Prostanoid receptor EP1 expression in breast cancer

Abstract

Cyclooxygenase enzymes play an important role in carcinogenesis, and increased expression of cyclooxygenase enzymes has been reported in cancers arising at a number of different sites. Most, if not all of these actions are thought to be mediated by prostaglandin E2 (PGE2). The actions of PGE2 are mediated via four main prostanoid receptors, designated EP1, EP2, EP3 and EP4, based on their different pharmacological properties and secondary messenger pathways. Recently, expression of EP1 has been reported in rat mammary gland and the inhibition of this receptor has been documented to have chemopreventive effect in this animal model. EP1 has also been shown to decrease the incidence of colon cancer in mouse models. In this study, we analysed the expression of EP1 in normal and malignant breast tissues. Expression of EP1 was analysed in breast (benign and cancer) cell lines by reverse-transcriptase polymerase chain reaction and by western blot analyses. Expression was also analysed by immunohistochemistry in normal breast tissues and in 89 cases of breast cancer. Semiquantitative analysis of the staining was performed. The data were compared with and correlated with other prognostic factors like tumour size, tumour grade, lymph node status, oestrogen receptor, progesterone receptor (PR), HER2/neu and cyclooxygenase-2. EP1 expression was demonstrated in human breast cancer by immunohistochemistry. Expression of EP1 was seen both in the cytoplasm and/or in the nuclear membrane in majority of cases. Nuclear EP1 expression correlated with PR (P ¼ 0.032) and inversely with node positivity (P ¼ 0.025). However, EP1 expression did not correlate with expression of cyclooxygenase-2 (P ¼ 0.059). Expression of EP1 is frequently seen in human breast cancers. Nuclear expression of EP1 correlates with good prognosis markers like node negative status and PR expression. Keywords: breast cancer; EP1 receptor; cyclooxygenase; PGE2; prostanoid receptor; immunohistochemistry Breast cancer is one of the most common malignancies in developed countries including USA, and the second leading cause of cancer-related deaths in women. 1 As the incidence of breast cancer is increasing, several attempts at testing various preventive agents have been made (reviewed by Arun and Hortobagyi 2 ). Nonsteroidal anti-inflammatory drugs (NSAIDs), which act through inhibition of cyclooxygenase enzyme (COX), are one such class of drugs that have been studied for their possible role in breast cancer prevention. Epidemiological studies investigating the relationship between NSAID use and breast cancer have reported conflicting results; some studies 3-5 show 30-40% reduction in breast cancer incidence with NSAID use, whereas others failed to confirm this relationship. 6,7 NSAIDs work by inhibiting both constitutive and inducible cyclooxygenase enzymes (COX-1 and COX-2, respectively), both of which have been postulated to play a role in carcinogenesis. Elevated cyclooxygenase-2 (COX-2) expression is a marker of poor prognosis in human breast cancer and correla...

Prostaglandin E Receptor EP1 Suppresses Breast Cancer Metastasis and Is Linked to Survival Differences and Cancer Disparities

“…By RT-PCR and western blotting we first showed that all three cell lines express EP1 as well as EP2-EP4 (Figure 1a, b). Others have reported that EP1 is expressed in the nucleus of malignant cells (13,19). By confocal microscopy, EP1 protein was detected in both the cytoplasm and nucleus of murine mammary tumor cells (Figure 1c).…”

“…The only reported finding is that EP1 is detected in both the cytoplasm and nucleus of primary human breast tumors by immunohistochemistry and that EP1 expression in the nucleus of malignant cells correlates with good prognostic markers of progesterone expression and lymph node negative status (13). We investigated the relationship between EP1 expression levels and survival in 55 invasive ductal carcinomas from women who had participated in the Breast Cancer Prognostic Study, a prospective study of 1,306 women newly diagnosed with breast cancer from 1975 to 1983 carried out at the Karmanos Cancer Institute, Detroit, MI.…”

“…We and others have shown that EP4 functions to promote metastasis in breast, lung and colon cancer (9–12), but other EPs, including EP1, had not been investigated. A study by Thorat et al (13) reported that nuclear expression of EP1 was associated with lymph-node negative breast cancer and we had reported some years ago that EP antagonists, then of unknown specificity, promoted metastasis (14), however, no study had directly examined the role of EP1 in metastasis. We now report that pharmacologic antagonism or gene silencing of EP1 promotes metastasis leading us to propose that EP1 is a novel metastasis suppressor.…”

Antagonism of the prostaglandin E receptor EP4 inhibits metastasis and enhances NK function

“…Murine mammary tumors arising in COX-2 transgenic mice have increased expression of EP1, EP2 and EP4, but decreased expression of EP3 in comparison to normal mammary gland [37]. EP1 antagonism prevents chemically-induced breast carcinogenesis in a mouse model [38], however, in advanced human breast cancer, EP1 is associated with lack of lymph node involvement indicating a better prognosis [39]. Several groups have shown that EP receptors mediate migration of tumor cells in vitro [15, 40, 41].…”

Cyclooxygenase-2 Expression in Animal Cancers

“…10,116,125 The presence of EP1 has also been demonstrated in human breast cancer cells, and EP4 antagonists have been shown to inhibit breast cancer metastasis. 68,119 Moreover, PGE 2 stimulates through the EP4 receptor the transcription of Id-1, a gene involved in breast cancer metastasis. 114 Via these receptors, PGE 2 is able to promote cell proliferation and survival (through different mechanisms, including suppression of apoptosis), promote tumor angiogenesis (through the production of proangiogenic growth factors such as vascular endothelial growth factor [VEGF] and basic fibroblast growth factor [bFGF]), increase cell invasion and metastasis, and suppress the immune response in order for the tumor cells to escape immunosurveillance (Fig.…”