title: 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.
abstract: 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 (E2)-induced growth of breast cancer cells. We demonstrated that E2-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 E2-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 E2-induced PDZK1 expression. This effect was accompanied by a similar decrease in the cell cycle protein cyclin D1. PARP appeared to regulate E2-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 E2-induced expression of the receptor at the protein and mRNA levels.
  
  
  CONCLUSIONS
  Overall, our results show for the first time that PARP regulates E2-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.
authors.affiliation: The Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, 1700 Tulane Ave, New Orleans, LA, 70112, USA. hkim8@tulane.edu.
authors.forename: Hogyoung
authors.initials: H
authors.lastname: Kim
authors.affiliation: The Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, 1700 Tulane Ave, New Orleans, LA, 70112, USA. atarhu@lsuhsc.edu.
authors.forename: Abdelmetalab
authors.initials: A
authors.lastname: Tarhuni
authors.affiliation: Tulane University Cancer Center, New Orleans, LA, 70112, USA. zabdelma@tulane.edu.
authors.forename: Zakaria Y
authors.initials: ZY
authors.lastname: Abd Elmageed
authors.affiliation: The Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, 1700 Tulane Ave, New Orleans, LA, 70112, USA. hboulr@lsuhsc.edu.
authors.forename: A Hamid
authors.initials: AH
authors.lastname: Boulares
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D008565:Membrane Proteins; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C530104:CCND1 protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; C484659:PDZK1 protein, human; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D019938:Cyclin D1; D004958:Estradiol; D011065:Poly(ADP-ribose) Polymerases; D017526:Receptor, IGF Type 1; C531550:olaparib