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[Cancer Research 63, 3546-3555, July 1, 2003]
© 2003 American Association for Cancer Research

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 development by converting androgen to estrogen. In this report, results are presented to demonstrate that estrogen, the product of aromatase, can up-regulate its expression. Estrogen receptor (ER) transient transfection experiments were performed using the SK-BR-3 breast cancer cell line, which is ER negative and expresses aromatase. When SK-BR-3 cells were transfected with the expression plasmid pCI-ER{alpha}, but not pCI-ERß, aromatase activity was elevated by 17ß-estradiol (E2) in a dose-dependent manner. The E2 induction could be enhanced by cotransfection with the coactivator GRIP1 and suppressed by antiestrogens such as tamoxifen and ICI 182,780. The aromatase activity in the ER{alpha}-transfected SK-BR-3 cells could also be induced by environmental chemicals that were known to have an estrogen-like activity. Using aromatase gene exon Is-specific reverse transcription-PCR, the level of promoter I.1-driven transcripts was found to be elevated in E2-treated ER{alpha}-transfected cells. This suggested that E2 induced aromatase expression through the up-regulation of promoter I.1. Using DNA deletion analysis of the 5'-flanking region of promoter I.1, the section between -300 and -280 bp upstream from exon I.1 was identified to be important for mediating E2 induction. However, a direct binding of ER{alpha} to this 20-bp region could not be demonstrated. It was found that E2 induction could be suppressed by the mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor, PD98059, and the epidermal growth factor receptor tyrosine kinase inhibitor, PD153035 hydrochloride. A significant induction of aromatase expression was also detected in ER-positive MCF-7 breast cancer cells after transfection with pCI-ER{alpha} and E2 treatment. Furthermore, after ER{alpha} transfection and E2 treatment, the aromatase activity in Her-2-overexpressing MCF-7 cells was drastically higher than that of the wild-type MCF-7 cells. In addition, aromatase induction in MCF-7 cells could also be suppressed by PD153035 hydrochloride. These results suggest that E2 up-regulates aromatase expression by a nongenomic action of ER{alpha} via cross-talk with growth factor-mediated pathways.




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