title: Sorafenib and nilotinib resensitize tamoxifen resistant breast cancer cells to tamoxifen treatment via estrogen receptor α.
abstract: Tamoxifen‑resistant breast cancer is a major clinical problem and new treatment strategies are highly warranted. In this study, the multitargeting kinase inhibitors sorafenib and nilotinib were investigated as potential new treatment options for tamoxifen‑resistant breast cancer. The two compounds inhibited cell growth, reduced expression of total estrogen receptor α (ER), Ser118-phosphorylated ER, FOXA1 and AIB1 and resensitized tamoxifen‑resistant cells to tamoxifen. The ER downmodulator fulvestrant exerted strong growth inhibition of tamoxifen‑resistant cells and addition of sorafenib and nilotinib could not further suppress growth, showing that sorafenib and nilotinib exerted growth inhibition via ER. In support of this, estradiol prevented sorafenib and nilotinib mediated growth inhibition. These results demonstrate that sorafenib and nilotinib act via ER and ER-associated proteins, indicating that these kinase inhibitors in combination with tamoxifen may be potential new treatments for tamoxifen‑resistant breast cancer.
authors.affiliation: Breast Cancer Group, Cell Death and Metabolism, Danish Cancer Society Research Center, 2100 Copenhagen Ø, Denmark.
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Pedersen
authors.affiliation: Breast Cancer Group, Cell Death and Metabolism, Danish Cancer Society Research Center, 2100 Copenhagen Ø, Denmark.
authors.forename: Susan
authors.initials: S
authors.lastname: Thrane
authors.affiliation: Breast Cancer Group, Cell Death and Metabolism, Danish Cancer Society Research Center, 2100 Copenhagen Ø, Denmark.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Lykkesfeldt
authors.affiliation: Breast Cancer Group, Cell Death and Metabolism, Danish Cancer Society Research Center, 2100 Copenhagen Ø, Denmark.
authors.forename: Christina W
authors.initials: CW
authors.lastname: Yde
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000096:biosynthesis; D006801:Humans; D061986:MCF-7 Cells; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D056921:Nuclear Receptor Coactivator 3 / Q000096:biosynthesis; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D000077157:Sorafenib; D013629:Tamoxifen / Q000008:administration & dosage*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D010671:Phenylurea Compounds; D011743:Pyrimidines; D013629:Tamoxifen; D009536:Niacinamide; D000077157:Sorafenib; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; C498826:nilotinib