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Mammary adipose stromal cells derived from obese women reduce sensitivity to the aromatase inhibitor anastrazole in an organotypic breast model.

ABSTRACT: Aromatase inhibitors are the preferred treatment for certain women with estrogen receptor (ER)-positive breast cancer, but evidence suggests that women with obesity experience aromatase inhibitor resistance at higher rates. To compare how stromal cells derived from women who are lean or obese influence response to the aromatase inhibitor (anastrazole), we incorporated patient-derived stroma in a previously characterized MCF7-derived in vitro duct model. Coculture with adipose stromal cells enabled the metabolism of testosterone (T) to E₂, which induced estrogen response element activity, epithelial proliferation, and hyperplasia in MCF7 cells. The effects of T were inhibited by the ER antagonist tamoxifen and aromatase inhibitor anastrazole and were increased by the aromatase inducer dexamethasone. Primary mammary adipose stromal cells derived from women with obesity displayed increased aromatase mRNA compared with lean controls. MCF7-derived ducts cocultured with obese stromal cells exhibited higher maximal aromatization-induced ER transactivation and reduced anastrazole sensitivity, a difference not seen in 2-dimensional coculture. Finally, tamoxifen was more effective than anastrazole at reducing aromatization-induced ER transactivation and proliferation. These findings suggest that patient-specific responses to hormone therapies can be modeled and studied organotypically in vitro and add to evidence advocating obesity as a parameter to consider when identifying treatments for patients with ER-positive breast cancer.-Morgan, M. M., Arendt, L. M., Alarid, E. T., Beebe, D. J., Johnson, B. P. Mammary adipose stromal cells derived from obese women reduce sensitivity to the aromatase inhibitor anastrazole in an organotypic breast model.

SUBMITTER: Morgan MM

PROVIDER: S-EPMC6593876 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:To examine the relationships between plasma and tissue markers of systemic and vascular inflammation and obesity and insulin resistance and determine the effects of aerobic exercise training plus weight loss (AEX+WL) and weight loss (WL) alone on these biomarkers.Prospective controlled study.Veterans Affairs Medical Center and University research setting.Overweight and obese sedentary postmenopausal women (N = 77).Six months, 3 d/wk AEX+WL (n = 37) or WL (n = 40).Total-body dual-energy X-ray absorptiometry, abdominal computed tomography, hyperinsulinemic-euglycemic clamps (a criterion standard method of assessing insulin sensitivity), adipose tissue biopsies (n = 28), and blood for homeostasis model assessment-insulin resistance, and soluble forms of intracellular adhesion molecule 1 (sICAM-1) and vascular cell adhesion molecule 1 (sVCAM-1), C-reactive protein (CRP), and serum amyloid A (SAA).Body weight (P < .001), percentage of fat (P < .001), visceral fat (P < .005), triglyceride levels (P < .001), and systolic blood pressure decreased comparably after WL and AEX+WL (P = .04). Maximal oxygen consumption increased 16% after AEX+WL (P < .001). Insulin resistance decreased in both groups (P = .005). Glucose utilization according to the clamp increased 10% (P = .04) with AEX+WL and 8% with WL (P = .07). AEX+WL decreased CRP by 29% (P < .001) and WL by 21% (P = .02). SAA levels decreased twice as much after AEX+WL (-19%, P = .02) as after WL (-9%, P = .08). Plasma sICAM-1 and sVCAM-1 levels did not change, but women with the greatest reduction in plasma sICAM-1 levels had the greatest reductions in fasting glucose (P = .02), insulin (P = .02), and insulin resistance (P = .004). Gluteal ICAM messenger ribonucleic acid levels decreased 27% after AEX+WL (P = .02) and did not change after WL.Obesity and insulin resistance worsen markers of systemic and vascular inflammation. A reduction in plasma sICAM-1 is important to improve insulin sensitivity. CRP, SAA, and tissue ICAM decrease with exercise and weight loss, suggesting that exercise training is a necessary component of lifestyle modification in obese postmenopausal women.

Project description:PurposeNonadherence to aromatase inhibitors (AIs) for breast cancer is common and increases the risk of recurrence. Text messaging increases adherence to medications for chronic conditions.MethodsWe conducted a randomized clinical trial of text messaging (TM) versus no text messaging (No-TM) at 40 sites in the United States. Eligible patients were postmenopausal women with early-stage breast cancer taking an AI for > 30 days with a planned duration of ≥ 36 months. Test messages were sent twice a week over 36 months. Content themes focused on overcoming barriers to medication adherence and included cues to action, statements related to medication efficacy, and reinforcements of the recommendation to take AIs. Both groups were assessed every 3 months. The primary outcome was time to adherence failure (AF), where AF was defined as urine AI metabolite assay results satisfying one of the following: < 10 ng/mL, undetectable, or no submitted specimen. A stratified log-rank test was conducted. Multiple sensitivity analyses were performed.ResultsIn total, 724 patients were registered between May 2012 and September 2013, among whom,702 patients (348 in the text-messaging arm and 354 in the no-text-messaging arm) were eligible at baseline. Observed adherence at 36 months was 55.5% for TM and 55.4% for No-TM. The primary analysis showed no difference in time to AF by arm (3-year AF: 81.9% TM v 85.6% No-TM; HR, 0.89 [95% CI, 0.76 to 1.05]; P = .18). Multiple time to AF sensitivity analyses showed similar nonsignificant results. Three-year self-reported time to AF (10.4% v 10.3%; HR, 1.16 [95% CI, 0.69 to 1.98]; P = .57) and site-reported time to AF (21.9% v 18.9%; HR, 1.31 [95% CI, 0.86 to 2.01]; P = .21) also did not differ by arm.ConclusionTo our knowledge, this was the first large, long-term, randomized trial of an intervention directed at improving AI adherence. We found high rates of AI AF. Twice-weekly text reminders did not improve adherence to AIs. Improving long-term adherence will likely require personalized and sustained behavioral interventions.

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Mammary adipose stromal cells derived from obese women reduce sensitivity to the aromatase inhibitor anastrazole in an organotypic breast model.

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