title: Salinomycin co-treatment enhances tamoxifen cytotoxicity in luminal A breast tumor cells by facilitating lysosomal degradation of receptor tyrosine kinases.
abstract: Luminal A breast cancer is the most common breast cancer subtype which is usually treated with selective estrogen receptor modulators (SERMS) like tamoxifen. Nevertheless, one third of estrogen receptor positive breast cancer patients initially do not respond to endocrine therapy and about 40% of luminal A breast tumors recur in five years. In this study, we investigated an alternative treatment approach by combining tamoxifen and salinomycin in luminal A breast cancer cell lines. We have found that salinomycin induces an additional cytotoxic effect by inhibiting the ligand independent activation of ERα. Thereby salinomycin increases the intracellular calcium level. This leads to a premature fusion of endosomes with lysosomes and thus to the degradation of Egfr family members. Since this process is essential for luminal A breast cancer cells to circumvent tamoxifen treatment, the combination of both drugs induces cytotoxicity in tamoxifen sensitive as well as resistant luminal A breast cancer cell lines.
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.|Department of Molecular Biology, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Ann-Katrin
authors.initials: AK
authors.lastname: Sommer
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Adam
authors.initials: A
authors.lastname: Hermawan
authors.affiliation: Physical Chemistry, Department of Chemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Frauke Martina
authors.initials: FM
authors.lastname: Mickler
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Bojan
authors.initials: B
authors.lastname: Ljepoja
authors.affiliation: Department of Molecular Biology, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Pjotr
authors.initials: P
authors.lastname: Knyazev
authors.affiliation: Physical Chemistry, Department of Chemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bräuchle
authors.affiliation: Department of Molecular Biology, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Roidl
mesh_terms: D001692:Biological Transport; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D011992:Endosomes / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D061986:MCF-7 Cells; D010634:Phenobarbital; D011714:Pyrans / Q000008:administration & dosage*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D013629:Tamoxifen / Q000008:administration & dosage*; D000095662:Polyether Polyketides
chemical_list: D047628:Estrogen Receptor alpha; D008024:Ligands; D010634:Phenobarbital; D011714:Pyrans; D020794:Receptor Protein-Tyrosine Kinases; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; C506487:ESR1 protein, human; C010327:salinomycin; D000095662:Polyether Polyketides
keywords: breast cancer; endosomal trafficking; resistance; salinomycin; tamoxifen