title: Sphingosine kinase isoforms as a therapeutic target in endocrine therapy resistant luminal and basal-A breast cancer.
abstract: Sphingosine kinase signaling has become of increasing interest as a cancer target in recent years. Two sphingosine kinase inhibitors, sphingosine kinase inhibitor (SKI)-II and ABC294640, are promising as potential breast cancer therapies. However, evidence for their therapeutic properties in specific breast cancer subtypes is currently lacking. In this study, we characterize these drugs in luminal, endocrine-resistant (MDA-MB-361) and basal-A, triple-negative (MDA-MB-468) breast cancer cells and compare them with previously published data in other breast cancer cell models. Both SKI-II and ABC294640 demonstrated greater efficacy in basal-A compared with luminal breast cancer. ABC294640, in particular, induced apoptosis and blocked proliferation both in vitro and in vivo in this triple-negative breast cancer system. Furthermore, Sphk expression promotes survival and endocrine therapy resistance in previously sensitive breast cancer cells. Taken together, these results characterize sphingosine kinase inhibitors across breast cancer cell systems and demonstrate their therapeutic potential as anti-cancer agents.
authors.affiliation: Tulane Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Antoon
authors.forename: Martin D
authors.initials: MD
authors.lastname: White
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Driver
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Burow
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Beckman
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000627:Aminophenols / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D017931:DNA Primers; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D000099157:Sphingosine Kinase
chemical_list: D000218:Adamantane; D000627:Aminophenols; D018931:Antineoplastic Agents, Hormonal; D017931:DNA Primers; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D017853:Phosphotransferases (Alcohol Group Acceptor); D011725:Pyridines; D011960:Receptors, Estrogen; D013844:Thiazoles; D000099157:Sphingosine Kinase; C525025:4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol; C548780:3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide