Modulation of Epithelial Biomarkers of Breast Cancer Risk by a Community-Based Intervention for Diabetes Prevention
Abstract
More than one-third of adults in the US have prediabetes. This condition disproportionally affects minorities and represents one of the few modifiable risk factors for breast and other cancers. Therefore, diabetes prevention efforts have the potential to reduce breast cancer incidence, even for the aggressive triple-negative breast cancer (TNBC) subtype for which no approved chemoprevention agent is available. The proposed research focuses on prediabetes and breast cancer risk, and thereby addresses the overarching challenges of (1) identifying determinants of breast cancer initiation, risk, or susceptibility and (2) preventing breast cancer. One question is driving our research: “Why is the risk of developing breast cancer increased in women with prediabetes?” Answering this question will make a major impact on prevention. First, the knowledge may lead to targeted and more efficient approaches to prevent breast cancer. Second, the knowledge will stimulate discussion of breast cancer risk by clinicians at the time of prediabetes diagnosis, which may increase motivation to adopt healthy habits (reducing both diabetes and cancer risks). Efforts to lower diabetes and breast cancer risk with weight loss interventions are important but not sufficient. Indeed, weight loss is often challenging and temporary, and weight fluctuations may increase risk for certain cancers. Also, a woman with a high body mass index (BMI) is not necessarily at increased risk for breast cancer. Rather, studies show that blood factors that are often (but not always) abundant in overweight and obese individuals are likely driving up breast cancer risk. These factors include insulin, IGF-1, and leptin, which are central to this proposal. We envision a future with personalized breast cancer prevention. To achieve this goal, a deep understanding of cancer initiation mechanisms, as well as tools and measures for individual risk assessment, is needed. Our preliminary results are based on 3D cell culture models of the mammary gland, and mice models of prediabetes (induced by a diet rich in fat). With both models of prediabetes, we measured a disruption of cell polarity in the mammary gland. Breast epithelial cells (which are the cells producing milk and from which most breast tumors are derived) are polarized, meaning that the contacts from cells to cells and between cells and their environment are precisely regulated. Loss of polarity disorients the cells and is one of the first identifiable events in breast cancer initiation. Additional results also suggest that leptin (a key factor in obesity and prediabetes) increases the amount of DNA damage. DNA damage is critical to breast cancer initiation, as illustrated by the sharp increased risk for women with mutations in DNA repair genes such as BRCA and p53. These results led us to the hypothesis that the metabolic derangement experienced in prediabetes leads to loss of epithelial polarity and DNA damage in the breast, thereby priming cancer initiation. Reversing prediabetes may restore cell polarity and reduce the amounts of mutations. To test this hypothesis, we will use 3D cultures of breast cells, mice models, and normal human breast tissue from donors at the Komen Tissue Bank. 3D cultures offer a good compromise of complexity and manipulability and mimic the organization of the breast gland (in particular polarity). We will also use newly developed “breast-on-a-chip” systems that mimic ducts in the breast (where most tumors initiate). The mice models will reproduce weight gain followed by weight loss or exercise, similar to lifestyle interventions with humans but in a very controlled way. Finally, relevance will be addressed with human breast tissue. Collectively, these systems will allow us to ask the following specific questions tied to our hypothesis: (1) Is the loss of breast cell polarity reversible? (2) Is prediabetes causing loss of polarity and DNA damage in huma
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810050
Entities
People
- Pierre-Alexandre Vidi
Organizations
- United States Army
- Wake Forest University