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This version published online on November 4, 2004
Endocrinology, doi:10.1210/en.2004-1239
A more recent version of this article appeared on February 1, 2005
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Submitted on September 17, 2004
Accepted on October 25, 2004

Transcriptional and post-transcriptional regulation of fibulin-1 by estrogens leads to differential induction of mRNA variants in ovarian and breast cancer cells

A Bardin, F Moll, R Margueron, C Delfour, ML Chu, T Maudelonde, V Cavailles, and P Pujol*

Unité INSERM 540, 60 rue de Navacelles, 34095 Montpellier, France; Service de Biologie Cellulaire et Hormonale, Centre Hospitalier Universitaire de Montpellier, Hôpital Arnaud de Villeneuve, 271, Av G. Giraud, 34095 Montpellier, France; Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA. 19107, USA

* To whom correspondence should be addressed. E-mail: p-pujol{at}chu-montpellier.fr.

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 E2 increases fibulin-1 gene transcription and that ER{alpha} is more potent than ER{beta} to mediate E2 regulation of the transfected fibulin-1 promoter. Using SL2 cells devoid of Sp1 and site-directed mutagenesis of GC boxes we evidenced that the E2-regulation occurs through a proximal Sp1 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 upon E2 treatment. In conclusion, our data show that estrogens, via ER{alpha}, are key regulators of fibulin-1 expression both at the transcriptional and post-transcriptional 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.
Key words: fibulin-1 • estrogens • ovarian • breast cancer




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