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Transcriptional and Posttranscriptional Regulation of Fibulin-1 by Estrogens Leads to Differential Induction of Messenger Ribonucleic Acid Variants in Ovarian and Breast Cancer Cells

Unité Institut National de la Santé et de la Recherche Médicale 540 (A.B., F.M., R.M., C.D., T.M., V.C., P.P.), and Service de Biologie Cellulaire et Hormonale (C.D., T.M., P.P.), Centre Hospitalier Universitaire de Montpellier, Hôpital Arnaud de Villeneuve, 34095 Montpellier, France; and Department of Dermatology and Cutaneous Biology (M.L.C.), Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Address all correspondence and requests for reprints to: P. Pujol, Service de Biologie Cellulaire et Hormonale, Hôpital Arnaud de Villeneuve, 271, Av G. Giraud, 34095 Montpellier, France. 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 17ß-estradiol (E2) increases fibulin-1 gene transcription and that ER is more potent than ERß 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 ER, 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.

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