Importance: Obesity is associated with increased risk of breast cancer, including the estrogen receptor (ER)-positive subtype in postmenopausal women. It is unknown whether excess adiposity is associated with increased risk in women with a normal body mass index (BMI). Objective: To investigate the association between body fat and breast cancer risk in normal BMI women. Design: This secondary analysis of the Women’s Health Initiative (WHI) cohort was restricted to participants with BMI 18.5 to <25.0 kg/m2. Setting: Women ages 50 to 79 years were enrolled from 1993 to 1998. Body fat was measured by dual energy X-ray absorptiometry (DXA) at 3 designated centers. Participants: 3,460 postmenopausal women with normal BMI who had DXA measures were included. At a median follow-up of 16 years, 182 incident breast cancers had been ascertained; 146 were ER-positive. Main Outcomes and Measures: DXA-derived body fat levels were measured at baseline and years 1, 3, 6, and 9. Information on demographic data, medical history, and lifestyle factors was collected at baseline. Invasive breast cancers were confirmed via central review of medical records by physician adjudicators. Blood analytes were measured in subsets of participants. Results: Multivariable-adjusted hazard ratios (HRs) for risk of invasive breast cancer were 1.89 (95% CI 1.21 to 2.95) and 1.88 (95% CI 1.18 to 2.98) in the uppermost versus lowest quartiles of whole body fat and trunk fat mass, respectively. The corresponding adjusted HRs for ER-positive breast cancer were 2.21 (95% CI 1.23 to 3.67) and 1.98 (95% CI 1.18 to 3.31), respectively. Similar positive associations were observed when accounting for serial DXA measurements in time-dependent covariate analyses for ER-positive breast cancer. Circulating insulin, C-reactive protein, interleukin-6, leptin and triglycerides were higher, while HDL-cholesterol and sex hormone binding globulin were lower in the uppermost versus lowest quartiles of trunk fat mass. Conclusions and Relevance: In normal BMI postmenopausal women, relatively high body fat was associated with elevated risk of invasive breast cancer and altered levels of circulating metabolic and inflammatory factors. Normal BMI categorization may be an inadequate proxy for the risk of breast cancer in postmenopausal women.

Background: Restless Legs Syndrome (RLS) is a neurological condition characterized by uncomfortable sensations in the legs at rest that leads to sleep disruption and impaired quality of life. Correlates of RLS in prior studies are inconsistent but include many correlates of cardiovascular disease (CVD) risk factors. The objective of our study is to describe the burden and correlates of RLS in an epidemiological study of middle-aged adults. Methods: Participants in the CARDIA study completed the Cambridge-Hopkins RLS questionnaire between 2020-2022. Sociodemographic characteristics, cigarette smoking, physical activity, alcohol intake, depressive symptoms, parity and menopausal status were determined based on self-report. Waist circumference, body mass index (BMI) and blood pressure were measured using standard procedures. Serum glucose and creatinine were measured in fasting samples. A spot urine collection was used to determine urinary albumin and creatinine. Hypertension and diabetes were determined based on current clinical guidelines. We carried out univariate and multivariable logistic regression modeling to identify correlates associated with RLS. Results: In 2337 CARDA participants (44% Black and 60% female) with a mean age of 55.2 years old (SD=3.6), 120 (5.5%) participants (white women=78, black women=12, white men=26 and black men=4) endorsed symptoms of RLS. White participants and females were significantly more likely to endorse having RLS (Table). Health behaviors assessed in our study were not associated with RLS; however, the presence of diabetes and markers of adverse kidney function (i.e., serum creatinine, ACR) were associated with a higher odds of RLS and these associations persisted in a multivariable model. Conclusion: Metabolic disorders that lead to microvascular and peripheral nerve damage were associated with RLS in this sample. Future research should investigate whether RLS and peripheral neuropathy are overlapping conditions.

