Expression of the pNR-2/pS2 protein in diverse human epithelial tumours

Henry, James A.; Bennett, MK; Piggott, Nigel H.; Levett, D.; May, Felicity E. B.; Westley, Bruce R.

doi:10.1038/bjc.1991.380

Cited by 109 publications

(74 citation statements)

References 21 publications

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“…The secreted protein pS2/pNR2 appears to be under primary oestrogen control in breast tumours and cell lines, but is also expressed by several epithelial tumours as well as some normal tissues (Brown et al, 1984;Cavailles et al, 1989;Henry et al, 1991;May & Westley, 1988). In addition pS2, via activation of its enhancer element, is also induced by insulin, IGF-I, bFGF, EGF, increased intracellular cAMP, stimulation of protein kinase C (PKC) by phorbol esters and some oncogene products Nunez et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Bile acids influence the growth, oestrogen receptor and oestrogen-regulated proteins of MCF-7 human breast cancer cells

Baker

Wilton²,

Jones³

et al. 1992

Br J Cancer

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Summary The effects of the major human serum bile acid, glycochenodeoxycholic acid (GCDC), as well as unconjugated chenodeoxycholic acid (CDC), on the MCF-7 human breast cancer cell line have been studied in vitro under oestrogen and bile acid deprived culture conditions. GCDC increased the growth of the breast cancer cells over the range 10-300 jiM. At concentrations in excess of the bile acid binding capacity of the medium cell growth was prevented. In contrast 10 jiM CDC tended to reduce cell growth. Oestrogen (ER) and progesterone (PgR) receptors, pS2 and total cathepsin D were quantified by monoclonal antibody based immunoassays. Ten to 100 jiM GCDC and 10 jIM CDC down-regulated ER protein and this was accompanied by induction of the oestrogen-regulated proteins PgR, pS2 and possibly cathepsin D, including increased secretion of the latter two proteins into the culture medium. All these changes were quantitatively similar to those observed with 10 nm oestradiol. The bile acid effects on ER and PgR were not due to interference with the assay procedures. Cells incubated with 50 jIM GCDC or 10 jIM CDC had higher pmolar concentrations of the bile acids than controls. This study suggests that naturally occurring bile acids influence the growth and steroid receptor function of human breast cancer cells.Although bile acids have been considered to play a role in the aetiology and/or growth of colorectal cancer (Hill, 1983) little attention has been paid to the possible activity of these steroidal compounds in breast cancer. Epidemiological studies have demonstrated that rates of breast and colon cancers are highly correlated with each other and with high fat and animal protein diets (Drasar & Irving, 1973). In the few studies published the data suggest that women with breast cancer may have differences in the faecal excretion of bile acids compared with controls; decreased (Murray et al., 1980) and increased (Papatestas et al., 1982) faecal concentrations, and altered ratio of individual bile acids (Owen et al., 1986) have been reported. Long-term follow-up of women undergoing cholecystectomy has revealed an increased risk of breast cancer which increased with time after operation (Gudmundsson et al., 1989). In contrast, by reducing the enterohepatic circulation of oestrogens and bile acids, the high consumption of fibre and fermented milk products, particularly in combination with low fat and animal protein intake, may provide some protection against breast cancer (Adlercreutz, 1990). These findings, while by no means conclusive, imply that breast cancer patients are subject to changes in circulating levels of bile acids and consequently the potential exposure of breast tissue and/or tumour. In support of the latter possibility is our observation, now confirmed by others, that breast cyst fluid contains very high levels of bile acids, notably the glycine conjugates of chenodeoxycholic (CDC), deoxycholic and cholic acids (Baker et al., 1986 and1988a;Raju et al., 1990).Bile acids have been shown to produce DNA chan...

