Small Heterodimer Partner Plays an Immunomodulatory Role to Impact Breast Cancer Progression
Abstract
Despite increased survivorship among patients, breast cancer remains the second leading cause of cancer death in women. The majority of mortality associated with breast cancer is due to the metastatic spread of the disease. Therefore, more studies are required that result in more effective treatments while at the same time minimizing side effects. Several studies have indicated that elevated cholesterol is a risk factor for recurrence with metastatic disease. We decided to investigate this further in order to identify factors involved in cholesterol biology that might also prove to be a good drug target. In doing so, we found that elevated expression of Small Heterodimer Partner (SHP) within human breast tumors was associated with a good prognosis. However, when we manipulated SHP in breast cancer cell lines, it had no effect on proliferation or migration. Thus, we speculated that it may exert its protective effects in the normal cells within the tumor microenvironment. Indeed, we found that SHP is highly expressed in macrophages, a type of white blood cell. Interestingly, when SHP is inhibited in macrophages, we observe an outgrowth of a type of T cell called a regulatory T cell (Treg). Tregs are involved in suppressing the immune system. This is normally a beneficial role in order to stop the immune system from damaging the host. However, in cancer, Tregs impair the body’s anti-cancer response. In particular, it has been speculated that a major reason why the majority of breast cancer patients do not respond to new immune-checkpoint inhibitor therapies is due to the presence of Tregs. The goals of this proposal are to (1) assess the role of SHP in macrophages and subsequent immune suppression via Tregs and (2) evaluate the clinical utility of combining drugs that target SHP with immune checkpoint-inhibitor therapy, for the treatment of metastatic breast cancer. By accomplishing these goals, we will address the following overarching challenges: eliminate the mortality associated with metastatic breast cancer; identify what drives breast cancer growth and determine how to stop it; and revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. Specific Aim 1: Elucidate the role of SHP in macrophage physiology. In this aim, we will utilize state-of-the-art cellular and murine models to determine whether macrophages lacking functional SHP promote the development of Tregs within the microenvironment of metastatic breast cancer. We will then test whether these cells actively suppress the anti-cancer activity of the immune system. This will be important information for the future development of SHP as a clinical target. Specific Aim 2: Develop SHP as a novel therapeutic target for the treatment of breast cancer. Using mouse models where SHP is genetically deleted from macrophages, we will assess tumor growth and metastasis. This will provide definitive proof of concept that SHP expression in macrophages is important for breast cancer progression. We will then evaluate targeting SHP in two different ways. First, it is known that activation of the Farnesoid X receptor (FXR) leads to increased SHP levels in macrophages. Fortuitously, there is an FXR drug already in clinical trials for the treatment of liver and gastrointestinal disorders. Thus, it can be rapidly translated into the clinic. The second approach will be to specifically target SHP with a new drug that has only been used in mice. This approach will likely prove better (fewer side effects) than targeting FXR, but will take longer to introduce into the clinic. For both approaches, we will combine the therapies with immune-checkpoint inhibitor therapy. Immune therapy has revolutionized cancer treatment and has tremendous success for certain cancers such as metastatic melanoma – even resulting in complete and durable regression. However, this therapy has had little success in
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810694
Entities
People
- Erik R Nelson
Organizations
- United States Army
- University of Illinois Urbana–Champaign