A role for TGF-beta in estrogen and retinoid mediated regulation of the nuclear receptor coactivator AIB1 in MCF-7 breast cancer cells.
AIB1 (amplified in breast cancer 1) is a nuclear receptor coactivator gene amplified and overexpressed in breast cancer. However, the mechanisms by which AIB1 is regulated are unclear. Here we show that 17beta-estradiol represses AIB1 mRNA and protein expression in MCF-7 human breast cancer cells primarily by suppressing AIB1 gene transcription. Estrogen levels present in fetal calf serum are sufficient to maintain AIB1 mRNA and protein at low basal levels, and this repression is reversed by the addition of antiestrogens or all-trans retinoic acid. Interestingly, cycloheximide inhibition experiments revealed that secondary protein synthesis was necessary to induce AIB1 expression by antiestrogens and retinoids. Experiments with TGF-beta and TGF-beta blocking antibodies demonstrated that this growth factor modulates AIB1 expression and showed that the antiestrogen and retinoid induction of AIB1 gene expression is mediated at least in part through TGF-beta. These data reveal a mechanism of estrogen-induced down-modulation of the overall hormone sensitivity of cells through feedback inhibition of coactivator gene expression. These data also suggest that antiestrogens can shift the sensitivity of cells to non-estrogenic proliferative signaling by increasing cellular levels of AIB1. This effect may play a role in breast cancer progression and resistance to drug treatment.
Lauritsen
Kristina J
KJ
Department of Oncology, Vincent T Lombardi Cancer Center, Research Building, E307, Georgetown University, 3970 Reservoir Road, Washington, DC 20007, USA.
List
Heinz-Joachim
HJ
Reiter
Ronald
R
Wellstein
Anton
A
Riegel
Anna T
AT
D001943:Breast Neoplasms / Q000378:metabolism*; D002453:Cell Cycle; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic; D006207:Half-Life; D006801:Humans; D056921:Nuclear Receptor Coactivator 3; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000077267:Fulvestrant; D004958:Estradiol; D014212:Tretinoin; D056921:Nuclear Receptor Coactivator 3