Increased proteasome-dependent degradation of estrogen receptor-alpha by TGF-beta1 in breast cancer cell lines.
Normal mammary epithelial cells are rapidly induced to G(1) arrest by the widely expressed cytokine, transforming growth factor beta (TGF-beta1). Studies in established breast cancer cell lines that express the estrogen receptor alpha (ERalpha) have demonstrated loss of this responsiveness. This inverse correlation suggests interpathway signaling important to cell growth and regulation. The adenocarcinoma breast cell line BT474, which was not growth arrested by TGF-beta1, was used as a model of estrogen-inducible growth to explore interpathway crosstalk. Although BT474 cells were not growth-arrested by TGF-beta1 as determined by flow cytometry analysis and 5'-bromo-3'-deoxyuridine incorporation into DNA, estrogen receptor protein levels were attenuated by 100 pM TGF-beta1 after 6 h. This decrease in ERalpha reached 50% of untreated control levels by 24 h of treatment and was further supported by a 50% decrease in estrogen-inducible DNA synthesis. Inspection of ERalpha transcripts suggested that this decrease was primarily the result of altered ERalpha protein stability or availability. Use of the proteasome inhibitor, MG132, abolished all effects on ERalpha by TGF-beta1. Collectively, this data supports a role for TGF-beta1 in regulating the growth of otherwise insensitive breast cancer cells through modulation of ERalpha stability.
Petrel
Trevor A
TA
The Ohio State Biochemistry Program, College of Medicine and Public Health, and OSU Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Brueggemeier
Robert W
RW
D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002455:Cell Division; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D005434:Flow Cytometry; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011960:Receptors, Estrogen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism
D047628:Estrogen Receptor alpha; D007976:Leupeptins; D009097:Multienzyme Complexes; D011960:Receptors, Estrogen; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D025801:Ubiquitin; D004958:Estradiol; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D001973:Bromodeoxyuridine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde