Wnt modulates MCL1 to control cell survival in triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) has higher rates of recurrence and distant metastasis, and poorer outcome as compared to non-TNBC. Aberrant activation of WNT signaling has been detected in TNBC, which might be important for triggering oncogenic conversion of breast epithelial cell. Therefore, we directed our focus on identifying the WNT ligand and its underlying mechanism in TNBC cells. METHODS: We performed large-scale analysis of public microarray data to screen the WNT ligands and the clinical significance of the responsible ligand in TNBC. WNT5B was identified and its overexpression in TNBC was confirmed by immunohistochemistry staining, Western blot and ELISA. ShRNA was used to knockdown WNT5B expression (shWNT5B). Cellular functional alteration with shWNT5B treatment was determined by using wound healing assay, mammosphere assay; while cell cycle and apoptosis were examined by flowcytometry. Mitochondrial morphology was photographed by electron microscope. Biological change of mitochondria was detected by RT-PCR and oxygen consumption assay. Activation of WNT pathway and its downstream targets were evaluated by liciferase assay, immunohistochemistry staining and immunoblot analysis. Statistical methods used in the experiments besides microarray analysis was two-tailed t-test. RESULTS: WNT5B was elevated both in the tumor and the patients' serum. Suppression of WNT5B remarkably impaired cell growth, migration and mammosphere formation. Additionally, G0/G1 cell cycle arrest and caspase-independent apoptosis was observed. Study of the possible mechanism indicated that these effects occurred through suppression of mitochondrial biogenesis, as evidenced by reduced mitochondrial DNA (MtDNA) and compromised oxidative phosphorylation (OXPHOS). In Vivo and in vitro data uncovered that WNT5B modulated mitochondrial physiology was mediated by MCL1, which was regulated by WNT/ß-catenin responsive gene, Myc. Clinic data analysis revealed that both WNT5B and MCL1 are associated with enhanced metastasis and decreased disease-free survival. CONCLUSIONS: All our findings suggested that WNT5B/MCL1 cascade is critical for TNBC and understanding its regulatory apparatus provided valuable insight into the pathogenesis of the tumor development and the guidance for targeting therapeutics.

[A case of the latex-induced anaphylaxis by contact with barium enema catheter].

The subject was a 34-year-old female with asthma and atopic dermatitis who had previously undergone a Cesarean section. In December 1995, the patient had an acute abdominal pain, so she underwent a barium enema examination. During the procedure, severe anaphylactic shock developed, and the examination was stopped. The patient responded well to appropriate emergency therapy, and her symptoms were resolved. However, the woman visited our outpatient clinic because the symptoms of her atopic dermatitis got worse. She indicated that she felt itchy when using rubber gloves. Also, at the age of thirty, she had urticaria and dyspnea after drinking a glass of fruit juice. Subsequently radioallergosorbent testing demonstrated the presence of specific IgEs against latex, banana, kiwi, grapefruit, and avocado. Skin prick tests were positive for banana, grapefruit, avocado, and latex extract at a dilution of 1:1000. A scratch test was positive to an extract of a balloon catheter which included 0.3 microg/g latex proteins by the LEAP method. In conclusion, the patient was diagnosed with an anaphylaxis to the latex contained in a balloon catheter used for the barium enema.