Circulating Adipose Stromal Cells (CASCs) as a Potential Biomarker of Response to Weight Loss Interventions in Obese Women at High Risk for Breast Cancer

Abstract

Background. Obesity is a modifiable risk factor for breast cancer in the United States. White adipose tissue is increased in obese (BMI ≥ 30 kg/m2) women and the dysfunction resulting from adipocyte hyperplasia and hypertrophy as well as the increase in visceral and ectopic fat results in an increase in local and often systemic pro-inflammatory cytokines and bioavailable estrogen. Adipose stromal cells play a key role in releasing estrogens and pro-inflammatory cytokines, while circulating adipose stromal cells (CASCs) home to tumor sites and promote angiogenesis and vascularization. CASCs have been implicated in promoting metastases in individuals with cancer and have been correlated with BMI in both cancer and non-cancer patients. In a cross sectional study in women at high risk for development of breast cancer, we examined whether CASC frequency correlates with additional measures of adiposity and tissue measures of short term risk. In a pilot study of a 3 month weight loss intervention in obese sedentary breast cancer survivors we also assessed whether CASC frequencies changed with weight and fat loss. Methods. 34 women at high risk for development of breast cancer were recruited primarily for random peri-areolar fine needle aspiration (RPFNA) for risk assessment and also underwent Dual-energy X-ray absorptiometry (DEXA) body composition, anthropomorphic assessment, and non-fasting venous blood collection as part of HSC4601. 10 obese sedentary breast cancer survivors recruited as part of a weight loss and exercise trial (STUDY00004575) underwent DEXA body composition, anthropomorphic measures, and phlebotomy prior to and after a 3-month intervention. Mononuclear cells were isolated from the non-fasting blood and the frequency of CASCs (characterized as CD34brightCD31-CD45- cells) was assessed by flow cytometry. Results. In the cross sectional study in high risk women, CASC frequency ranged from 0 to 0.013% (median 0.001%) for 14 non-obese and 20 obese women. There was an association between CASC frequency and BMI (range 19 – 46 kg/m2), as both a linear correlation (P=0.03) and when dichotomized at a BMI of 30 kg/m2 (P=0.05). A stronger relationship was observed between BMI and CASCs when dichotomizing BMI at < 35 kg/m2 and ≥ 35 kg/m2 (P=0.009). CASC frequency was correlated with low mammographic breast density (P=0.018) in high risk women possibly due to high BMI in women with < 5% density. Decrease in CASC frequency in 10 obese breast cancer survivors undergoing a 3 month diet and exercise intervention was linearly correlated with decreases in weight, BMI, and visceral fat. Conclusions. These findings suggest that evaluation of circulating adipose stromal cells could have value as a response biomarker in weight loss intervention trials of both high risk women and breast cancer survivors.