The nuclear BAG-1 isoform, BAG-1L, enhances oestrogen-dependent transcription.
BAG-1 is a multifunctional protein that interacts with a wide range of cellular targets including heat-shock proteins and some nuclear hormone receptors. BAG-1 exists as three major isoforms, BAG-1L, BAG-1M and BAG-1S. BAG-1L contains a nuclear localization signal, which is not present in the other isoforms, and is predominantly localized in the cell nucleus. Here we have investigated the effects of BAG-1 on function of the oestrogen receptor (ER), a key growth control molecule and target for hormonal therapy in breast cancer. We demonstrate that BAG-1L, but not BAG-1S or BAG-1M, increased oestrogen-dependent transcription in breast cancer cells. BAG-1L interacted with and stimulated the activity of both ER alpha and beta. Although BAG-1L and ERs colocalize to the nucleus, fusing BAG-1S to an heterologous nuclear localization sequence was not sufficient to stimulate transcription. Consistent with an important effect on receptor function, nuclear BAG-1 expression in breast cancers was associated with expression of the progesterone receptor, a transcriptional target of ERalpha, and was associated with improved survival in patients treated with hormonal therapy. These data suggest that BAG-1L is an important determinant of ER function in vitro and in human breast cancer.
Cutress
Ramsey I
RI
Cancer Research UK Oncology Unit, Cancer Sciences Division, School of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
Townsend
Paul A
PA
Sharp
Adam
A
Maison
Anna
A
Wood
Lynn
L
Lee
Ron
R
Brimmell
Matthew
M
Mullee
Mark A
MA
Johnson
Peter W M
PW
Royle
Gavin T
GT
Bateman
Adrian C
AC
Packham
Graham
G
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D011233:Precipitin Tests; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics*
C091732:BCL2-associated athanogene 1 protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004967:Estrogens; D020033:Protein Isoforms; D011960:Receptors, Estrogen; D014157:Transcription Factors