Steroid receptor coactivator-3 expression in lung cancer and its role in the regulation of cancer cell survival and proliferation.

Abstract

Steroid receptor coactivator-3 (SRC-3) is a histone acetyltransferase and nuclear hormone receptor coactivator, located on 20q12, which is amplified in several epithelial cancers and well studied in breast cancer. However, its possible role in lung cancer pathogenesis is unknown. We found SRC-3 to be overexpressed in 27% of non-small cell lung cancer (NSCLC) patients (n = 311) by immunohistochemistry, which correlated with poor disease-free (P = 0.0015) and overall (P = 0.0008) survival. Twenty-seven percent of NSCLCs exhibited SRC-3 gene amplification, and we found that lung cancer cell lines expressed higher levels of SRC-3 than did immortalized human bronchial epithelial cells (HBEC), which in turn expressed higher levels of SRC-3 than did cultured primary human HBECs. Small interfering RNA-mediated downregulation of SRC-3 in high-expressing, but not in low-expressing, lung cancer cells significantly inhibited tumor cell growth and induced apoptosis. Finally, we found that SRC-3 expression is inversely correlated with gefitinib sensitivity and that SRC-3 knockdown results in epidermal growth factor receptor tyrosine kinase inhibitor-resistant lung cancers becoming more sensitive to gefitinib. Taken together, these data suggest that SRC-3 may be an important oncogene and therapeutic target for lung cancer.

• Authors: Di Cai, David S Shames, Maria Gabriela Raso, Yang Xie, Young H Kim, Jonathan R Pollack, Luc Girard, James P Sullivan, Boning Gao, Michael Peyton, Meera Nanjundan, Lauren Byers, John Heymach, Gordon Mills, Adi F Gazdar, Ignacio Wistuba, Thomas Kodadek, John D Minna
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 16 Pg. 6477-85 (Aug 15 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 20663904 (Publication Type: Journal Article)
• Copyright: (c)2010 AACR.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Protein Kinase Inhibitors
• Quinazolines
• RNA, Messenger
• NCOA3 protein, human
• Nuclear Receptor Coactivator 3
• ErbB Receptors
• Cetuximab
• Gefitinib

Topics

• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, enzymology, genetics, pathology)
• Cell Growth Processes (physiology)
• Cell Line, Tumor
• Cell Survival (physiology)
• Cetuximab
• Disease-Free Survival
• Drug Synergism
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Gefitinib
• Gene Dosage
• Gene Knockdown Techniques
• Humans
• Immunohistochemistry
• Lung Neoplasms (drug therapy, enzymology, genetics, pathology)
• Nuclear Receptor Coactivator 3 (antagonists & inhibitors, biosynthesis, genetics)
• Protein Kinase Inhibitors (pharmacology)
• Quinazolines (pharmacology)
• RNA, Messenger (biosynthesis, genetics)
• Signal Transduction