The DEAD-box protein p72 regulates ERalpha-/oestrogen-dependent transcription and cell growth, and is associated with improved survival in ERalpha-positive breast cancer.

Abstract

The DEAD-box RNA helicases p68 (DDX5) and p72 (DDX17) have been shown to act as transcriptional co-activators for a diverse range of transcription factors, including oestrogen receptor-alpha (ERalpha). Here, we show that, although both proteins interact with and co-activate ERalpha in reporter gene assays, small interfering RNA-mediated knockdown of p72, but not p68, results in a significant inhibition of oestrogen-dependent transcription of endogenous ERalpha-responsive genes and oestrogen-dependent growth of MCF-7 and ZR75-1 breast cancer cells. Furthermore, immunohistochemical staining of ERalpha-positive primary breast cancers for p68 and p72 indicate that p72 expression is associated with an increased period of relapse-free and overall survival (P=0.006 and 0.016, respectively), as well as being inversely associated with Her2 expression (P=0.008). Conversely, p68 shows no association with relapse-free period, or overall survival, but it is associated with an increased expression of Her2 (P=0.001), AIB-1 (P<0.001) and higher tumour grade (P=0.044). Our data thus highlight a crucial role for p72 in ERalpha co-activation and oestrogen-dependent cell growth and provide evidence in support of distinct but important roles for both p68 and p72 in regulating ERalpha activity in breast cancer.

• Authors: N C Wortham, E Ahamed, S M Nicol, R S Thomas, M Periyasamy, J Jiang, A M Ochocka, S Shousha, L Huson, S E Bray, R C Coombes, S Ali, F V Fuller-Pace
• Journal: Oncogene (Oncogene) Vol. 28 Issue 46 Pg. 4053-64 (Nov 19 2009) ISSN: 1476-5594 [Electronic] England
• PMID: 19718048 (Publication Type: Journal Article)

Chemical References

• Estrogen Receptor alpha
• Estrogens
• NCOA1 protein, human
• Nuclear Receptor Coactivator 1
• DDX17 protein, human
• DEAD-box RNA Helicases

Topics

• Animals
• Breast Neoplasms (genetics, metabolism, pathology)
• COS Cells
• Cell Proliferation (drug effects)
• Cell Survival (drug effects, genetics)
• Chlorocebus aethiops
• DEAD-box RNA Helicases (metabolism, physiology)
• Estrogen Receptor alpha (genetics, metabolism, physiology)
• Estrogens (metabolism, pharmacology)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Nuclear Receptor Coactivator 1 (metabolism, physiology)
• Protein Binding
• Transcription, Genetic (drug effects, genetics)
• Transcriptional Activation
• Tumor Cells, Cultured