instnjctions): Existing epidemiologic studies suggest a complex relationship between obesity and breast cancer, with obesity generally associated with increased risk among postmenopausal women but reduced risk among premenopausal women. Limited information exists on the obesity-breast cancer association for black women, the group with the highest prevalence of obesity, higher incidence of triple negative (and basal-like) breast cancer), but lower incidence of the luminal subtype. It is possible that inconsistent associations between obesity and breast cancer risk in blacks and whites are explained by their differences in underlying mechanisms through which obesity is related to breast cancer risk. Although these mechanisms are not entirely clear, it is in general believed that obesity acts primarily by inducing insulin signaling and resistance, increased estrogen biosynthesis and inflammation to increase the risk of breast cancer. The relative contribution of these mechanisms to the pathogenesis of breast cancer may differ between blacks and whites, which may contribute to racial difference in risk of breast cancer by subtype. We propose herein a case- control study of postmenopausal breast cancer nested within the prospective Southern Community Cohort Study that is tracking over 50,000 women, two-thirds of whom are black, for breast and other cancer incidence. This cohort was recruited from a low-income population where obesity is common (58% of SCCS black women have a BMI>30 kg/m^.
Specific aims are:
Aim 1. To determine whether circulating levels of IGF1, IGF-binding protein 3, adiponectin, leptin, CRP and sex hormones [estradiol, estrone, testosterone and sex hormone-binding globulin (SHBG)] are associated with risk of postmenopausal breast cancer, and whether they differ by race and/or tumor estrogen/progesterone receptor status.
Aim 2. To determine whether the obese state upregulates tumor IGF1 signaling, estrogen receptor (ER) signaling and inflammation gene expression signatures to increase breast cancer risk, and if the extent of upregulation differs by race Aim 3. To determine whether pre-diagnostic circulating levels of IGF1, sex hormones and inflammation markers are associated with IGF1 signaling, ER signaling and inflammation gene expression signatures, respectively, in breast cancer tissues
The results of this study will enhance our understanding of specific pathways through which obesity increases breast cancer risk, particularly among black women. For the first time, through this SPORE Project, a study will use prospectively derived risk estimates for large numbers of black women. This new information may assist in the development of breast cancer prediction models, perhaps specific to race, and testable biomarkers, thus providing novel targets for development of rational therapies for the prevention of breast cancer.
|Mayer, Ingrid A; Abramson, Vandana G; Formisano, Luigi et al. (2016) A Phase Ib Study of Alpelisib (BYL719), a PI3KÎ±-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer. Clin Cancer Res :|
|Lee, Taekyu; Bian, Zhiguo; Zhao, Bin et al. (2016) Discovery and Biological Characterization of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors. FEBS Lett :|
|Harris, Leonard A; Frick, Peter L; Garbett, Shawn P et al. (2016) An unbiased metric of antiproliferative drug effect in vitro. Nat Methods 13:497-500|
|Zhao, Min; Kim, Pora; Mitra, Ramkrishna et al. (2016) TSGene 2.0: an updated literature-based knowledgebase for tumor suppressor genes. Nucleic Acids Res 44:D1023-31|
|Bhola, Neil E; Jansen, Valerie M; Koch, James P et al. (2016) Treatment of Triple-Negative Breast Cancer with TORC1/2 Inhibitors Sustains a Drug-Resistant and Notch-Dependent Cancer Stem Cell Population. Cancer Res 76:440-52|
|Degnim, Amy C; Dupont, William D; Radisky, Derek C et al. (2016) Extent of atypical hyperplasia stratifies breast cancer risk in 2 independent cohorts of women. Cancer 122:2971-8|
|Zhao, Junfei; Cheng, Feixiong; Wang, Yuanyuan et al. (2016) Systematic Prioritization of Druggable Mutations in âˆ¼5000 Genomes Across 16 Cancer Types Using a Structural Genomics-based Approach. Mol Cell Proteomics 15:642-56|
|Pelz, Nicholas F; Bian, Zhiguo; Zhao, Bin et al. (2016) Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods. J Med Chem 59:2054-66|
|Jansen, Valerie M; Mayer, Ingrid A; Arteaga, Carlos L (2016) Is There a Future for AKT Inhibitors in the Treatment of Cancer? Clin Cancer Res 22:2599-601|
|Hassanein, Mohamed; Hight, Matthew R; Buck, Jason R et al. (2016) Preclinical Evaluation of 4-[18F]Fluoroglutamine PET to Assess ASCT2 Expression in Lung Cancer. Mol Imaging Biol 18:18-23|
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