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    Research Grants Awarded

    Effects Of Biologically-Related Genetic Variants And Biomarkers Of Obesity And Type 2 Diabetes On Breast Cancer Survival And Incidence

    Grant Mechanism:
    Career Catalyst Research

    Scientific Abstract:
    Background/Rationale. Breast cancer is the second leading cause of death due to cancer among women in the United States. In 2007, approximately 213,000 women will be diagnosed with breast cancer, and about 41,000 of those will die from the disease. Obesity is a well-established risk factor for breast cancer in postmenopausal women and is associated with poor prognosis regardless of menopausal status. The number of overweight and obese women in the U.S. has reached epidemic proportions, with over 60% of American women falling into one of these two categories. An important related issue is that the rise of obesity has brought about increasing numbers women with type 2 diabetes (diabetes) and metabolic syndrome. There is strong evidence for a link between the recent increases in diabetes and breast cancer. Study results suggest that diabetes is associated with a small but significant increase in breast cancer risk, an association that has been attributed to the insulin resistance and resulting hyperinsulinemia present in diabetes. In addition to the growth-promoting effects of insulin, diabetes is also associated with increased abdominal obesity, which can lead to increased estrogen production and disruption of adipokines. It has also been shown that insulin receptors are over-expressed by breast cancer cells, which may confer a selective growth advantage to pre-existing malignant cells in the setting of hyperinsulinemia. There is additional evidence that insulin resistance and diabetes may affect breast cancer prognosis. Although few studies have looked at the effects of diabetes on survival, some studies have found that markers of insulin resistance, such as elevated waist-to-hip ratio, adult weight gain and presence of the metabolic syndrome are associated with a worse prognosis after breast cancer. Objective/Hypothesis. Our hypothesis is that variations in genes that are associated with pathways of insulin resistance, glucose and lipid metabolism, and estrogen biosynthesis and metabolism could influence breast cancer risk and survival. Our proposed study would be among the first large, population-based studies to evaluate whether polymorphisms in these pathways play a role in breast cancer development and survival in a systematic manner, considering many of these polymorphisms in a single study. Study Aims. AIM 1. Determine whether all-cause and/or breast cancer-specific mortality is independently associated with diabetes among women with breast cancer. AIM 2. Determine whether all-cause and/or breast cancer-specific mortality among women with breast cancer is associated with urinary biomarker levels of estrogen metabolism (2-hydroxyestrone (2-OHE1) and 16[alpha]-hydroxyestrone (16-OHE1)). AIM 3. Determine whether all-cause and/or breast cancer-specific mortality among women with breast cancer is associated with variations of genes in the biologically related pathways of insulin resistance, glucose and lipid metabolism, and estrogen biosynthesis and metabolism, using individual SNPs and a haplotype approach. AIM 4. Determine whether the risk of developing breast cancer is associated with diabetes, and whether this risk varies by characteristics of the case tumor, such as hormone receptor status. AIM 5. Determine whether breast cancer risk is associated with variations in genes in the biologically related pathways of insulin resistance, glucose and lipid metabolism, and estrogen biosynthesis and metabolism, using a single SNP and a haplotype approach. AIM 6. Determine whether breast cancer risk is associated with interactions between diabetes and genetic polymorphisms in biologically related pathways (insulin resistance, glucose and lipid metabolism, and estrogen biosynthesis and metabolism). Study Design. To evaluate our hypothesis we will utilize DNA that has already been isolated from blood donated by women who participated in a population-based, case-control study of breast cancer on Long Island. The cases have also been followed-up to determine their 5-year survival. We have DNA available on 1,052 breast cancer cases and 1,098 controls without breast cancer. The DNA will be assayed in the lab for carefully selected polymorphisms in the diabetes and obesity pathways, using standard techniques. A single SNP and haplotype-based approach to group will be used to identify combinations of alleles in a more comprehensive and systematic manner. These data can then be statistically analyzed to determine whether the at-risk genetic variants occur more frequently in deaths than do in those who survive, and to explore whether these at-risk variants interact with diabetes and obesity to further affect breast cancer survival. Similar statistical analyses will be undertaken for breast cancer risk. Public Health Significance. The proposed study, by combining previously collected information with a new analysis of genetic variation, bridges the gap between genetics and epidemiology, offering a unique training opportunity and an occasion to further our understanding of how obesity and diabetes affect breast cancer risk and survival. This study will provide information on women who may be genetically susceptible to breast cancer, particularly those who have type 2 diabetes and/or are considered clinically overweight. This information could help us to target vulnerable subgroups of women who would particularly benefit from interventions designed to prevent weight gain or induce weight loss, with the specific purpose of reducing their likelihood of developing breast cancer, or if they have already been diagnosed with breast cancer, then to increase the likelihood that they will survive.

