Synergistic Up-Regulation of Prostaglandin E Synthase Expression in Breast Cancer Cells by 17β-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.

miR-892b Silencing Activates NF-κB and Promotes Aggressiveness in Breast Cancer

“…However, there is an increasing amount of evidence that NF-kB activation occurs in a subset of endocrineresistant ER-positive tumors, and NF-kB activation in ER-positive tumors is associated with a more aggressive phenotype, which was caused by positive cross-talk between ER and the NF-kB pathway. For example, ER and p65 can cooperate to synergistically regulate expression of specific genes, such as PTGES, BIRC3, and ABCG2, which are important in regulation of invasiveness, survival, and chemoresistance of breast cancer cells (34,35). Meanwhile, it has been also reported that IKK-a could interact and phosphorylate ER, and then both proteins form a complex with SRC-3, leading to the phosphorylation of histone H3, and additional histone modifications that favor gene expression are recruited to the promoter of cyclin D1 and E2F1 (36,37).…”

The DHEA metabolite 7β-hydroxy-epiandrosterone exerts anti-estrogenic effects on breast cancer cell lines

“…Dans des lignées cellulaires de carcinome mammaire estrogéno-sensible, l'E2 par sa liaison au REα induit la transcription de la m-PGES pro-inflammatoire et entraîne une augmentation de la prolifération cellulaire (Frasor et al, 2003(Frasor et al, et 2008. Ces résultats sont en accord avec une diminution de la prolifération de ces cellules par l'ajout de 15d-PGJ2 dans les cultures cellulaires (Diers et al, 2010).…”

“…Dans des lignées cancéreuses mammaires, il a été décrit que l'E2 régulerait la transcription de la m-PGES qui permet la formation de la PGE2 pro-inflammatoire (Frasor et al, 2003 ;Frasor et al, 2008). Cette prostaglandine favorise notamment la croissance tumorale et la survenue de métastases .…”

“…Un feedback positif entre l'action des estrogènes sur le REα et l'inflammation contribuant à la croissance des tumeurs mammaires hormono-dépendantes (Frasor et al, 2008) existerait également. En effet, la m-PGES serait surexprimée dans des lignées de carcinomes mammaires estrogéno-dépendantes en présence d'E2 (Frasor et al, 2003).…”

“…Enfin, les REs sont impliqués dans la modulation de la transcription des gènes de l'inflammation et, plus particulièrement, de la m-PGES (Frasor et al, 2008) et de la L-PGDS (Otsuki, 2003) respectivement par les REα et le REβ. Le Mée et al, 2008).…”