title: Antiproliferative effects of selective cyclooxygenase-2 inhibitor modulated by nimotuzumab in estrogen-dependent breast cancer cells.
abstract: Breast cancer is the most common malignancy in women, and many breast cancer patients fail conventional treatment strategies of chemotherapy, radiation, and antiestrogen therapy. Research into the molecular pathways and biomarkers involved in the development of breast cancer should yield information that will guide therapeutic decisions. Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are involved in the carcinogenesis of breast cancer and exist tight crosstalk with estrogen receptor (ER) pathway. Combination of EGFR and COX-2 inhibitors, therefore, could be an effective strategy for reducing cell growth in estrogen-dependent breast cancer. In order to verify the effects of EGFR and COX-2 inhibitors, breast cancer cells MCF-7 and SKBR-3 were characterized for receptors status and then treated with respective inhibitors (nimotuzumab and celecoxib) alone and in combination. Both cell lines were sensitive to celecoxib, but not to nimotuzumab. However, combination of two drugs demonstrated synergistic effects on cell killing. Moreover, association of two drugs resulted in SKBR-3 cells, a further G0/G1 phase arrest than one drug alone. Downregulation of p-EGFR, p-Akt, p-mTOR, and amplified in breast cancer 1 (AIB1) were observed in both cell lines, and upregulation of E-cadherin was only found in MCF-7, after treatment with single agent or in combination. These studies suggest that nimotuzumab and celecoxib exert synergistic antiproliferation effects in breast cancer, which partly correlates with ER status. Due to Akt/mTOR, EMT and AIB1 pathways participate in this process, therefore, E-cadherin and AIB1 may be considered as possible biomarkers to predict response in ER-positive breast cancer cells treated with EGFR and COX-2 inhibitors.
authors.affiliation: Department of Endocrinology, School of Clinical Medicine, Binzhou Medical University, No.661, Yellow-River Second Street, 256603 Binzhou, China. wangyx1011@163.com
authors.forename: Ying-Xue
authors.initials: YX
authors.lastname: Wang
authors.forename: Jin-Xiang
authors.initials: JX
authors.lastname: Gao
authors.forename: Xiu-Yun
authors.initials: XY
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Chang-Mei
authors.initials: CM
authors.lastname: Liu
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D000068579:Celecoxib; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015820:Cadherins; D052246:Cyclooxygenase 2 Inhibitors; D004967:Estrogens; D011720:Pyrazoles; D011960:Receptors, Estrogen; D013449:Sulfonamides; C501466:nimotuzumab; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; C546842:MTOR protein, human; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D000068579:Celecoxib