Synergistic up-regulation of prostaglandin E synthase expression in breast cancer cells by 17beta-estradiol and proinflammatory cytokines.

Abstract:

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

journal_name

Endocrinology

journal_title

Endocrinology

authors

Frasor J,Weaver AE,Pradhan M,Mehta K

doi

10.1210/en.2008-0352

subject

Has Abstract

pub_date

2008-12-01 00:00:00

pages

6272-9

issue

12

eissn

0013-7227

issn

1945-7170

pii

en.2008-0352

journal_volume

149

pub_type

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