ciclesonide and Breast-Neoplasms

Ciclesonide is an FDA-approved glucocorticoid used to treat asthma and allergic rhinitis. However, whether it has anticancer and anti-cancer stem cell (CSC) effects is unknown. This study focused on investigating the effect of ciclesonide on breast cancer and CSCs and determining its underlying mechanism. Here, we showed that ciclesonide inhibits breast cancer and CSC formation. Similar glucocorticoids-dexamethasone and prednisone-did not inhibit CSC formation. Ciclesonide-induced glucocorticoid receptor (GR) degradation was dependent on ubiquitination. We showed via GR small interfering RNA (siRNA) that GR plays an important role in CSC formation. We showed via western blot and immunofluorescence assays that ciclesonide reduces the nuclear level of GR. The GR antagonist RU-486 also inhibited CSC formation. Ciclesonide reduced the protein level of the Hippo transducer Yes-associated protein (YAP). GR siRNA induced a decrease in YAP protein expression and inhibited mammosphere formation. The YAP inhibitor verteporfin inhibited CSC formation and transcription of the connective tissue growth factor and cysteine-rich protein 61 genes. The GR/YAP1 pathway regulated breast CSC formation. We showed that the GR/YAP signaling pathway regulates breast CSC formation and revealed a new approach for targeting GR and YAP to inhibit CSC formation.

Topics: Adaptor Proteins, Signal Transducing; Anti-Asthmatic Agents; Breast Neoplasms; Cell Line, Tumor; Connective Tissue Growth Factor; Cysteine-Rich Protein 61; Glucocorticoids; Humans; MCF-7 Cells; Neoplastic Stem Cells; Pregnenediones; Protein Serine-Threonine Kinases; Receptors, Glucocorticoid; RNA, Small Interfering; Signal Transduction; Transcription Factors; Verteporfin; YAP-Signaling Proteins

Efflux transporters, p-glycoprotein and breast cancer resistance protein (BCRP), located at barrier sites such as the blood-brain barrier may affect distribution of steroids used for treating chronic inflammatory conditions and thus the extent to which they may perturb the hypothalamic-pituitary-adrenal axis. In the present study, six different glucocorticoids were investigated for their possible interactions with these efflux transporters. Beclomethasone dipropionate, mometasone furoate and ciclesonide active principle but not fluticasone propionate or triamcinolone, (all at 0.1 to 10 microM) caused inhibition of efflux, resulting in increased accumulation of mitoxantrone in BCRP-expressing MCF7/MR breast cancer cells and of calcein in p-glycoprotein-expressing SW620/R colon carcinoma cell. At 5 microM the same three increased sensitivity of p-glycoprotein-expressing SW620/R to doxorubicin and stimulated ATPase activity associated with BCRP expressed in bacterial membrane vesicles. Budesonide also stimulated ATPase activity. These data demonstrate the capacity of some clinically used glucocorticoids to interact with efflux transporters.

Topics: Adenosine Triphosphatases; Adrenal Cortex Hormones; Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Beclomethasone; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Colonic Neoplasms; Dose-Response Relationship, Drug; Doxorubicin; Drug Synergism; Fluoresceins; Humans; Mitoxantrone; Mometasone Furoate; Neoplasm Proteins; Pregnadienediols; Pregnenediones