p38 regulates cyclooxygenase-2 in human mammary epithelial cells and is activated in premalignant tissue

Autor: Hal K. Berman, Caroline J. Miller, Thea D. Tlsty, Curtis R. Pickering, Colleen A. Fordyce, Mona L. Gauthier, Karen L. Chew
Rok vydání: 2005
Předmět:
Enzymologic
Cancer Research
Pathology
Cytoplasm
Transcription
Genetic
Apoptosis
medicine.disease_cause
p38 Mitogen-Activated Protein Kinases
Noninfiltrating
2.1 Biological and endogenous factors
Breast
Aetiology
Enzyme Inhibitors
Phosphorylation
Cancer
Kinase
Middle Aged
Phenotype
medicine.anatomical_structure
Oncology
Female
Transcription
Biotechnology
medicine.medical_specialty
1.1 Normal biological development and functioning
Intraductal
Oncology and Carcinogenesis
Breast Neoplasms
Biology
Gene Expression Regulation
Enzymologic
Genetic
Underpinning research
Breast Cancer
medicine
Genetics
Humans
Oncology & Carcinogenesis
Cell Proliferation
Cell Nucleus
Cell growth
Prevention
Carcinoma
Membrane Proteins
Epithelial Cells
Epithelium
In vitro
Enzyme Activation
Cell nucleus
Carcinoma
Intraductal
Noninfiltrating
Gene Expression Regulation
Cyclooxygenase 2
Prostaglandin-Endoperoxide Synthases
Cancer research
Prostaglandins
Carcinogenesis
Precancerous Conditions
Zdroj: Cancer research, vol 65, iss 5
ISSN: 0008-5472
Popis: 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.
Databáze: OpenAIRE
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