Prostaglandin E receptor EP4 is a therapeutic target in breast cancer cells with stem-like properties

Kundu, Namita; Ma, Xinrong; Kochel, Tyler; Goloubeva, Olga; Staats, Paul N.; Thompson, Keyata N.; Martin, Stuart S.; Reader, Jocelyn; Take, Yukinori; Collin, Peter D.; Fulton, Amy M.

doi:10.1007/s10549-013-2779-4

Cited by 54 publications

(69 citation statements)

References 32 publications

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“…However, these studies also showed that prostaglandin E receptor, which is a downstream regulator of COX-2 enzyme, plays critical role in regulation of stemness of BC cells. 60,61 We found that ASA was unable to regulate COX-2 expression at the protein levels in Aspirin prevents breast cancer cell growth G Maity et al Figure S3). Therefore, from these collective studies, we neither strongly support the involvement of COX-2 signaling nor are able to exclude that the COX-2 protein might not play any role in the growth of BC cells or breast tumor-initiating cells or both.…”

Section: Discussionmentioning

confidence: 97%

Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition

Maity

Das

et al. 2015

Laboratory Investigation

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Acetylsalicylic acid (ASA), also known as aspirin, a classic, nonsteroidal, anti-inflammatory drug (NSAID), is widely used to relieve minor aches and pains and to reduce fever. Epidemiological studies and other experimental studies suggest that ASA use reduces the risk of different cancers including breast cancer (BC) and may be used as a chemopreventive agent against BC and other cancers. These studies have raised the tempting possibility that ASA could serve as a preventive medicine for BC. However, lack of in-depth knowledge of the mechanism of action of ASA reshapes the debate of risk and benefit of using ASA in prevention of BC. Our studies, using in vitro and in vivo tumor xenograft models, show a strong beneficial effect of ASA in the prevention of breast carcinogenesis. We find that ASA not only prevents breast tumor cell growth in vitro and tumor growth in nude mice xenograft model through the induction of apoptosis, but also significantly reduces the self-renewal capacity and growth of breast tumor-initiating cells (BTICs)/breast cancer stem cells (BCSCs) and delays the formation of a palpable tumor. Moreover, ASA regulates other pathophysiological events in breast carcinogenesis, such as reprogramming the mesenchymal to epithelial transition (MET) and delaying in vitro migration in BC cells. The tumor growth-inhibitory and reprogramming roles of ASA could be mediated through inhibition of TGF-β/ SMAD4 signaling pathway that is associated with growth, motility, invasion, and metastasis in advanced BCs. Collectively, ASA has a therapeutic or preventive potential by attacking possible target such as TGF-β in breast carcinogenesis.

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Section: Discussionmentioning

confidence: 97%

Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition

Maity

Das

et al. 2015

Laboratory Investigation

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“…COX-2 is a major driver of human breast cancer progression (1)(2)(3)(4)(5), in which EP4 receptor activity plays a significant role (17,19,20). The role of COX-2 in regulating miRNAs has never been tested.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed thrombo-embolic side effects of COX-2 inhibitors (11,12), resulting from inhibition of cardioprotective prostanoids such as PGI2 (13) may possibly be avoided by targeting EP4. We and others have shown that EP4 activity contributes to multiple mechanisms in breast cancer progression, including: inactivation of host antitumor immune cells (14,15); stimulation of tumor cell migration (16); invasiveness (16); angiogenesis (16,17); and lymphangiogenesis due to EP4-mediated upregulation of lymphangiogenic factors VEGF-C (17,18) or VEGF-D (19); induction of stem-like cell (SLC) phenotype in vitro (19,20) and in vivo (19). The role of EP4 in tumor progression has also been reported in colonic tumors (21).…”

