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

TY - JOUR

T1 - The DEAD-box protein p72 regulates ER alpha-/oestrogen-dependent transcription and cell growth, and is associated with improved survival in ER alpha-positive breast cancer

AU - Wortham, N. C.

AU - Ahamed, E.

AU - Nicol, S.M.

AU - Thomas, R. S.

AU - Periyasamy, M.

AU - Jiang, J.

AU - Ochocka, A. M.

AU - Shousha, S.

AU - Huson, L.

AU - Bray, S. E.

AU - Coombes, R. C.

AU - Ali, S.

AU - Fuller-Pace, F.V.

PY - 2009/11/19

Y1 - 2009/11/19

N2 - 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 (ER alpha). Here, we show that, although both proteins interact with and co-activate ER alpha 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 ER alpha-responsive genes and oestrogen-dependent growth of MCF-7 and ZR75-1 breast cancer cells. Furthermore, immunohistochemical staining of ER alpha-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 ER alpha co-activation and oestrogen-dependent cell growth and provide evidence in support of distinct but important roles for both p68 and p72 in regulating ER alpha activity in breast cancer. Oncogene (2009) 28, 4053-4064; doi:10.1038/onc.2009.261; published online 31 August 2009

AB - 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 (ER alpha). Here, we show that, although both proteins interact with and co-activate ER alpha 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 ER alpha-responsive genes and oestrogen-dependent growth of MCF-7 and ZR75-1 breast cancer cells. Furthermore, immunohistochemical staining of ER alpha-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 ER alpha co-activation and oestrogen-dependent cell growth and provide evidence in support of distinct but important roles for both p68 and p72 in regulating ER alpha activity in breast cancer. Oncogene (2009) 28, 4053-4064; doi:10.1038/onc.2009.261; published online 31 August 2009

KW - p68 RNA helicase

KW - p72 RNA helicase

KW - oestrogen receptor-alpha

KW - gene regulation

KW - breast cancer

KW - tamoxifen

KW - ESTROGEN-RECEPTOR-ALPHA

KW - P68 RNA HELICASE

KW - PHOSPHORYLATION

KW - COACTIVATOR

KW - ACTIVATION

KW - TAMOXIFEN

KW - PROMOTER

KW - COMPLEX

KW - DIFFERENTIATION

KW - IDENTIFICATION

UR - https://www.scopus.com/pages/publications/70450199132

U2 - 10.1038/onc.2009.261

DO - 10.1038/onc.2009.261

M3 - Article

C2 - 19718048

SN - 0950-9232

VL - 28

SP - 4053

EP - 4064

JO - Oncogene

JF - Oncogene

IS - 46

ER -