Nuclear Factor-κB Is Central to the Expression of Truncated Neurokinin-1 Receptor in Breast Cancer: Implication for Breast Cancer Cell Quiescence within Bone Marrow Stroma

Ramkissoon, Shakti; Patel, Prem; Taborga, Marcelo; Rameshwar, Pranela

doi:10.1158/0008-5472.can-06-3813

Cited by 33 publications

(35 citation statements)

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“…A study by Ramkissoon et al (24) showed that the expression of tr-NK-1R is dependent upon the activation of the proinflammatory transcription factor NF-κB in breast cancer cell lines in vitro. NF-κB is activated by a number of inflammatory signals present in UC.…”

Section: Discussionmentioning

confidence: 99%

“…In response to the hypoxia, inflamed mucosa have increased vascularity compared with normal tissue, potentially due to increased vascular endothelial growth factor, an HIF-1α downstream target (40). The mucosal hypoxia characteristic of UC is interesting in light of research showing hypoxia can activate NF-κB (42,43), which is capable of specifically increasing expression of tr-NK-1R (24). In addition, hypoxia has been shown to induce alternative splicing events in other genes in vitro, and these splice variants are also associated with mutations to the tumor suppressor p53, a common finding in CAC (44).…”

Section: Discussionmentioning

confidence: 99%

“…The truncated isoform of NK-1R has received little attention in the study of cancer; however, recent evidence does suggest that it may play a role in breast cancer. tr-NK-1R is present in breast cancer tissue (24), and transfection of truncated but not full-length NK-1R into nontumorigenic breast epithelial cell lines creates a transformed phenotype with greatly increased growth capability (25). Signaling studies have shown that unlike fl-NK-1R, tr-NK-1R can neither initiate calcium influx via G q , nor activate PKC or NF-κB; however, ERK activation still occurs but at a slower rate (26).…”

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confidence: 99%

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Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer

Gillespie¹,

Leeman²,

Watts³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Patients with chronic ulcerative colitis (UC) are at high risk for developing colorectal cancer. In this study, archival formalin-fixed paraffin-embedded colonic tissue from patients with UC who developed carcinoma (CA) or high-grade dysplasia (HGD) was examined for changes in expression of the proinflammatory and mitogenic neurokinin-1 receptor (NK-1R). Laser capture microscopy was used to microdissect epithelia from areas of colons that showed histologic evidence of CA, HGD, and epithelia that were not dysplastic or cancerous but did contain evidence of prior inflammation (quiescent colitis). mRNA was extracted from the dissected tissue, and PCR array analysis was performed on extracted mRNA. Two antibodies were necessary to separately estimate the protein levels of the truncated (tr-NK-1R) and full-length (fl-NK-1R) receptors by immunohistochemistry. mRNA expression of tr-NK-1R increased 14-fold (P = 0.02) when comparing the HGD and CA groups. In contrast, the fl-NK-1R transcript showed no significant differences among groups. The protein levels of the total NK-1R increased by 40% (P = 0.02) in HGD and 80% (P = 0.0007) in CA compared with quiescent colitis. There were no significant changes in protein levels of the fl-NK-1R. We conclude that the increase in total NK-1R protein in HGD and CA is attributable to an increase in tr-NK-1R, suggesting there may be a functional role for tr-NK-1R in malignant transformation in colitis-associated cancer. The tr-NK-1R could prove useful as a diagnostic marker to identify patients at risk for neoplasia and may serve as a useful therapeutic target in the treatment of colitisassociated cancer.colon cancer | receptor splice variants | substance P | IBD C hronic inflammation is associated with a higher rate of cancer development in various organs (1). More specifically, patients with ulcerative colitis (UC) are at high risk for developing colorectal cancer (2); both extent and duration of intestinal inflammation further increase risk (3, 4). These associations suggest that chronic intestinal inflammation is a causative factor in carcinogenesis in patients with UC, and that there is a causal link between chronic inflammation and increased risk of cancer. These observations raise the question of the signaling pathways by which long-standing inflammation might underlie the development of cancer.Substance P (SP) is a proinflammatory neuropeptide described by von Euler and Gaddum (5) and later isolated and characterized by Chang and Leeman (6). SP is synthesized by a variety of cells, most notably neurons and inflammatory cells such as macrophages (7). SP's primary receptor, the neurokinin-1 receptor (NK-1R), can mediate a variety of physiologic and pathophysiologic responses, including cell proliferation, migration, and inflammation (8). The NK-1R has been identified in epithelial cells in rodent models of colonic inflammation (9, 10) and in patients with UC as well as Crohn disease (11)(12)(13)(14). However, not all of these studies are in agreement regarding epithelial NK-1R e...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer

