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.

Lipid Metabolism Genes in Contralateral Unaffected Breast and Estrogen Receptor Status of Breast Cancer

“…Its presence at higher levels in ERÀ cases suggests other roles in normal breast tissue. The HPGD gene encoding an alcohol dehydrogenase regulated by progesterone is a poor prognostic marker in breast cancer (47), and is overexpressed in ERÀ cell lines and ERÀ tumors (48). The specific roles and interaction of these genes in the genesis of ERÀ tumors clearly needs further work, but just as clearly, point to a heretofore unsuspected role of lipid metabolism abnormalities in the genesis of ERÀ breast cancer.…”

Regulation of lipid metabolism in breast cancer provides diagnostic and therapeutic opportunities

“…Recently the authors have shown that the key enzyme degrading PGE2, 15-hydroxyprostaglandin dehydrogenase, has a dual role in breast cancer. On the one hand previous studies have indicated HPGD as a tumor-suppressor gene and downregulated in cancer as compared with normal tissues [66], but on the other hand it is highly upregulated in those breast cancer patients with poor outcome [67].…”

Disseminated Tumor Cells Persist in the Bone Marrow of Breast Cancer Patients through Sustained Activation of the Unfolded Protein Response

“…A breast cancer tissue microarray (TMA, see ref. 18) and a sector of a lung cancer TMA (19) were used for the Grp78 analysis. One-hundred and eighty-two primary breast and 36 primary lung tumors became eligible for evaluation.…”