Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein (MVP).

INTRODUCTION: Clinical studies suggest that obesity, in addition to promoting breast cancer aggressiveness, is associated with a decrease in chemotherapy efficacy, although the mechanisms involved remain elusive. As chemotherapy is one of the main treatments for aggressive or metastatic breast cancer, we investigated whether adipocytes can mediate resistance to doxorubicin (DOX), one of the main drugs used to treat breast cancer, and the mechanisms associated. METHODS: We used a coculture system to grow breast cancer cells with in vitro differentiated adipocytes as well as primary mammary adipocytes isolated from lean and obese patients. Drug cellular accumulation, distribution, and efflux were studied by immunofluorescence, flow cytometry, and analysis of extracellular vesicles. Results were validated by immunohistochemistry in a series of lean and obese patients with cancer. RESULTS: Adipocytes differentiated in vitro promote DOX resistance (with cross-resistance to paclitaxel and 5-fluorouracil) in a large panel of human and murine breast cancer cell lines independently of their subtype. Subcellular distribution of DOX was altered in cocultivated cells with decreased nuclear accumulation of the drug associated with a localized accumulation in cytoplasmic vesicles, which then are expelled into the extracellular medium. The transport-associated major vault protein (MVP), whose expression was upregulated by adipocytes, mediated both processes. Coculture with human mammary adipocytes also induced chemoresistance in breast cancer cells (as well as the related MVP-induced DOX efflux) and their effect was amplified by obesity. Finally, in a series of human breast tumors, we observed a gradient of MVP expression, which was higher at the invasive front, where tumor cells are at close proximity to adipocytes, than in the tumor center, highlighting the clinical relevance of our results. High expression of MVP in these tumor cells is of particular interest since they are more likely to disseminate to give rise to chemoresistant metastases. CONCLUSIONS: Collectively, our study shows that adipocytes induce an MVP-related multidrug-resistant phenotype in breast cancer cells, which could contribute to obesity-related chemoresistance.

Impact of micronutrient deficiency & malnutrition in systemic sclerosis: Cohort study and literature review.

OBJECTIVES: The purpose of our study was to determine the prevalence and risk factors associated with malnutrition, and selenium (Se) and vitamin C (vitC) deficiencies in systemic sclerosis (SSc) patients. METHODS: We included adult SSc patients fulfilling the 2013 ACR/EULAR criteria from the Toulouse University Hospital cohort who underwent a micronutrient workup (including vitC, Se or thiamine levels) between 2011 and 2016. RESULTS: 82 patients were included, mostly women (76%), with a median age of 60 years. SSc was limited in 76% of the cases, with Scl-70 and centromere antibodies in 32% and 44%, respectively. Median disease duration was 7.4 years. Cardiac involvement was noticed in 19% and gastrointestinal tract in and 95%; 9% had pulmonary artery hypertension (PAH) and 63% had interstitial lung disease. Overt malnutrition was present in 14 (17%) patients. Micronutrient deficiencies included Se (35%), vitC (31%) and/or thiamine (6%). Malnourished patients had significantly a higher summed Medsger disease severity scales (7.5 vs. 5, P = .003), lower hemoglobin (10.6 vs. 12.9 g/dL, P < .0001) and vitC levels (3.6 vs. 10.6 mg/L, P = .003). Cardiac involvement was significantly associated with Se deficiency (OR 6.2, IC 95%[1.48-32.70], P = .05). The factors associated with vitC deficiency were malnutrition (OR 8.57, IC 95%[2.16-43.39], P = .003), modified Rodnan skin score ≤ 14 (OR 0.33, IC95[0.11-1], P = .05), PAH (27% in deficient vs. none in non-deficient patients, P = .0006) and esophagitis or Barrett's mucosa (OR 4.05, IC95[1.27-13.54], P = .02). CONCLUSIONS: Se testing should be considered as soon as cardiac involvement is suspected. VitC testing should be considered in malnourished SSc patients, especially if skin involvement is extensive.