Poly(ADP-ribose) polymerase as a novel regulator of 17β-estradiol-induced cell growth through a control of the estrogen receptor/IGF-1 receptor/PDZK1 axis

Journal of Translational Medicine

A Hamid Boulares²  Zakaria Y Abd Elmageed¹  Abdelmetalab Tarhuni²  Hogyoung Kim² 

[1] Tulane University Cancer Center, New Orleans 70112, LA, USA;The Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, 1700 Tulane Ave, New Orleans 70112, LA, USA

关键词: MCF-7 cells;    IGF-1R;    PDZK1;    Breast cancer;    Cell growth;    Gene regulation;    PARP, 17β-estradiol;   

Others  :  1221449
DOI  :  10.1186/s12967-015-0589-7

 received in 2015-01-10, accepted in 2015-06-29,  发布年份 2015

【 摘 要 】

Background

We and others have extensively investigated the role of PARP-1 in cell growth and demise in response to pathophysiological cues. Most of the clinical trials on PARP inhibitors are targeting primarily estrogen receptor (ER) negative cancers with BRCA-deficiency. It is surprising that the role of the enzyme has yet to be investigated in ER-mediated cell growth. It is noteworthy that ER is expressed in the majority of breast cancers. We recently showed that the scaffolding protein PDZK1 is critical for 17β-estradiol (E ₂ )-induced growth of breast cancer cells. We demonstrated that E ₂ -induced PDZK1 expression is indirectly regulated by ER and requires IGF-1 receptor (IGF-1R).

Methods

The breast cancer cell lines MCF-7 and BT474 were used as ER(+) cell culture models. Thieno[2,3-c]isoquinolin-5-one (TIQ-A) and olaparib (AZD2281) were used as potent inhibitors of PARP. PARP-1 knockdown by shRNA was used to show specificity of the effects to PARP-1.

Results

In this study, we aimed to determine the effect of PARP inhibition on estrogen-induced growth of breast cancer cells and examine whether the potential effect is linked to PDZK1 and IGF-1R expression. Our results show that PARP inhibition pharmacologically by TIQ-A or olaparib or by PARP-1 knockdown blocked E ₂ -dependent growth of MCF-7 cells. Such inhibitory effect was also observed in olaparib-treated BT474 cells. The effect of PARP inhibition on cell growth coincided with an efficient reduction in E ₂ -induced PDZK1 expression. This effect was accompanied by a similar decrease in the cell cycle protein cyclin D1. PARP appeared to regulate E ₂ -induced PDZK1 at the mRNA level. Such regulation may be linked to a modulation of IGF-1R as PARP inhibition pharmacologically or by PARP-1 knockdown efficiently reduced E ₂ -induced expression of the receptor at the protein and mRNA levels.

Conclusions

Overall, our results show for the first time that PARP regulates E ₂ -mediated cell growth by controlling the ER/IGF-1R/PDZK1 axis. These findings suggest that the relationship between ER, PDZK1, and IGF-1R may be perturbed by blocking PARP function and that PARP inhibitors may be considered in clinical trials on ER(+) cancers.

【 授权许可】

   
2015 Kim et al.

【 图 表 】

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