Salinomycin co-treatment enhances tamoxifen cytotoxicity in luminal A breast tumor cells by facilitating lysosomal degradation of receptor tyrosine kinases

// Ann-Katrin Sommer 1, 2 , Adam Hermawan 1 , Frauke Martina Mickler 3 , Bojan Ljepoja 1 , Pjotr Knyazev 2 , Christoph Brauchle 3 , Axel Ullrich 2 , Ernst Wagner 1 , Andreas Roidl 1 1 Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universitat Munchen, 81377 Munich, Germany 2 Department of Molecular Biology, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany 3 Physical Chemistry, Department of Chemistry, Ludwig-Maximilians-Universitat Munchen, 81377 Munich, Germany Correspondence to: Andreas Roidl, email: andreas.roidl@cup.uni-muenchen.de Keywords: tamoxifen, resistance, salinomycin, endosomal trafficking, breast cancer Received: February 3, 2016     Accepted: June 17, 2016     Published: July 07, 2016 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.