Abstract
BackgroundWe 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).MethodsThe 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.ResultsIn 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.ConclusionsOverall, 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.
Highlights
We and others have extensively investigated the role of Poly (ADP-ribose) polymerase (PARP)-1 in cell growth and demise in response to pathophysiological cues
PARP inhibition blocks E2‐dependent growth of MCF‐7 cells Figure 1a shows that PARP inhibition with the specific inhibitor TIQ-A exerted no effect on the growth of the breast cancer cell line MCF-7 except at a very high concentration of 50 μM. This result is consistent with our previous report which concluded that the growth inhibition caused by the high concentrations of PARP inhibitors is most likely associated with toxicity of the drugs rather than an effect related to PARP inhibition [16, 17]
PARP inhibition by TIQ-A blocked E2-induced growth of MCF-7 cells even at a concentration as low as 0.5 μM. The specificity of this effect was confirmed using a PARP-1 shRNA-mediated knockdown approach (Figure 1c, d). These results clearly show that PARP plays a role in E2-mediated cell growth and that its inhibition can be regarded as a means to block abnormal proliferation of estrogen receptor (ER) positive breast cancer cells
Summary
We and others have extensively investigated the role of PARP-1 in cell growth and demise in response to pathophysiological cues. We demonstrated that E2-induced PDZK1 expression is indirectly regulated by ER and requires IGF-1 receptor (IGF-1R). It is well established that estrogen receptor (ER) is expressed in the majority of breast cancers and are responsive to standard therapy with tamoxifen as the leading drug [1]. PDZK1 plays this important role through stabilization of the integrity of Akt, Her2/Neu, and EGFR [4]. The co-chaperone Cdc appears to play an important role in PDZK1mediated stability of Akt [4]. These aforementioned findings demonstrated a novel relationship between PDZK1, Akt, Her2/Neu, EGFR and Cdc in breast cancer unraveling a new axis that can be targeted therapeutically to reduce the burden of human breast cancer
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