Odyssey of trefoil factors in cancer: Diagnostic and therapeutic implications

Jahan, Rahat; Shah, Ashu; Kisling, Sophia G.; Macha, Muzafar A.; Thayer, Sarah P.; Batra, Surinder K.; Kaur, Sukhwinder

doi:10.1016/j.bbcan.2020.188362

Cited by 19 publications

(17 citation statements)

References 172 publications

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“…Mthfd1l is involved in the synthesis of tetrahydrofolate, required for purine synthesis; its expression significantly correlates with the infiltration of immune cells including M2 (mainly anti-inflammatory) macrophages; and it appears to promote cell proliferation, migration, and invasion via the Akt/mTOR pathway [ 33 , 86 ]. Tff3 facilitates migration and inhibits apoptosis, and its expression is increased in a variety of cancers [ 87 ]. This set of genes may be critical in mediating Esr1 ′s suppression of HCC, individually or in combination, and merits further study.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Receptor-α Suppresses Liver Carcinogenesis and Establishes Sex-Specific Gene Expression

O'Brien

Pitot

Chung

et al. 2021

Cancers

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Estrogen protects females from hepatocellular carcinoma (HCC). To determine whether this protection is mediated by classic estrogen receptors, we tested HCC susceptibility in estrogen receptor-deficient mice. In contrast to a previous study, we found that diethylnitrosamine induces hepatocarcinogenesis to a significantly greater extent when females lack Esr1, which encodes Estrogen Receptor-α. Relative to wild-type littermates, Esr1 knockout females developed 9-fold more tumors. Deficiency of Esr2, which encodes Estrogen Receptor-β, did not affect liver carcinogenesis in females. Using microarrays and QPCR to examine estrogen receptor effects on hepatic gene expression patterns, we found that germline Esr1 deficiency resulted in the masculinization of gene expression in the female liver. Six of the most dysregulated genes have previously been implicated in HCC. In contrast, Esr1 deletion specifically in hepatocytes of Esr1 conditional null female mice (in which Cre was expressed from the albumin promoter) resulted in the maintenance of female-specific liver gene expression. Wild-type adult females lacking ovarian estrogen due to ovariectomy, which is known to make females susceptible to HCC, also maintained female-specific expression in the liver of females. These studies indicate that Esr1 mediates liver cancer risk, and its control of sex-specific liver gene expression involves cells other than hepatocytes.

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Section: Discussionmentioning

confidence: 99%

Estrogen Receptor-α Suppresses Liver Carcinogenesis and Establishes Sex-Specific Gene Expression

O'Brien

Pitot

Chung

et al. 2021

Cancers

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“…TFF1 is an autocrine/paracrine factor which is frequently overexpressed in several cancers, including breast cancer ( Perry et al , 2008 ), and forced expression of TFF1 results in increased cell proliferation in mammary carcinoma cells ( Amiry et al , 2009 ). However, the role of TFF1 in cancer is still under debate, as both oncogenic and tumor-suppressive roles have been described in various organ systems ( Jahan et al , 2020 ). The reporter cell lines we generated can be used to gain more insight in the roles of GREB1, PGR, and TFF1 in the estrogenic response.…”

Section: Discussionmentioning

confidence: 99%

Physiologically Relevant Estrogen Receptor Alpha Pathway Reporters for Single-Cell Imaging-Based Carcinogenic Hazard Assessment of Estrogenic Compounds

