Transcriptional and posttranscriptional regulation of fibulin-1 by estrogens leads to differential induction of messenger ribonucleic acid variants in ovarian and breast cancer cells.
Fibulin-1 is an extracellular matrix protein overexpressed in epithelial ovarian and breast cancers. In estrogen receptor (ER)-positive ovarian and breast cancer cell lines, fibulin-1 mRNA levels are markedly increased by estrogens. Transfection experiments using fibulin-1 promoter constructs indicate that 17beta-estradiol (E2) increases fibulin-1 gene transcription and that ERalpha is more potent than ERbeta to mediate E2 regulation of the transfected fibulin-1 promoter. Using SL2 cells devoid of specificity protein 1 (Sp1) and site-directed mutagenesis of GC boxes, we evidenced that the E2 regulation occurs through a proximal specificity protein 1 binding site. In addition, we show that fibulin-1C and -1D mRNAs, the two major fibulin-1 splicing variants, are differentially induced by E2. The induction of both mRNAs variants is direct and independent of a newly synthesized protein intermediate. Interestingly, actinomycin D chase experiments demonstrate that E2 treatment selectively shortens the fibulin-1D mRNA half-life. This indicates that estrogens affect differentially the stability of fibulin-1 variants and may explain the lower accumulation of fibulin-1D mRNA on E2 treatment. In conclusion, our data show that estrogens, via ERalpha, are key regulators of fibulin-1 expression at both the transcriptional and posttranscriptional levels. The preferential induction of the fibulin-1C variant, which is overexpressed in ovarian and breast cancer, might play an important role in estrogen-promoted carcinogenesis.
Bardin
A
A
Unité Institut National de la Santé et de la Recherche Médicale, Centre Hospitalier Universitaire de Montpellier, Hôpital Arnaud de Villeneuve, 34095 Montpellier, France.
Moll
F
F
Margueron
R
R
Delfour
C
C
Chu
M L
ML
Maudelonde
T
T
Cavailles
V
V
Pujol
P
P
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000503:physiopathology; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D002135:Calcium-Binding Proteins; D012333:RNA, Messenger; C060820:fibulin; D004958:Estradiol