The DEAD-box protein p72 regulates ERα-/oestrogen-dependent transcription and cell growth, and is associated with improved survival in ERα-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 estrogen receptor α (ERα). Here, we show that, although both proteins interact with and co-activate ERα in reporter gene assays, siRNA-mediated knockdown of p72, but not p68, results in a significant inhibition of estrogen-dependent transcription of endogenous ERα-responsive genes and estrogen-dependent growth of MCF-7 and ZR75-1 breast cancer cells. Furthermore, immunohistochemical staining of ERα-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 p=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 ERα co-activation and estrogen-dependent cell growth and provide evidence in support of distinct but important roles for both p68 and p72 in regulating ERα activity in breast cancer.

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…The DEAD-box RNA helicases p68 (DDX5) and p72 (DDX17), which are primarily involved in RNA splicing, also act as ERα coactivators in breast cancer cells. Although helicase activity is not required for their coactivator function, they act in synergy with SRC-1, another ERα coactivator [184]. p72 interacts with ERα in a ligand-dependent manner in the nucleus.…”

“…Therefore, p72 is important for ligand-dependent transcriptional activity of ERα and E2-dependent cell growth in breast cancer cells. Furthermore, p72 expression, but not p68 expression, is associated with an increased relapse-free and overall survival in ERα-positive primary breast cancers [184]. MUC1, a transmembrane glycoprotein normally expressed on the apical borders of secretory mammary epithelia, is also a potent coactivator of ERα.…”

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

“…There are now many reports indicating that these multifunctional proteins have important implications for cancer development, as recently reviewed (Janknecht, 2010;FullerPace and Moore, 2011). For example, on one hand, as transcriptional coactivators of estrogen receptor alpha, they may contribute to the proliferative effect of estradiol on breast cancer cells (Wortham et al, 2009;Dutertre et al, 2010a) and, as coregulators of betacatenin, they may contribute to the epithelial to mesenchymal transition, which has been associated with breast cancer progression (Yang et al, 2006). On the other hand, as coactivators of p53 and Smad, ddx5/ ddx17 may exert tumor suppressor functions (Warner et al, 2004;Bates et al, 2005).…”

Cancer/Testis Antigen CAGE Exerts Negative Regulation on p53 Expression through HDAC2 and Confers Resistance to Anti-cancer Drugs

“…Cell Lines and Cell Culture-Cancer cell lines used in this study were cultured in Dulbecco's modified minimal essential medium (Invitrogen) supplemented with heat-inactivated 10% fetal bovine serum (Invitrogen) and antibiotics at 37°C in a humidified incubator with a mixture of 95% air and 5% CO 2 .…”

“…CAGE contains helicase and DEAD box domain (1). DEAD box family proteins are known to play important roles in RNA metabolism, cellular growth, and spermatogenesis (2,3).…”