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Section: Discussionmentioning

confidence: 99%

Bile acids influence the growth, oestrogen receptor and oestrogen-regulated proteins of MCF-7 human breast cancer cells

Baker

Wilton²,

Jones³

et al. 1992

Br J Cancer

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“…In the human stomach, TFF1 protein is expressed predominantly in the superficial foveolar epithelium of the gastric body and antrum (5,31), and this expression is frequently lost in human gastric cancer (32,33). qRT-PCR analysis of TFF1 in 70 human gastric tumors revealed a significant overall reduction of TFF1 expression in tumors as compared with 36 normal gastric epithelia samples (P < 0.001) (Supplemental Figure 8, A and B).…”

Section: Tff1 Suppresses the Expression Of Pro-inflammatory And Pro-smentioning

confidence: 99%

Loss of TFF1 is associated with activation of NF-κB–mediated inflammation and gastric neoplasia in mice and humans

et al. 2011

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Trefoil factor 1 (TFF1) is a tumor suppressor gene that encodes a peptide belonging to the trefoil factor family of protease-resistant peptides. Although TFF1 expression is frequently lost in gastric carcinomas, the tumorigenic pathways this affects have not been determined. Here we show that Tff1-knockout mice exhibit age-dependent carcinogenic histological changes in the pyloric antrum of the gastric mucosa, progressing from gastritis to hyperplasia, low-grade dysplasia, high-grade dysplasia, and ultimately malignant adenocarcinoma. The histology and molecular signatures of gastric lesions in the Tff1-knockout mice were consistent with an inflammatory phenotype. In vivo, ex-vivo, and in vitro studies showed that TFF1 expression suppressed TNF-α-mediated NF-κB activation through the TNF receptor 1 (TNFR1)/IκB kinase (IKK) pathway. Consistent with these mouse data, human gastric tissue samples displayed a progressive decrease in TFF1 expression and an increase in NF-κB activation along the multi-step carcinogenesis cascade. Collectively, these results provide evidence that loss of TFF1 leads to activation of IKK complex-regulated NF-κB transcription factors and is an important event in shaping the NF-κB-mediated inflammatory response during the progression to gastric tumorigenesis.

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“…A large number of studies indicate that TFF1 expression is absent or occurs at low levels in nonmalignant pancreatic and prostate tissues. Elevated expression levels of TFF1 are frequently observed in pancreatic and prostate malignancies (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31), suggesting that TFF1 may be involved in the tumorigenesis of these cancers. These data are not, however, sufficiently convincing because of the lack of strict statistical analysis in some studies and the reduced statistical power in others with small sample sizes.…”

Section: Tff1 Expressionmentioning

confidence: 99%

Trefoil factor 1 acts to suppress senescence induced by oncogene activation during the cellular transformation process

Radiloff

Wakeman²,

Feng³

et al. 2011

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

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Senescence is a cellular stress response characterized by persistent cell growth arrest under various stress conditions, including oncogene activation or tumor suppressor loss, which functions as a critical barrier that must be overcome to allow the progression from a precancerous or preinvasive lesion to a malignant tumor. Trefoil factor 1 (TFF1) is a secreted protein involved in maintaining the gastrointestinal epithelium by serving a tumor-suppressive role; however, TFF1 is overexpressed in several types of cancers. Here we report that TFF1 acts as a promoter of tumorigenesis in the context of prostate and pancreatic cancers by suppressing oncogene-induced senescence (OIS). Expression of TFF1 allows human prostate epithelial cells to escape OIS caused by the activated Ras oncogene or by reduced expression of the tumor suppressor PTEN, in part by the involvement of the EGF receptor-mediated pathway and inhibition of the expression of the cell cycle regulator p21. Without intrinsic promitogenic activity TFF1 may act in both autocrine and paracrine manners to enable cells to undergo the initial transformation and expansion against the restrictive microenvironment during early stage tumorigenesis. Taken together, our findings identify TFF1 as a soluble factor designed to act mainly to antagonize the OIS process to accelerate tumorigenesis.

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Expression of the pNR-2/pS2 protein in diverse human epithelial tumours

Cited by 109 publications

References 21 publications

Bile acids influence the growth, oestrogen receptor and oestrogen-regulated proteins of MCF-7 human breast cancer cells

Bile acids influence the growth, oestrogen receptor and oestrogen-regulated proteins of MCF-7 human breast cancer cells

Loss of TFF1 is associated with activation of NF-κB–mediated inflammation and gastric neoplasia in mice and humans

Trefoil factor 1 acts to suppress senescence induced by oncogene activation during the cellular transformation process

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