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.
|Werfel, Thomas A; Wang, Shan; Jackson, Meredith A et al. (2018) Selective mTORC2 Inhibitor Therapeutically Blocks Breast Cancer Cell Growth and Survival. Cancer Res 78:1845-1858|
|Zhao, Shilin; Li, Chung-I; Guo, Yan et al. (2018) RnaSeqSampleSize: real data based sample size estimation for RNA sequencing. BMC Bioinformatics 19:191|
|Santos Guasch, Gabriela L; Beeler, J Scott; Marshall, Clayton B et al. (2018) p73 Is Required for Ovarian Follicle Development and Regulates a Gene Network Involved in Cell-to-Cell Adhesion. iScience 8:236-249|
|Croessmann, Sarah; Sheehan, Jonathan H; Lee, Kyung-Min et al. (2018) PIK3CA C2 Domain Deletions Hyperactivate Phosphoinositide 3-kinase (PI3K), Generate Oncogene Dependence, and Are Exquisitely Sensitive to PI3K? Inhibitors. Clin Cancer Res 24:1426-1435|
|Elion, David L; Cook, Rebecca S (2018) Harnessing RIG-I and intrinsic immunity in the tumor microenvironment for therapeutic cancer treatment. Oncotarget 9:29007-29017|
|Williams, Michelle M; Lee, Linus; Werfel, Thomas et al. (2018) Intrinsic apoptotic pathway activation increases response to anti-estrogens in luminal breast cancers. Cell Death Dis 9:21|
|Hyman, David M; Piha-Paul, Sarina A; Won, Helen et al. (2018) HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature 554:189-194|
|Luo, Na; Nixon, Mellissa J; Gonzalez-Ericsson, Paula I et al. (2018) DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer. Nat Commun 9:248|
|Sudhan, Dhivya R; Schwarz, Luis J; Guerrero-Zotano, Angel et al. (2018) Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial. Clin Cancer Res :|
|Jovanovi?, Bojana; Sheng, Quanhu; Seitz, Robert S et al. (2017) Comparison of triple-negative breast cancer molecular subtyping using RNA from matched fresh-frozen versus formalin-fixed paraffin-embedded tissue. BMC Cancer 17:241|
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