Transforming growth factor-beta promotes survival of mammary carcinoma cells through induction of antiapoptotic transcription factor DEC1.

Abstract

Transforming growth factor-beta (TGF-beta) signaling facilitates tumor growth and metastasis in advanced cancer. In the present study, we identified differentially expressed in chondrocytes 1 (DEC1, also known as SHARP2 and Stra13) as a downstream target of TGF-beta signaling, which promotes the survival of breast cancer cells. In the mouse mammary carcinoma cell lines JygMC(A) and 4T1, the TGF-beta type I receptor kinase inhibitors A-44-03 and SB431542 induced apoptosis of cells under serum-free conditions. Oligonucleotide microarray and real-time reverse transcription-PCR analyses revealed that TGF-beta induced DEC1 in these cells, and the increase of DEC1 was suppressed by the TGF-beta type I receptor kinase inhibitors as well as by expression of dominant-negative TGF-beta type II receptor. Overexpression of DEC1 prevented the apoptosis of JygMC(A) cells induced by A-44-03, and knockdown of endogenous DEC1 abrogated TGF-beta-promoted cell survival. Moreover, a dominant-negative mutant of DEC1 prevented lung and liver metastasis of JygMC(A) cells in vivo. Our observations thus provide new insights into the molecular mechanisms governing TGF-beta-mediated cell survival and metastasis of cancer.

• Authors: Shogo Ehata, Aki Hanyu, Makoto Hayashi, Hiroyuki Aburatani, Yukio Kato, Makoto Fujime, Masao Saitoh, Keiji Miyazawa, Takeshi Imamura, Kohei Miyazono
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 20 Pg. 9694-703 (Oct 15 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17942899 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Bhlhe40 protein, mouse
• DELEC1 protein, human
• Homeodomain Proteins
• Protein Kinase Inhibitors
• RNA, Messenger
• Receptors, Transforming Growth Factor beta
• Smad Proteins
• Transforming Growth Factor beta
• Tumor Suppressor Proteins
• Receptors, Platelet-Derived Growth Factor
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Receptor, Transforming Growth Factor-beta Type I

Topics

• Animals
• Apoptosis (physiology)
• Basic Helix-Loop-Helix Transcription Factors (biosynthesis, genetics)
• Cell Survival (physiology)
• Homeodomain Proteins (biosynthesis, genetics)
• Humans
• Liver Neoplasms (secondary)
• Lung Neoplasms (secondary)
• Mammary Neoplasms, Experimental (genetics, metabolism, pathology)
• Mice
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Messenger (biosynthesis, genetics)
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, Platelet-Derived Growth Factor (metabolism)
• Receptors, Transforming Growth Factor beta (antagonists & inhibitors)
• Signal Transduction
• Smad Proteins (metabolism)
• Transforming Growth Factor beta (metabolism, pharmacology)
• Tumor Suppressor Proteins (biosynthesis, genetics)