Estrogen-induced post-transcriptional modulation of c-myc proto-oncogene expression in human breast cancer cells.
The effects of estradiol (E2) on c-myc proto-oncogene expression were studied in the estrogen receptor (ER)-positive human breast cancer cell line, MCF-7. A biphasic modulation in c-myc mRNA levels occurs during the first 24 h of E2 (1 nM) exposure and in the absence of changes in MCF-7 culture growth, with transcript levels rising 4-6-fold within 1 h, returning to near base-line level after 3-6 h, and increasing again after 24 h of exposure. In contrast, the growth-inhibiting antiestrogen, tamoxifen (1 microM), reduces c-myc to 20% of the pretreatment level within 3-6 h of exposure, and this early decline is followed by a gradual return toward base-line level after continuous 72-h treatment. In ER-negative cells there is no change in c-myc expression following E2 exposure. MCF-7 nuclear runon assays show that c-myc transcription rates remain unchanged from base line for 24 h after E2 administration; as well, cycloheximide inhibition of protein synthesis superinduces c-myc expression and prevents E2 modulation of transcript levels. These results indicate that post-transcriptional modulation of c-myc by E2 is mediated by a labile degradative protein or otherwise dependent on active protein synthesis. We also developed MCF/nm and MCF/dm sublines by transfecting normal cells with human c-myc exons 2-3, transcriptionally driven by a retroviral long terminal repeat. Expression of the transfected c-myc genes in these sublines remains constant and elevated 10-fold, while transcript levels from the endogenous proto-oncogene continue to be modulated by E2. These findings suggest that in ER-positive breast cancer cells, E2 can modulate c-myc mRNA levels by a post-transcriptional mechanism that depends on gene sequences upstream from c-myc exon 2.
Santos
G F
GF
Cancer Research Institute, University of California, San Francisco 94143.
Scott
G K
GK
Lee
W M
WM
Liu
E
E
Benz
C
C
D001943:Breast Neoplasms / Q000235:genetics*; D003513:Cycloheximide / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D005091:Exons; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007438:Introns; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D014407:Tumor Cells, Cultured
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D013629:Tamoxifen; D004958:Estradiol; D003513:Cycloheximide