Section: Introductionmentioning

confidence: 99%

COX-2 Elevates Oncogenic miR-526b in Breast Cancer by EP4 Activation

Majumder

Landman

Liu

et al. 2015

Molecular Cancer Research

115

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MicroRNAs (miRs) are small regulatory molecules emerging as potential biomarkers in cancer. Previously, it was shown that COX-2 expression promotes breast cancer progression via multiple mechanisms, including induction of stem-like cells (SLC), owing to activation of the prostaglandin E2 receptor EP4 (PTGER4). COX-2 overexpression also upregulated microRNA526b (miR-526b), in association with aggressive phenotype. Here, the functional roles of miR-526b in breast cancer and the mechanistic role of EP4 signaling in miR-526b upregulation were examined. A positive correlation was noted between miR-526b and COX-2 mRNA expression in COX-2 disparate breast cancer cell lines. Stable overexpression of miR-526b in poorly metastatic MCF7 and SKBR3 cell lines resulted in increased cellular migration, invasion, EMT phenotype and enhanced tumorsphere formation in vitro, and lung colony formation in vivo in immunodeficient mice. Conversely, knockdown of miR-526b in aggressive MCF7-COX-2 and SKBR3-COX-2 cells reduced oncogenic functions and reversed the EMT phenotype, in vitro. Furthermore, it was determined that miR-526b expression is dependent on EP4 receptor activity and downstream PI3K-AKT and cyclic AMP (cAMP) signaling pathways. PI3K-AKT inhibitors blocked EP4 agonist-mediated miR526b upregulation and tumorsphere formation in MCF7 and SKBR3 cells. NF-kB inhibitor abrogates EP agonist-stimulated miRNA expression in MCF7 and T47D cells, indicating that the NF-kB pathway is also involved in miR-526b regulation. In addition, inhibition of COX-2, EP4, PI3K, and PKA in COX-2-overexpressing cells downregulated miR-526b and its functions in vitro. Finally, miR-526b expression was significantly higher in cancerous than in noncancerous breast tissues and associated with reduced patient survival. In conclusion, miR-526b promotes breast cancer progression, SLC-phenotype through EP4-mediated signaling, and correlates with breast cancer patient survival.Implications: This study presents novel findings that miRNA 526b is a COX-2 upregulated, oncogenic miRNA promoting SLCs, the expression of which follows EP4 receptor-mediated signaling, and is a promising biomarker for monitoring and personalizing breast cancer therapy.

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“…39 EP receptor antagonists have been tested for their ability to suppress breast cancer metastasis. 40,41 Although the targeted modulation of T-cell function by blocking specific EP receptor signaling seems to be a promising approach, there are several limitations in the usage of EP receptor antagonist for therapy. EP receptor antagonists display many compensatory and opposing roles, such as their ability to ameliorate not only Th1 responses but also Th17 responses.…”

Section: E988460-6mentioning

confidence: 99%

Resistance of cyclooxygenase-2 expressing pancreatic ductal adenocarcinoma cells against γδ T cell cytotoxicity

Gonnermann

Oberg

Kellner³

et al. 2015

OncoImmunology

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Keywords: Cox-2, cytotoxicity, gammadelta T lymphocytes, human, pancreatic ductal adenocarcinoma, PGE2Abbreviations: BrHPP, bromohydrin-pyrophosphate; Cox, cyclooxygenase; n-BP, nitrogen-containing bisphosphonates; PAg, phosphorylated antigen; PDAC, pancreatic ductal adenocarcinoma; PG, prostaglandins; RTCA, Real Time Cell Analyzer; TCR, T cell receptor.The prostaglandin (PG) synthetase cyclooxygenase 2 (Cox-2) promotes tumorigenesis, tumor progression, and metastasis in a variety of human cancer entities including pancreatic ductal adenocarcinoma (PDAC). In this study, we demonstrate that in PDAC cells such as Colo357 cells, enhanced Cox-2 expression and increased release of the Cox-2 metabolite prostaglandin E2 (PGE2) promotes resistance against gd T cell-mediated lysis. Co-culture with activated gd T cells induced an upregulation of Cox-2 expression in Colo357 cells, and thereby an enhanced PGE2 release, in response to tumor necrosis factor a .TNFa/ secretion from gd T cells. The PGE2-mediated inhibition of gd T cell cytotoxicity against Cox-2-expressing PDAC cells can be partially overcome by Cox-2 inhibitors. Our results show that differences between PDAC cells in regards to sensitivity to gd T-cell cytotoxicity can be due to distinct levels of Cox-2 expression associated with varying amounts of PGE2 release. While gd T cell cytotoxicity against PDAC cells expressing low levels of Cox-2 can be effectively enhanced by tribody [(Her2) 2 £Vg9] with specificity for Vg9 T cell receptor and HER-2/neu on PDAC cells, a combination of tribody [(Her2) 2 £Vg9] and Cox-2 inhibitor is necessary to induce complete lysis of Cox-2 high expressing Colo357. In conclusion, our results suggest that the application of tribody [(Her2) 2 £Vg9] that enhances gd T-cell cytotoxicity and Cox-2 inhibitors that overcome PGE2-mediated resistance of PDAC cells to the cytotoxic activity of gd T cells might offer a promising combined immunotherapy for pancreatic cancer.

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Prostaglandin E receptor EP4 is a therapeutic target in breast cancer cells with stem-like properties

Cited by 54 publications

References 32 publications

Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition

Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition

COX-2 Elevates Oncogenic miR-526b in Breast Cancer by EP4 Activation

Resistance of cyclooxygenase-2 expressing pancreatic ductal adenocarcinoma cells against γδ T cell cytotoxicity

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