title: Fulvestrant treatment alters MDM2 protein turnover and sensitivity of human breast carcinoma cells to chemotherapeutic drugs.
abstract: The human homologue of mouse double minute 2 (MDM2) is overexpressed in tumors and contributes to tumorigenesis through inhibition of p53 activity. We investigated the effect of the anti-estrogen fulvestrant on MDM2 expression and sensitivity of estrogen receptor positive human breast cancer cell lines to chemotherapeutics. Fulvestrant down-regulated MDM2 through increased protein turnover. Fulvestrant blocked estrogen-dependent up-regulation of MDM2 and decreased basal expression of MDM2 in the absence of estradiol. As combinations of fulvestrant with doxorubicin, etoposide or paclitaxel were synergistic, altering cell cycle distribution and increasing cell death, this provides rationale for testing combinatorial chemotherapy with fulvestrant as a novel therapeutic strategy for patients with advanced breast cancer.
authors.affiliation: Department of Medicine, Rutgers Cancer Institute of New Jersey, Rutgers The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, United States.
authors.forename: Sonia C
authors.initials: SC
authors.lastname: Dolfi
authors.affiliation: Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
authors.forename: Adriana V
authors.initials: AV
authors.lastname: Jäger
authors.affiliation: Department of Medicine, Rutgers Cancer Institute of New Jersey, Rutgers The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Medina
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, United States.
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Haffty
authors.affiliation: Department of Pharmacology, The Penn State Cancer Institute, Pennsylvania State University College of Medicine, and Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, United States.
authors.forename: Jin-Ming
authors.initials: JM
authors.lastname: Yang
authors.affiliation: Department of Medicine, Rutgers Cancer Institute of New Jersey, Rutgers The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, United States. Electronic address: hirshfie@cinj.rutgers.edu.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Hirshfield
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D061986:MCF-7 Cells; D017239:Paclitaxel / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D018931:Antineoplastic Agents, Hormonal; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004965:Estrogen Antagonists; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53; D000077267:Fulvestrant; D004958:Estradiol; D005047:Etoposide; D004317:Doxorubicin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D017239:Paclitaxel
keywords: Breast cancer; Chemotherapy; Estrogen receptor; Fulvestrant; MDM2
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