title: 15-Hydroxyprostaglandin dehydrogenase associates with poor prognosis in breast cancer, induces epithelial-mesenchymal transition, and promotes cell migration in cultured breast cancer cells.
abstract: Breast cancer is the most frequent cancer and the leading cause of cancer-related deaths in women worldwide. The prognosis of breast cancer is tightly correlated with the degree of spread beyond the primary tumour. Arachidonic acid (AA) and prostaglandin E(2) (PGE(2)) are known to regulate tumour metastasis enabling epithelial-mesenchymal transition (EMT). However, the detailed role of 15-hydroxyprostaglandin dehydrogenase (HPGD), the key enzyme degrading prostaglandin E(2) , remains unclear in breast cancer. Here, we show that HPGD mRNA is overexpressed in a subset of clinical breast cancers compared to normal breast tissue samples and that high HPGD mRNA expression associates with poor prognosis. Immunohistochemical staining of primary breast cancer and lymph node metastasis tissue samples confirmed high HPGD protein expression in 20% of the samples, as well as associated HPGD expression with aggressive characteristics, such as increased risk of disease relapse and shorter disease-free survival. Results from cultured cells indicated abundant HPGD expression in highly metastatic breast cancer cells, and impairment of HPGD expression using RNA interference led to a significant decrease in transforming growth factor-β signalling, in cellular arachidonic acid levels as well as in cell migration. Furthermore, gene expression microarray analysis followed by quantitative RT-PCR validation showed that HPGD silencing decreased aryl hydrocarbon receptor signalling and induced mesenchymal-epithelial transition. In conclusion, our results indicate that HPGD is highly expressed in metastatic and aggressive breast cancer and promotes EMT and migration in breast cancer cells.
authors.affiliation: Medical Biotechnology, VTT Technical Research Centre of Finland and Turku Centre for Biotechnology, University of Turku, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Lehtinen
authors.forename: Paula
authors.initials: P
authors.lastname: Vainio
authors.forename: Harriet
authors.initials: H
authors.lastname: Wikman
authors.forename: Johannes
authors.initials: J
authors.lastname: Reemts
authors.forename: Mika
authors.initials: M
authors.lastname: Hilvo
authors.forename: Rana
authors.initials: R
authors.lastname: Issa
authors.forename: Sirkku
authors.initials: S
authors.lastname: Pollari
authors.forename: Burkhard
authors.initials: B
authors.lastname: Brandt
authors.forename: Matej
authors.initials: M
authors.lastname: Oresic
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.forename: Kristiina
authors.initials: K
authors.lastname: Iljin
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000556:secondary*; D016718:Arachidonic Acid / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005858:Germany / Q000453:epidemiology; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D015996:Survival Rate; D046888:Tissue Array Analysis; D014945:Wound Healing
chemical_list: D016718:Arachidonic Acid; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase