to unregulated hormone receptors. It was recently shown that women who were taking hormone replacement therapy that included progesterone had an increased risk of developing breast cancer, underscoring the importance of studying PR in breast cancer. Understanding PR action in the context of breast cancer is important to the development of better therapies. PR is required during normal breast development and pregnancy, activating genes in the nucleus that stimulate cell growth. Recently, we identified that PR also regulates genes that drive inflammation, a normal cellular process that can function uncontrollably in cancer, generating mutations that may drive cancer growth. Decreasing inflammation has been shown to reduce the risk of developing breast cancer. The objective of the proposed experiments is to determine how PR regulates genes involved in inflammation, and if PR-dependent inflammation can be detected, and eventually blocked, in breast cancer. Understanding how PR regulates inflammation could lead to the development of a new area of therapies for breast cancer, combining currently existing hormone-based therapies with treatments aimed at reducing inflammation. The proposed research will address the overarching challenge: "Identify what drives breast cancer growth; determine how to stop it." These experiments rigorously test the hypothesis that there is a link between PR and inflammation that affects breast cancer progression, using breast cancer cells cultured in the lab and animal models that develop tumors similar to human breast cancer. These experiments will test if our question about PR and inflammation is correct (years 1-3, the project period covered by this grant). Completion of these experiments will generate sufficient preliminary data to apply for a research grant that would fund the next phase of the project (R01 level, years 4-6): test if drugs can target and block this pathway. Using the same types of model systems, we will screen currently existing chemical libraries that contain thousands of drugs and see which ones can block breast cancer growth/progression, aimed at targeting the PR/inflammation connection. These experiments would then open the doors for preclinical experiments, first in animal models (years 7-8) and then in human breast cancer patients (years 8+). Experiments of this caliber require strong collaborations with clinicians who treat breast cancer patients. Being part of a National Cancer Institute-designated cancer center like The University of Kansas Cancer Center affords great access to build these types of relationships.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610320
Entities
People
- Christy R Hagan
Organizations
- United States Army
- University of Kansas Medical Center