Duijndam

Goudriaan

Hoorn

et al. 2021

Toxicological Sciences

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Estrogen receptor alpha (ERα) belongs to the nuclear hormone receptor family of ligand-inducible transcription factors and regulates gene networks in biological processes such as cell growth and proliferation. Disruption of these networks by chemical compounds with estrogenic activity, can result in adverse outcomes such as unscheduled cell proliferation, ultimately culminating in tumor formation. To distinguish disruptive activation from normal physiological responses, it is essential to quantify relationships between different key events leading to a particular adverse outcome. For this purpose, we established fluorescent protein MCF7 reporter cell lines for ERα-induced proliferation by bacterial artificial chromosome-based tagging of three ERα target genes: GREB1, PGR and TFF1. These target genes are inducible by the non-genotoxic carcinogen and ERα agonist 17β-estradiol in an ERα-dependent manner and are essential for ERα-dependent cell cycle progression and proliferation. The three GFP reporter cell lines were characterized in detail and showed different activation dynamics upon exposure to 17β-estradiol. In addition, they demonstrated specific activation in response to other established reference estrogenic compounds of different potencies, with similar sensitivities as validated OECD test methods. This study shows that these fluorescent reporter cell lines can be used to monitor the spatial and temporal dynamics of ERα pathway activation at the single cell level for more mechanistic insight, thereby allowing a detailed assessment of the potential carcinogenic activity of estrogenic compounds in humans.

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“…Through anti-apoptotic effects, TFFs protect epithelia from death and promote cell migration (6,9,27,28). TFFs are involved in the development and progression of various types of cancer (8)(9)(10)(12)(13)(14)16), including CRC (17)(18)(19). The role of TFF3 in the pathogenesis of CRC, however, remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…TFF3 is involved in tumorigenesis and the progression of various solid tumors (8)(9)(10)(11)(12)(13)(14)(15)(16). The function of this protein in CRCs, however, remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Expression of trefoil factor 3 is decreased in colorectal cancer

et al. 2020

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In colorectal cancer (CRC), high expression of trefoil factor 3 (TFF3) is associated with tumor progression and reduced patient survival; however, bioinformatics analyses of public ‘omics’ databases show low TFF3 expression in CRCs as compared to normal tissues. Thus, we examined TFF3 expression in CRCs and matching normal tissues to evaluate its role in CRC progression. TFF3 gene expression was characterized using the bioinformatics portal UALCAN ( ). Tissue microarrays (TMAs) of archival CRC specimens (n=96) were immunostained with anti-human TFF3 antibodies. Immunohistochemical (IHC) staining intensity was semi-quantitatively scored. For this cohort, the median follow-up was 5.4 years. Associations between clinical and pathological variables were determined using Chi-square or Fisher's exact tests. Univariate disease-free survival was estimated by the Kaplan-Meier method. Omics data analyses by UALCAN showed downregulation of TFF3 expression in CRC relative to normal tissue at protein (χ 2 , P<0.0001) levels. There was a similar decreasing trend of TFF3 expression in the pathologic stages of the CRCs (RNA, χ 2 , P=0.88 and protein, χ 2 P<0.0001). UALCAN data analysis showed that TFF3 exhibited 27% lower mRNA expression in tumors with mutant TP53 (P=0.007). Confirming the findings of omics analyses, IHC analysis of TMAs exhibited lower TFF3 expression in 95.6% (65 of 68) of the available normal-tumor matching pairs (χ 2 , P<0.0001). There was no statistically significant association of tumor TFF3 expression with patient sex, race/ethnicity, tumor location within the colorectum, Tumor, Node, Metastasis (TNM) stage, lymph node metastasis, or surgical margins. However, low TFF3 IHC staining in tumor tissue was associated with histological grade (P=0.026). Kaplan-Meier survival analysis showed no prognostic value of low TFF3 expression relative to those with high expression (log-rank, P=0.605). Our findings demonstrate low expression of TFF3 in CRCs. Association between low TFF3 and histopathological features suggests involvement of this molecule in progression of CRC.

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Odyssey of trefoil factors in cancer: Diagnostic and therapeutic implications

Cited by 19 publications

References 172 publications

Estrogen Receptor-α Suppresses Liver Carcinogenesis and Establishes Sex-Specific Gene Expression

Estrogen Receptor-α Suppresses Liver Carcinogenesis and Establishes Sex-Specific Gene Expression

Physiologically Relevant Estrogen Receptor Alpha Pathway Reporters for Single-Cell Imaging-Based Carcinogenic Hazard Assessment of Estrogenic Compounds

Expression of trefoil factor 3 is decreased in colorectal cancer

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