Metalloprotease-disintegrin ADAM12 actively promotes the stem cell-like phenotype in claudin-low breast cancer.

BACKGROUND: ADAM12 is upregulated in human breast cancers and is a predictor of chemoresistance in estrogen receptor-negative tumors. ADAM12 is induced during epithelial-to-mesenchymal transition, a feature associated with claudin-low breast tumors, which are enriched in cancer stem cell (CSC) markers. It is currently unknown whether ADAM12 plays an active role in promoting the CSC phenotype in breast cancer cells. METHODS: ADAM12 expression was downregulated in representative claudin-low breast cancer cell lines, SUM159PT and Hs578T, using siRNA transfection or inducible shRNA expression. Cell characteristics commonly associated with the CSC phenotype in vitro (cell migration, invasion, anoikis resistance, mammosphere formation, ALDH activity, and expression of the CD44 and CD24 cell surface markers) and in vivo (tumor formation in mice using limiting dilution transplantation assays) were evaluated. RNA sequencing was performed to identify global gene expression changes after ADAM12 knockdown. RESULTS: We found that sorted SUM159PT cell populations with high ADAM12 levels had elevated expression of CSC markers and an increased ability to form mammospheres. ADAM12 knockdown reduced cell migration and invasion, decreased anoikis resistance, and compromised mammosphere formation. ADAM12 knockdown also diminished ALDEFLUOR+ and CD44hi/CD24-/lo CSC-enriched populations in vitro and reduced tumorigenesis in mice in vivo. RNA sequencing identified a significant overlap between ADAM12- and Epidermal Growth Factor Receptor (EGFR)-regulated genes. Consequently, ADAM12 knockdown lowered the basal activation level of EGFR, and this effect was abolished by batimastat, a metalloproteinase inhibitor. Furthermore, incubation of cells with exogenously added EGF prevented the downregulation of CD44hi/CD24-/lo cell population by ADAM12 knockdown. CONCLUSIONS: These results indicate that ADAM12 actively supports the CSC phenotype in claudin-low breast cancer cells via modulation of the EGFR pathway.

Medium-Chain Triglyceride Oil and Dietary Intervention Improved Body Composition and Metabolic Parameters in Children with Glycogen Storage Disease Type 1 in Jordan: A Clinical Trial.

Glycogen storage diseases (GSDs) are a group of carbohydrate metabolism disorders, most of which are inherited in autosomal recessive patterns. GSDs are of two types: those that have to do with liver and hypoglycaemia (hepatic GSDs) and those that are linked to neuromuscular presentation. This study aims to assess the impact of dietary intervention, including medium-chain triglyceride (MCT) oil, on anthropometric measurements, body composition analysis and metabolic parameters among Jordanian children and is expected to be the first in the country. A sample of 38 children with glycogen storage disease type 1 (GSD-1) (median age = 6.4 years) were on a diet that included uncooked cornstarch therapy and a fructose-, sucrose- and lactose-restricted diet. Patients started to take MCT oil along with the prescribed diet after the first body composition test. Patients' nutritional status was re-evaluated three months later. The study results show that the percentage of patients who suffered from hypoglycaemia at the beginning of the study decreased significantly from 94.7% to 7.9% (p < 0.0001). The serum levels of triglycerides, cholesterol, uric acid and lactate decreased significantly after three months of intervention (100-71.1%, 73.7-21.1%, 97.4-52.6% and 94.7-18.4%, respectively). In contrast, there was no statistical difference in neutrophil count. Regarding clinical parameters, liver span was significantly reduced from (16.01 ± 2.65 cm) to (14.85 ± 2.26 cm) (p < 0.0001). There were significant improvements in growth parameters, including height-for-age and BMI-for-age for children aged ≥2 years (p = 0.034 and p = 0.074, respectively). Significant improvements in skeletal muscle mass and bone mineral content were also noticed at the end of the trial (p ≤ 0.05). In conclusion, medium-chain triglyceride therapy is found to improve biochemical and growth parameters in children with GSD-1 in Jordan.