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Project 4: The obesity-metabolic biomarker axis and breast cancer risk

Specific Aims

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 women1, although results have been noted to vary by cancer subtype and race. 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 in part by their differences in underlying mechanisms through which obesity is related to postmenopausal 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 a study to directly evaluate the relationship of these mechanisms to breast cancer risk and, further, to investigate through which pathway(s) obesity is related to breast cancer risk. The proposed research builds upon substantial published and preliminary analyses, in which we have demonstrated striking variation between black and white women in mean serum levels of adiponectin and leptin, anti- and pro-inflammatory cytokines, respectively, produced in adipose tissue, insulin-like growth factor 1 (IGF1) and C-reactive protein (CRP) and their associations with obesity. Our data support the hypothesis that these biomarkers act differently in their association with obesity and risk of breast cancer between racial groups.

We propose herein a case-control study of postmenopausal breast cancer nested within the prospective Southern Community Cohort Study (SCCS) that is tracking over 50,000 women, two-thirds of whom are black, for breast and other cancer incidence. The SCCS is the largest ongoing prospective cohort study of black women with stored pre-diagnostic blood samples. Adding to this project’s novelty is the availability of tumor tissue for breast cancer cases, enabling one of the first prospective joint examinations of blood and tissue markers of risk. Further, the SCCS is uniquely positioned to assess obesity-related biomarkers as this cohort was recruited from a low-income population where obesity is common (58% of SCCS black women have a BMI>30 kg/m2). Diabetes also is a prevalent co-morbidity in this cohort. The 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. We hypothesize that risk will increase with all of these biomarker indices, except for a decrease with SHBG, and that the association will be modified by race and/or ER/PR status. We will test these hypotheses using a nested case-control approach and pre-diagnostic blood for 400 postmenopausal cases (~65% black) and 800 controls.

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. We hypothesize that obesity upregulates these pathways in breast tissue to increase risk of breast cancer, but that the extent of the upregulation by obesity differs by race. We will test these hypotheses using tumor samples from 500 postmenopausal breast cancer cases (~65% black) and adjacent normal tissue samples from a subset of 100 cases.

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. We hypothesize that circulating levels of IGF1, sex hormones and inflammation markers (leptin, adiponectin and CRP) will correlate with markers of IGF1, ER and inflammation signaling, respectively, in breast cancer tissues. We will test these hypotheses in the subgroup of 240 breast cancer cases that have both pre-diagnostic serum and tumor biopsies available.