Transcriptional and posttranscriptional regulation of fibulin-1 by estrogens leads to differential induction of messenger ribonucleic acid variants in ovarian and breast cancer cells

Endocrinology. 2005 Feb;146(2):760-8. doi: 10.1210/en.2004-1239. Epub 2004 Nov 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / physiopathology
  • Calcium-Binding Proteins / genetics*
  • Cell Line, Tumor
  • Estradiol / pharmacology*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / physiology*
  • Humans
  • Molecular Sequence Data
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / physiopathology
  • RNA Processing, Post-Transcriptional / drug effects
  • RNA Processing, Post-Transcriptional / physiology
  • RNA, Messenger / genetics
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology


  • Calcium-Binding Proteins
  • RNA, Messenger
  • fibulin
  • Estradiol