Gillespie¹,

Leeman²,

Watts³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…For instance, until recently, little attention has been given to the different splice variants of NK1R. Previous studies pointed out the central role of NK1R-tr in breast cancer (104,105). Likewise, Gillespie et al analyzed NK1R-tr and NK1R-fl in colitis-associated cancer and found that it was the expression of NK1R-tr alone that predicted the progression from quiescent colitis to highgrade dysplasia and cancer (106).…”

Section: Therapeutic Innovations In Hepatoblastoma the Nk1r As A Tumomentioning

confidence: 99%

Therapeutic Innovations for Targeting Hepatoblastoma

Garnier

Ilmer

Kappler

et al. 2016

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“…Compared with full-length (fl-TACR1), tr-NK1R lacks 96 amino acids at the cytoplasmic C-terminus of the receptor that are responsible for intracellular signal transduction. Although this splice variant is considered to be able to couple G proteins, it exhibits decreased efficiency with respect to internalization and desensitization (8,(13)(14)(15). The net result of this is a decreased ability for negative feedback inhibition, allowing constant activation despite saturation of the receptor complex (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Truncated neurokinin-1 receptor is an ubiquitous antitumor target in hepatoblastoma, and its expression is independent of tumor biology and stage

et al. 2015

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Abstract. The substance P (SP; also known as TAC1)/neurokinin-1 receptor (NK1R; also known as TACR1) complex is a critical part in the development of cancer. Therefore, NK1R antagonists, such as the clinical drug aprepitant, are currently under investigation as future anticancer agents. In a previous study, NK1R (TACR1) was identified as a potent anticancer target in hepatoblastoma (HB). However, little is known regarding the exact distribution of this target among HB subsets and whether it correlates with clinical features and prognosis. In the present study, mRNA was isolated from 47 children with HB, and reverse transcription-quantitative polymerase chain reaction was performed on the samples to analyze the expression of full-length-TACR1 (fl-TACR1) and truncated-TACR1 (tr-TACR1). These data were correlated with data obtained from 9 tumor-free controls, as well as with the presence of metastasis, PRETEXT, vascular invasion, histology, age of diagnosis, multifocality, CTNNB1 mutation, gender and overall survival. Additionally, the present study investigated a recently described 16-gene signature characteri zing HB known to correlate with prognosis. Compared with tumor-free liver tissue, tumorous tissue expressed TACR1 significantly higher for the truncated version (P=0.0301), and by trend also for the full-length version. Accordingly, the expression of fl-TACR1 correlated with the expression of the truncated version (P=0.0074). Furthermore, a low expression of fl-TACR1 correlated with characteristics of the 16-gene signature known to predict prognosis (P=0.0222). However, there was no correlation between tr-TACR1 and the tumor characteristics investigated, including outcome, although a clear trend was observed for some tumor characteristics. The current results reinforced the previously described findings that in HB, tr-TACR1 is overexpressed compared with tumor-free liver tissue. Furthermore, to the best of our knowledge, the present study demonstrated for the first time that tr-TACR1 is expressed ubiquitously among the different subsets of HB. Therefore, NK1R may serve as a potent anticancer target in a large variety of patients with HB, independent of tumor biology and clinical stage.

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Nuclear Factor-κB Is Central to the Expression of Truncated Neurokinin-1 Receptor in Breast Cancer: Implication for Breast Cancer Cell Quiescence within Bone Marrow Stroma

Cited by 33 publications

References 35 publications

Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer

Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer

Therapeutic Innovations for Targeting Hepatoblastoma

Truncated neurokinin-1 receptor is an ubiquitous antitumor target in hepatoblastoma, and its expression is independent of tumor biology and stage

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