    Lay Abstract:
    Background/Rationale. Breast cancer is the second leading cause of death due to cancer among women in the United States. In 2007, approximately 213,000 women will be diagnosed with breast cancer, and about 41,000 of those will die from the disease. Obesity is a well-established risk factor for breast cancer in postmenopausal women and is associated with poor prognosis. The number of overweight and obese women in the U.S. has reached epidemic proportions, with over 60% of American women falling into one of these two categories. An important related issue is that the rise of obesity has brought about increasing numbers women with type 2 diabetes and metabolic syndrome. There is strong evidence for a link between the recent increases in type 2 diabetes and breast cancer. Study results suggest that type 2 diabetes is associated with a small increase in breast cancer risk, which has been attributed to the insulin resistance and hyperinsulinemia present in type 2 diabetes. In addition to the growth-promoting effects of insulin, type 2 diabetes is also associated with increased abdominal obesity, which can lead to increased estrogen production and disruption of adipokines, hormones that are associated with breast cancer risk. Objective/Hypothesis: Our objective is to understand whether type 2 diabetes is detrimental to women with breast cancer, and if so, why. We propose to look at genes that are associated with type 2 diabetes and obesity to determine if there are variations in these genes that will explain the associations. Our hypothesis is that variations in genes that are associated with pathways that are related to type 2 diabetes and obesity, such as insulin resistance, glucose and lipid metabolism, and estrogen production and metabolism, could influence breast cancer risk and survival. To the best of our knowledge, no other study has evaluated these type 2 diabetes and obesity pathway genes and their interactions and how they affect breast cancer risk and survival. Study Aims: AIM 1 Study the relationship between type 2 diabetes and breast cancer mortality; AIM 2 Study the relationship between urinary markers of estrogen metabolism and breast cancer mortality; AIM 3 Study the relationship between variations in genes associated with type 2 diabetes and obesity and breast cancer mortality, using both individual gene variants and combinations of variants; AIM 4 Study the relationship between type 2 diabetes and risk of developing breast cancer; AIM 5 Study the relationship between variations in genes associated with type 2 diabetes and obesity and risk of developing breast cancer, using both individual gene variants and combinations of variants; AIM 6. Study the relationship between type 2 diabetes and breast cancer varies according to variations in genes associated with type 2 diabetes and obesity. Study Design: To evaluate our hypotheses, the proposed study will be carried out in the Long Island Breast Cancer Study Project (LIBCSP), a large population-based case-control study. Extensive information already exists on their reproduction, diet and lifestyle as well as biological specimens collected from its participants, including DNA for over 1,000 women with breast cancer and 1,000 controls without breast cancer. The cases have also been followed-up to determine their 5-year survival. Our study will take advantage of this rich resource to investigate effects of genetic factors associated with type 2 diabetes and obesity in breast cancer development and survival. Public Health Significance. The proposed study, by combining previously collected information with a new analysis of genetic variation, bridges the gap between genetics and epidemiology, offering a unique training opportunity and an occasion to further our understanding of how obesity and type 2 diabetes affect breast cancer risk and survival. A great strength of this study is the multi-disciplinary epidemiologic approach which builds upon an established population-based study. The impact of this research lies in its potential not only to clarify the etiology of breast cancer and correlates of prognosis, but also to guide prevention efforts through identification of subgroups of women who may have a higher risk of developing breast cancer and/or having a worse prognosis. These results promise to provide important information for breast cancer prevention, and will offer new evidence between type 2 diabetes, obesity, and breast cancer.