This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Frasor, J. Articles by Mehta, K. Search for Related Content PubMed PubMed Citation Articles by Frasor, J. Articles by Mehta, K.

Synergistic Up-Regulation of Prostaglandin E Synthase Expression in Breast Cancer Cells by 17β-Estradiol and Proinflammatory Cytokines

Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois 60612

Address all correspondence and requests for reprints to: Jonna Frasor, Ph.D., University of Illinois at Chicago, Department of Physiology and Biophysics, 835 South Wolcott Avenue, MC 901, Chicago, Illinois 60612. E-mail: jfrasor{at}uic.edu.

Inflammatory mediators, such as cytokines and prostaglandins, play a fundamental role in estrogen-dependent breast cancer through their ability to up-regulate aromatase expression and subsequent local production of estrogens in the breast. To study the link between estrogens and inflammation further, we examined the regulation of prostaglandin E synthase (PTGES), a key enzyme in the production of prostaglandin E2. We found that 17β-estradiol (E2) rapidly and robustly up-regulates PTGES mRNA and protein levels in estrogen receptor (ER)-positive breast cancer cells through ER recruitment to an essential estrogen response element located in the 5' flanking region of the PTGES gene. PTGES is also up-regulated by the proinflammatory cytokines TNF or IL-1β. Surprisingly, the combination of E2 and cytokines leads to a synergistic up-regulation of PTGES in an ER and nuclear factor-B (NFB)-dependent manner. This is in contrast to the mutual transrepression between ER and NFB that has been well characterized in other cell types. Furthermore, we found enhanced recruitment of ER as well as the NFB family member, p65, to the PTGES estrogen response element by the combination of E2 and TNF compared with either E2 or TNF alone. The synergistic up-regulation of PTGES may result in enhanced prostaglandin E2 production, which in turn may further enhance aromatase expression and production of local estrogens. Our findings suggest that a finely tuned positive feedback mechanism between estrogens and inflammatory factors may exist in the breast and contribute to hormone-dependent breast cancer growth and progression.