title: Combination treatment with proteasome inhibitors and antiestrogens has a synergistic effect mediated by p21WAF1 in estrogen receptor-positive breast cancer.
abstract: Although antiestrogens significantly improve the survival of patients with ER-positive breast cancer, therapeutic resistance remains a major limitation. The combinatorial use of antiestrogen with other therapies was proposed to increase their efficiency and more importantly, to prevent or delay the resistance phenomenon. In the present study, we addressed their combined effects with proteasome inhibitors (PIs). The effects of antiestrogens (hydroxyl-tamoxifen, raloxifen and fulvestrant) currently used in endocrine therapy were tested in combination with PIs, bortezomib or MG132, on the growth of three ER-positive breast cancer cell lines and in two cellular models of acquired antiestrogen resistance. When compared to single treatments, these combined treatments were significantly more effective in preventing the growth of the cell lines. The regulation of key cell cycle proteins, the cyclin-dependent kinase inhibitors, p21WAF1 and p27KIP1, were also studied. Bortezomib and MG132 drastically increased p21WAF1 expression through elevation of its mRNA concentration. Notably, p27KIP1 regulation was quite different from that of p21WAF1. Furthermore, the effect of bortezomib in combination with antiestrogen was evaluated on antiestrogen-resistant cell lines. The growth of two antiestrogen-resistant cell lines appeared responsive to proteasome inhibition and was strongly decreased by a combined therapy with an antiestrogen. Collectively, these findings provide new perspectives for the use of PIs in combination with endocrine therapies for breast cancer and possibly to overcome acquired hormonal resistance.
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), CNRS, Université Montpellier, ENSCM, Faculté de Montpellier, 34093 Montpellier Cedex 5, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Maynadier
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), CNRS, Université Montpellier, ENSCM, Faculté de Montpellier, 34093 Montpellier Cedex 5, France.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Basile
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), CNRS, Université Montpellier, ENSCM, Faculté de Montpellier, 34093 Montpellier Cedex 5, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Gallud
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), CNRS, Université Montpellier, ENSCM, Faculté de Montpellier, 34093 Montpellier Cedex 5, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Gary-Bobo
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), CNRS, Université Montpellier, ENSCM, Faculté de Montpellier, 34093 Montpellier Cedex 5, France.
authors.forename: Marcel
authors.initials: M
authors.lastname: Garcia
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000069286:Bortezomib / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D007976:Leupeptins / Q000008:administration & dosage; D061986:MCF-7 Cells; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000008:administration & dosage; D012333:RNA, Messenger / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000008:administration & dosage; D011960:Receptors, Estrogen / Q000378:metabolism*; D013629:Tamoxifen / Q000008:administration & dosage
chemical_list: D018797:Cell Cycle Proteins; D020847:Estrogen Receptor Modulators; D007976:Leupeptins; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D013629:Tamoxifen; D000077267:Fulvestrant; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D000069286:Bortezomib; D018844:Cyclin-Dependent Kinases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde