The effects of beta-estradiol on Raf activity, cell cycle progression and growth factor synthesis in the MCF-7 breast cancer cell line.
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.
Weinstein-Oppenheimer
Caroline R
CR
Department of Microbiology ond Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina 27858, USA.
Burrows
Carlo
C
Steelman
Linda S
LS
McCubrey
James A
JA
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
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