The role of cyclooxygenase-2-dependent signaling via cyclic AMP response element activation on aromatase up-regulation by o,p'-DDT in human breast cancer cells.

Eun Hee Han, Hyung Gyun Kim, Yong Pil Hwang, Jae Ho Choi, Ji Hye Im, Bonghwan Park, Ji Hye Yang, Tae Cheon Jeong, Hye Gwang Jeong

Index: Toxicol. Lett. 198 , 331-41, (2010)

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Abstract

o,p'-Dichlorodiphenyltrichloroethane (o,p'-DDT) is a DDT isomer and xenoestrogen that can induce inflammation and cancer. However, the effect of o,p'-DDT on aromatase is unclear. Thus, we investigated the effects of o,p'-DDT on aromatase expression in human breast cancer cells. We also examined whether cyclooxygenase-2 (COX-2) is involved in o,p'-DDT-mediated aromatase expression. Treatment with o,p'-DDT-induced aromatase protein expression in MCF-7 and MDA-MB-231 human breast cancer cells; enhancing aromatase gene expression, and enzyme and promoter activity. Treatment with ICI 182.780, a estrogen receptor antagonist, did not affect the inductive effects of o,p'-DDT on aromatase expression. In addition, o,p'-DDT increased COX-2 protein levels markedly, increased COX-2 mRNA expression and promoter activity, enhanced the production of prostaglandin E(2) (PGE(2)), induced cyclic AMP response element (CRE) activation, and cAMP levels and binding of CREB. o,p'-DDT also increased the phosphorylation of PKA, Akt, ERK, and JNK in their signaling pathways in MCF-7 and MDA-MB-231 cells. Finally, o,p'-DDT induction of aromatase was inhibited by various inhibitors [COX-2 (by NS-398), PKA (H-89), PI3-K/Akt (LY 294002), EP2 (AH6809), and EP4 receptor (AH23848)]. Together, these results suggest that o,p'-DDT increases aromatase, and that o,p'-DDT-induced aromatase is correlated with COX-2 up-regulation, mediated via the CRE activation and PKA and PI3-kinase/Akt signaling pathways in breast cancer cells.Copyright 2010 Elsevier Ireland Ltd. All rights reserved.