An isoform of the coactivator AIB1 that increases hormone and growth factor sensitivity is overexpressed in breast cancer.
The AIB1 (amplified in breast cancer 1) protein is a coactivator that potentiates the transcriptional activity of nuclear hormone receptors, and its gene is amplified in a subset of human breast cancers. Here we report a splice variant of AIB1 mRNA that lacks the exon 3 sequence. We determined that the AIB-Delta3 mRNA encoded a 130-kDa protein that lacks the NH(2)-terminal basic helix-loop-helix and a portion of the PAS (Per-Arnt-Sim homology) dimerization domain. The 130-kDa protein was detected in MCF-7 breast cancer cells at levels that were 5-10% of the full-length protein, whereas in non-transformed mammary epithelium lines, the AIB-Delta3 protein was present at significantly lower levels compared with the full-length AIB1. Consistent with this finding, the abundance of AIB1-Delta3 mRNA was increased in human breast cancer specimens relative to that in normal breast tissue. To determine whether there were phenotypic changes associated with the overexpression of the AIB-Delta3 isoform, we performed functional reporter gene assays. These revealed that the ability of AIB1-Delta3 to promote transcription mediated by the estrogen or progesterone receptors was significantly greater than that of the full-length protein. Surprisingly, the AIB1-Delta3 isoform was also more effective than AIB1 in promoting transcription induced by epidermal growth factor. Overexpression of AIB1-Delta3 may thus play an important role in sensitizing breast tumor cells to hormone or growth factor stimulation.
Reiter
R
R
Department of Oncology, Lombardi Cancer Center, Georgetown University Medical Center, Washington, D. C. 20007, USA.
Wellstein
A
A
Riegel
A T
AT
D000123:Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D017398:Alternative Splicing; D001943:Breast Neoplasms / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D051548:Histone Acetyltransferases; D006801:Humans; D011374:Progesterone / Q000494:pharmacology*; D014176:Protein Biosynthesis; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction
D047628:Estrogen Receptor alpha; D004967:Estrogens; D020033:Protein Isoforms; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D029701:Saccharomyces cerevisiae Proteins; C097314:progesterone receptor B; D011374:Progesterone; D004815:Epidermal Growth Factor; D000123:Acetyltransferases; D051548:Histone Acetyltransferases