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Changes in expression, and/or mutations in TGF-beta receptors (TGF-beta RI and TGF-beta RII) and Smad 4 in human

Marie Lue Antony1, Rema Nair, Paul Sebastian

  • 1Division of Cancer Biology, Rajiv Gandhi Center for Biotechnology, Thiruvananthapuram, Kerala 695014, India.

Journal of Cancer Research and Clinical Oncology
|November 17, 2009
PubMed
Abstract

Insights

Transforming growth factor beta (TGF-beta) signaling alterations, including receptor mutations and Smad 4 loss, are frequent in ovarian tumors. These changes may explain the common loss of TGF-beta responsiveness in ovarian cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Transforming growth factor beta (TGF-beta) signaling is crucial in cellular processes.
  • Loss of TGF-beta signaling sensitivity is common in ovarian cancer cells.
  • Information on TGF-beta signaling in ovarian tumors is limited.

Purpose of the Study:

  • To investigate the association between inactivating mutations and/or expression variations of TGF-beta signaling components and human ovarian tumors.
  • To evaluate the frequency of TGF-beta receptor mutations and Smad 4 alterations in ovarian cancer.

Main Methods:

  • Analysis of 40 human ovarian tissue samples for mutations and expression levels of TGF-beta signaling components.
  • Mutation detection using RT-PCR, single-strand conformation polymorphism, and DNA sequencing.
  • Expression analysis via semi-quantitative RT-PCR and western blotting; assessment of Smad complex DNA binding and downstream target expression.

Main Results:

  • TGF-beta receptor variants (RI six alanine repeat, RII polyadenine tract deletion) found in 27% and 22% of tumors, respectively.
  • 45 bp deletions in TGF-beta RI exon 1 observed in two samples.
  • Loss or decreased Smad 4 protein expression, reduced Smad complex DNA binding, and deregulated p21 and c-Myc expression noted in tumor samples.

Conclusions:

  • Mutations and expression alterations in TGF-beta receptors are frequent in human ovarian cancers.
  • Loss of Smad 4 is also common in these tumors.
  • These molecular changes likely contribute to the observed loss of TGF-beta responsiveness in ovarian cancer.

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