160 Background: Body mass index (BMI) does not accurately reflect body composition, particularly among cancer survivors. Sarcopenia (low skeletal muscle mass) and low muscle radio-density (MD; suggesting fat infiltration into muscle, compromising function) increase risk of surgical complications and chemotherapy toxicity and are associated with worse survival in advanced cancer. Little is known about the prevalence or predictors of sarcopenia and low MD in early-stage breast cancer. Methods: We studied 2,914 Kaiser Permanente members diagnosed with Stage I-III breast cancer from 2005-2013. Using computed tomography (CT) scans of the third lumbar vertebra from clinical care, we determined sarcopenia (skeletal muscle index < 41 muscle [cm2]/height [m2]) and low MD ( < 25-Hounsfield Units for non-obese; < 33 for obese) using published cut points. We assessed associations with characteristics including age, race, BMI, age, stage, lifestyle and co-morbidities with logistic regression. We also examined moderate/vigorous physical activity among a subset of 672 women with activity questionnaires. Results: At diagnosis, mean age was 56 years and time to CT was 1 month. Both sarcopenia and low MD were common among early-stage breast cancer survivors (40% and 38% respectively). In multivariate analyses, the odds of sarcopenia and low MD increased with age (per 5 years, Odds Ratio [OR] 95% Confidence Interval [CI] of OR = 1.33; 95%CI: 1.27, 1.39 and OR = 1.41; 95%CI: 1.35, 1.47 respectively). The odds of sarcopenia decreased with greater BMI (OR = 0.80; 95%CI: 0.78, 0.82 per kg/m2), while the odds of low MD increased (OR = 1.03; 95%CI: 1.01, 1.04 per kg/m2). Black race was associated with lower odds of sarcopenia and low MD, while physical activity levels were associated with lower odds of sarcopenia and more favorable MD. Conclusions: Sarcopenia and low MD are highly prevalent among breast cancer survivors. While older age is strongly associated with these conditions, they occur across ages and stages. Differences in body composition by race and age may underlie differences in the association of BMI with cancer outcomes; understanding these may help guide clinical interventions.

Curli, a type of proteinaceous cell surface filament, found on enteric bacteria such as E. Coli and Salmonella, are thought to play an important role in host cell adhesion and invasion. The assembly of CsgA, the major structural protein of Curli, into fibers is aided by three non‐structural proteins, CsgE, CsgF, and CsgG. CsgE and CsgF are thought to be periplasmic chaperone proteins that play a vital role in the assembly of Curli fibers. It has been shown that CsgE is able to prevent the aggregation of CsgA into Curli fibers. We determined the ability of CsgE and CsgF to inhibit the aggregation of human Islet Amyloid Polypeptide (hIAPP), an amyloidogenic protein unrelated to Curli formation. We monitored the aggregation of hIAPP, using the fluorescent dye ThT, in the absence and presence of CsgE and CsgF. An increase in ThT fluorescence emission intensity is routinely used to detect the aggregation of amyloidogenic polypeptides. In the absence of CsgE or CsgF we observe a greater than 5‐fold increase in fluorescence intensity when freshly dissolved hIAPP is monitored in the presence of ThT. Such an increase in intensity is typically taken to indicate the aggregation of hIAPP. In the presence of CsgE and CsgF no significant increase in ThT intensity is observed suggesting that both CsgE and CsgF prevented the aggregation of hIAPP.Support or Funding Information1. This work is supported by NIH grant 1R15GM123430‐01This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

12089 Background: Metabolic abnormalities may impact breast cancer prognosis, but research has been limited by small samples and assessment of laboratory values at a single time point, often prior to cancer diagnosis and treatment. In a population based cohort, we utilized time-updated laboratory values and adjusted for cancer treatment to assess the association between metabolic risk factors (glucose, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides) and breast cancer survival. Methods: 13,434 women diagnosed with stage I-III breast cancer from 2005-15 at Kaiser Permanente were included. All outpatient fasting glucose, HDL, LDL, and triglyceride values from diagnosis through 2019 or death were extracted from electronic medical records. Lab values were updated a median of 5 times between 1-7 years post-diagnosis. Risk of breast cancer-specific mortality was evaluated with Cox proportional hazards models adjusted for metabolic labs, demographics, body mass index, and diabetes, and then for dyslipidemia and anti-hypertensive medications, tumor characteristics (stage, ER and HER2 receptor status) and cancer treatment (use of chemotherapy, and tamoxifen v. aromatase inhibitors). Results: Mean (SD) age at diagnosis was 62.3 (11.8) years. Over median follow-up of 9 years, 2,876 patients died (1,080 of breast cancer). Patients with low HDL (≤45 vs. >45 mg/dL) had higher breast cancer-specific mortality (HR, 1.87; 95% CI, 1.62-2.16); high levels of glucose, triglycerides, and LDL were not associated. The increased risk associated with low HDL persisted after adjusting for tumor characteristics, cancer treatment, and medications. Conclusions: Low HDL evaluated over time after cancer diagnosis is associated with higher breast cancer mortality independent of cancer treatments and changes in other metabolic risk factors. Cholesterol may play a role in breast cancer due to its role in cell membrane structure, signaling pathways, and steroid hormone synthesis. Future studies should address whether pharmacologic or lifestyle treatment of lipids after breast cancer diagnosis can optimize survival outcomes.[Table: see text]