p38 regulates cyclooxygenase-2 in human mammary epithelial cells and is activated in premalignant tissue.
The immediate-early gene, cyclooxygenase-2 (COX-2), is induced in a variety of inflammatory and neoplastic processes and is believed to play an important role in tumorigenesis. In this study, we identify an important upstream regulatory pathway of COX-2 expression in variant human mammary epithelial cells (vHMEC), which has been shown to exhibit phenotypes important for malignancy. We find that the stress-activated kinase, p38, is phosphorylated and activated in vHMEC compared with HMEC and is responsible for the expression of COX-2 in vHMEC as cells grow in culture. Furthermore in this capacity, p38 acts to stabilize the COX-2 transcript rather than activate COX-2 transcription. Inhibition of p38 kinase, using a chemical inhibitor, down-regulates COX-2 and decreases cell survival. Examination of archived tissue from women with ductal carcinoma in situ reveals epithelial cells that not only overexpress COX-2 but also have an abundance of activated phospho-p38 in the nucleus and cytoplasm, mirroring the expression observed in vitro. These epithelial cells are found within premalignant lesions as well as in fields of morphologically normal tissue that surround the lesions. In contrast, low phospho-p38 staining was observed in the majority of normal tissue obtained from reduction mammoplasty. These data help define the regulation of COX-2 expression in early carcinogenesis and provide alternative candidates for targeted prevention of COX-2-induced phenotypes and breast cancer.
Gauthier
Mona L
ML
Department of Pathology, University of California San Francisco Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94143-0511, USA.
Pickering
Curtis R
CR
Miller
Caroline J
CJ
Fordyce
Colleen A
CA
Chew
Karen L
KL
Berman
Hal K
HK
Tlsty
Thea D
TD
D017209:Apoptosis / Q000187:drug effects; D001940:Breast / Q000201:enzymology / Q000473:pathology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000201:enzymology* / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000201:enzymology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008565:Membrane Proteins; D008875:Middle Aged; D010766:Phosphorylation; D011230:Precancerous Conditions / Q000201:enzymology / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D011453:Prostaglandins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D048051:p38 Mitogen-Activated Protein Kinases