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

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 17 beta-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 alpha or IL-1 beta. Surprisingly, the combination of E2 and cytokines leads to a synergistic up-regulation of PTGES in an ER and nuclear factor-kappa B (NF kappa B)-dependent manner. This is in contrast to the mutual transrepression between ER and NF kappa B that has been well characterized in other cell types. Furthermore, we found enhanced recruitment of ER alpha as well as the NF kappa B family member, p65, to the PTGES estrogen response element by the combination of E2 and TNF alpha compared with either E2 or TNF alpha 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. (Endocrinology 149: 6272-6279, 2008)