Induction of Aromatase (CYP19) Expression in Breast Cancer Cells through a Nongenomic Action of Estrogen Receptor {alpha}

Endocrinology

Induction of Aromatase (CYP19) Expression in Breast Cancer Cells through a Nongenomic Action of Estrogen Receptor ${alpha}$ ¹

Yoshiyuki Kinoshita and Shiuan Chen²

Department of Surgical Research, Beckman Research Institute of the City of Hope, Duarte, California 91010

Aromatase plays a critical role in breast cancer developmentby converting androgen to estrogen. In this report, resultsare presented to demonstrate that estrogen, the product of aromatase,can up-regulate its expression. Estrogen receptor (ER) transienttransfection experiments were performed using the SK-BR-3 breastcancer cell line, which is ER negative and expresses aromatase.When SK-BR-3 cells were transfected with the expression plasmidpCI-ER ${alpha}$ , but not pCI-ERß, aromatase activity was elevatedby 17ß-estradiol (E₂) in a dose-dependent manner.The E₂ induction could be enhanced by cotransfection with thecoactivator GRIP1 and suppressed by antiestrogens such as tamoxifenand ICI 182,780. The aromatase activity in the ER ${alpha}$ -transfectedSK-BR-3 cells could also be induced by environmental chemicalsthat were known to have an estrogen-like activity. Using aromatasegene exon Is-specific reverse transcription-PCR, the level ofpromoter I.1-driven transcripts was found to be elevated inE₂-treated ER ${alpha}$ -transfected cells. This suggested that E₂ inducedaromatase expression through the up-regulation of promoter I.1.Using DNA deletion analysis of the 5'-flanking region of promoterI.1, the section between -300 and -280 bp upstream from exonI.1 was identified to be important for mediating E₂ induction.However, a direct binding of ER ${alpha}$ to this 20-bp region could notbe demonstrated. It was found that E₂ induction could be suppressedby the mitogen-activated protein/extracellular signal-regulatedkinase kinase inhibitor, PD98059, and the epidermal growth factorreceptor tyrosine kinase inhibitor, PD153035 hydrochloride.A significant induction of aromatase expression was also detectedin ER-positive MCF-7 breast cancer cells after transfectionwith pCI-ER ${alpha}$ and E₂ treatment. Furthermore, after ER ${alpha}$ transfectionand E₂ treatment, the aromatase activity in Her-2-overexpressingMCF-7 cells was drastically higher than that of the wild-typeMCF-7 cells. In addition, aromatase induction in MCF-7 cellscould also be suppressed by PD153035 hydrochloride. These resultssuggest that E₂ up-regulates aromatase expression by a nongenomicaction of ER ${alpha}$ via cross-talk with growth factor-mediated pathways.

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