15-hydroxyprostaglandin dehydrogenase associates with poor prognosis in breast cancer, induces epithelial-mesenchymal transition and promotes cell migration in cultured breast cancer cells

Laura Lehtinen, Paula Vainio, H. Wikman, J. Reemts, Mika Hilvo, R. Issa, Sirkku Pollari, B. Brandt, Matej Oresic, K. Pantel, Olli Kallioniemi, Kristiina Iljin (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

18 Citations (Scopus)

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 E2 (PGE2) 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 E2, 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.
Original languageEnglish
Pages (from-to)674-686
Number of pages13
JournalJournal of Pathology
Volume226
Issue number4
DOIs
Publication statusPublished - 2012
MoE publication typeA1 Journal article-refereed

Fingerprint

15-hydroxyprostaglandin dehydrogenase
Epithelial-Mesenchymal Transition
Cell Movement
Breast Neoplasms
Dinoprostone
Arachidonic Acid
Neoplasm Metastasis
Aryl Hydrocarbon Receptors
Neoplasms
Messenger RNA
Transforming Growth Factors
Microarray Analysis
RNA Interference

Keywords

  • breast cancer
  • metastasis
  • HPGD
  • arachidonic acid
  • mesenchymal-epithelial transition

Cite this

Lehtinen, Laura ; Vainio, Paula ; Wikman, H. ; Reemts, J. ; Hilvo, Mika ; Issa, R. ; Pollari, Sirkku ; Brandt, B. ; Oresic, Matej ; Pantel, K. ; Kallioniemi, Olli ; Iljin, Kristiina. / 15-hydroxyprostaglandin dehydrogenase associates with poor prognosis in breast cancer, induces epithelial-mesenchymal transition and promotes cell migration in cultured breast cancer cells. In: Journal of Pathology. 2012 ; Vol. 226, No. 4. pp. 674-686.
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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 E2 (PGE2) 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 E2, 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.",
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15-hydroxyprostaglandin dehydrogenase associates with poor prognosis in breast cancer, induces epithelial-mesenchymal transition and promotes cell migration in cultured breast cancer cells. / Lehtinen, Laura; Vainio, Paula; Wikman, H.; Reemts, J.; Hilvo, Mika; Issa, R.; Pollari, Sirkku; Brandt, B.; Oresic, Matej; Pantel, K.; Kallioniemi, Olli; Iljin, Kristiina (Corresponding Author).

In: Journal of Pathology, Vol. 226, No. 4, 2012, p. 674-686.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - 15-hydroxyprostaglandin dehydrogenase associates with poor prognosis in breast cancer, induces epithelial-mesenchymal transition and promotes cell migration in cultured breast cancer cells

AU - Lehtinen, Laura

AU - Vainio, Paula

AU - Wikman, H.

AU - Reemts, J.

AU - Hilvo, Mika

AU - Issa, R.

AU - Pollari, Sirkku

AU - Brandt, B.

AU - Oresic, Matej

AU - Pantel, K.

AU - Kallioniemi, Olli

AU - Iljin, Kristiina

PY - 2012

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N2 - 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 E2 (PGE2) 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 E2, 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.

AB - 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 E2 (PGE2) 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 E2, 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.

KW - breast cancer

KW - metastasis

KW - HPGD

KW - arachidonic acid

KW - mesenchymal-epithelial transition

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DO - 10.1002/path.3956

M3 - Article

VL - 226

SP - 674

EP - 686

JO - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

IS - 4

ER -