Journal of Pharmacology and Experimental Therapeutics 2014-10-01

Resolvin D2 supports MCF-7 cell proliferation via activation of estrogen receptor.

Nuha Al-Zaubai, Cameron N Johnstone, May May Leong, John Li, Mark Rizzacasa, Alastair G Stewart

Index: J. Pharmacol. Exp. Ther. 351(1) , 172-80, (2014)

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Abstract

Inflammation has been implicated in tumor initiation, angiogenesis, and metastasis, and linked to the development of more aggressive, therapy-resistant estrogen receptor (ER)-positive breast cancer. Resolvin D2 (RvD2) is a potent anti-inflammatory lipid mediator. As RvD2 may be synthesized within breast tumors by both tumor cells and the surrounding stroma cells and is present in plasma at bioactive concentrations, we sought to characterize the impact of RvD2 on cell processes underlying breast tumor growth and spread. Trypan-blue exclusion, transfection with estrogen response element (ERE) reporter, real-time quantitative polymerase chain reaction, competitive radioligand binding assays, Western blotting, and immunofluorescence were the techniques used. Unexpectedly, whereas RvD2 (10-1000 nM) supported the proliferation of the ER-positive breast tumor (MCF-7) cells, it did not affect the ER-negative MDA-MB-231 cell number. The proliferative effect of RvD2 in MCF-7 cells was attenuated by the ER antagonist ICI 182,780 (7α-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17β-diol). Furthermore, RvD2 increased ERE transcriptional activity in a number of ER-positive breast and ovarian tumor cell lines. This activation was also inhibited by ICI 182,780. RvD2 altered the expression of a subset of estrogen-responsive genes. Although binding experiments showed that RvD2 did not directly compete with [(3)H]17β-estradiol for ER binding, prior exposure of MCF-7 cells to RvD2 resulted in a significant reduction in the apparent cytosolic ER density. Confocal immunocytochemistry and Western blotting studies showed that RvD2 promoted nuclear localization of ERα. These observations indicate that RvD2 displays significant but indirect estrogenic properties and has the potential to play a role in estrogen-dependent breast cancer progression. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.