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Regulatory T Cells and Breast Cancer Risk
Risk, Prevention and Epidemiology
Established risk factors explain only a small proportion of breast cancer incidence, underscoring the necessity of investigations of novel risk factors for this disease. The role of immunological factors in breast cancer etiology is a topic of recent interest. We propose to study the association between regulatory T cells (Treg) and breast cancer risk. Treg cells are a unique subset of T cell with immunosuppressive properties. Previous research has demonstrated that patients with a wide variety of autoimmune disease have lower levels of Treg cells than healthy controls. In contrast, higher Treg levels have been consistently demonstrated among patients with a wide range of malignancies, including breast cancer. The objective of the proposed study is to conduct the first comprehensive epidemiological study on the association between Treg cells and breast cancer risk. We hypothesize that Treg cells are elevated in breast cancer patients compared to controls, as well as that genetic polymorphisms associated with high Treg cell levels will be overrepresented in breast cancer patients. In specific aim 1, we intend to compare Treg cell levels measured in blood sample from a well-defined sample of breast cancer patients and healthy controls. In aim 2, we propose to examine the association between a panel of candidate genes (FOXP3, IL-2, IDO, CTLA-4, TGF-â) directly relevant to Treg cell function, and breast cancer risk. In our exploratory aims, we propose to examine the associations between genotype and epidemiological data and Treg cell levels. We will utilize samples and data that have been or will be collected as part of our cancer center?s program in which we systematically enroll patients, family members and visitors and collect detailed epidemiological data and biological specimens. From this pool of patients and controls, we will randomly select 100 cases and 100 controls for aim 1, as well as 820 cases and 820 controls for aim 2. We will use flow cytometry for measurement of Treg cells in peripheral blood samples and MALDI-TOF technology for genotyping analyses. If we can demonstrate that Treg cell levels are elevated among breast cancer patients, such findings will stimulate immunological research, aimed at safe Treg cell manipulation.
Many scientific studies have been carried out in order to uncover important risk factors for breast cancer. Unfortunately, results from these studies can only explain 40 to 50 percent of breast cancer occurrence in the US and worldwide. Thus, important risk factors for this disease remain to be uncovered and new studies are needed that focus on possible risk factors that have not been studied before. The objective of the proposed study is to examine the role of a unique type of immune function cell in the development of breast cancer. In contrast to so-called "effector T cells", which are responsible for attacking foreign substances, such as viruses or bacteria, regulatory T cells (or Treg cells) can actually prevent the immune system from protecting the body from foreign substances. One of the body's defense mechanism against cancer is the immune system, because cancer cells are foreign to the body and will be attacked by the effector T cells mentioned above. Our hypothesis states that women with higher levels of Treg cells in their bodies will be more likely to develop breast cancer, because these Treg cells might prevent the immune system from attacking cancer cells in the early development of breast cancer. Thus, in our first specific aim, we propose to compare Treg cell levels in blood samples from a well-chosen group of women with breast cancer and women without breast cancer. In our second aim, we are interested in looking at the role of certain genetic traits, also called genetic polymorphisms that influence the amount of Treg cells in ones body. We expect that women with genetic traits that are associated with high Treg cell levels will be more likely to develop breast cancer than women with genetic traits that are associated with lower Treg cell levels. Our study design will employ epidemiological case-control study methodology. We will use samples and epidemiological data that were collected from women with breast cancer who were treated at our cancer center. We have also available samples and data from women without cancer who were visitors or family members of cancer patients. Due to the fact that these samples have been or will be collected by our cancer center resource, our study will be very efficient. We will collaborate with our colleagues in the Genetics and Immunology departments for the measurements of the genetic polymorphisms and Treg cell levels, respectively. Further, all data analyses will be carried out by a collaborating biostatistician. We believe that the proposed research is not only novel, but results could have an important impact on our understanding of breast cancer. If we indeed find out that Treg cells are important in breast cancer development, such findings could stimulate further research. Specifically, scientists in the immunology field could try to figure out how Treg cell levels could be lowered, which might lead to a way to prevent breast cancer before it starts to develop.