title: The effects of beta-estradiol on Raf activity, cell cycle progression and growth factor synthesis in the MCF-7 breast cancer cell line.
abstract: The aim of this study was to test the hypothesis that some of the proliferative effects of steroid hormones on cancer cells are mediated by the Raf proto-oncogenes. The human breast cancer cell line MCF-7 is estrogen-receptor (ER) positive (+). NCI/ADR-RES is a human cell line lacking the estrogen receptor (ER-) that was initially named MCF-ADR. Raf-1, A-Raf and B-Raf kinase activities were examined in cell lines treated with beta-estradiol for 24 hours. Increases in Raf-1 and A-Raf activities were observed after treatment with beta-estradiol in the ER (+) MCF-7 cells but not in the ER (-) NCI/ADR-RES cells. In contrast, no significant changes in B-Raf activity were observed. Thus beta-estradiol can induce Raf-1 and A-Raf activities in ER (+) cells. In addition, beta-estradiol caused cell cycle progression in MCF-7 cells and an increased proliferative response to beta-estradiol was observed in MCF-7, which overexpressed constitutively-active Raf-1 (MCF/DeltaRaf-1). Increased mRNA levels of the ligand for the c-erb-B2 receptor, amphiregulin (ARG) were observed after beta-estradiol treatment of MCF-7 cells whereas constitutively higher levels of ARG and its receptor, c-erb-B2 mRNAs were detected in MCF/DeltaRaf-1 cells. These findings suggest that targeting Raf may prove efficacious in breast cancer therapies.
authors.affiliation: Department of Microbiology ond Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina 27858, USA.
authors.forename: Caroline R
authors.initials: CR
authors.lastname: Weinstein-Oppenheimer
authors.forename: Carlo
authors.initials: C
authors.lastname: Burrows
authors.forename: Linda S
authors.initials: LS
authors.lastname: Steelman
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
mesh_terms: D066258:Amphiregulin; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D066255:EGF Family of Proteins; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D048491:Proto-Oncogene Proteins A-raf; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D017384:Sequence Deletion; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D066258:Amphiregulin; D066255:EGF Family of Proteins; D004958:Estradiol; D006023:Glycoproteins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D048491:Proto-Oncogene Proteins A-raf; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C587848:AREG protein, human