A pan-cancer analysis of secreted Frizzled-related proteins: re-examining their proposed tumour suppressive function

Vincent, Krista; Postovit, Lynne-Marie

doi:10.1038/srep42719

Cited by 43 publications

(49 citation statements)

References 39 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…FZD2 is elevated in many cancers, including breast cancer, and its expression correlated with markers of EMT and cell migration through a non-canonical pathway that predicts metastasis and overall survival in patients [22]. Similarly, SFRP2 is shown to be associated with poor prognosis concomitant with the expression of genes associated with EMT [47]. In agreement with the above findings, the pathway analysis of the gene expression data in this study showed enrichment of WNT (both canonical and non-canonical) pathways, the planar cell polarity (PCP) pathway, and signaling pathways regulating the pluripotency of stem cells in DCIS (generally induced by WNT signaling).…”

Section: Discussionmentioning

confidence: 98%

Ductal Carcinoma In Situ Progression in Dog Model of Breast Cancer

Mohammed

Utturkar

Lee

et al. 2020

Cancers

View full text Add to dashboard Cite

The mechanisms that drive ductal carcinoma in situ (DCIS) progression to invasive cancer are not clear. Studying DCIS progression in humans is challenging and not ethical, thus necessitating the characterization of an animal model that faithfully resembles human disease. We have characterized a canine model of spontaneous mammary DCIS and invasive cancer that shares histologic, molecular, and diagnostic imaging characteristics with DCIS and invasive cancer in women. The purpose of the study was to identify markers and altered signaling pathways that lead to invasive cancer and shed light on early molecular events in breast cancer progression and development. Transcriptomic studies along the continuum of cancer progression in the mammary gland from healthy, through atypical ductal hyperplasia (ADH), DCIS, and invasive carcinoma were performed using the canine model. Gene expression profiles of preinvasive DCIS lesions closely resemble those of invasive carcinoma. However, certain genes, such as SFRP2, FZD2, STK31, and LALBA, were over-expressed in DCIS compared to invasive cancer. The over-representation of myoepithelial markers, epithelial-mesenchymal transition (EMT), canonical Wnt signaling components, and other pathways induced by Wnt family members distinguishes DCIS from invasive. The information gained may help in stratifying DCIS as well as identify actionable targets for primary and tertiary prevention or targeted therapy.

show abstract

Section: Discussionmentioning

confidence: 98%

Ductal Carcinoma In Situ Progression in Dog Model of Breast Cancer

Mohammed

Utturkar

Lee

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“…The expression of SFRP1 mRNA is detectable in all tested human tissues and broad expression was observed in the endometrium [19], ovary [20], colon [21], prostate [22], and breast [17]. The Cancer Genome Atlas (TCGA) revealed reduced expression of SFRP1 various cancers including breast, colorectal, lung, bladder urothelial carcinoma, cervical squamous cell carcinoma, head and neck squamous cell carcinoma, glioblastoma multiforme, kidney renal clear cell carcinoma, stomach adenocarcinoma, and endometrium cancer compared to the normal tissues [23].…”

Section: Epigenetic Inactivation and Genomic Alterations In Sfrp1 Genementioning

confidence: 99%

“…While SFRP2 and SFRP4 were more recently reviewed [15,16], an updated review that recapitulates the association between SFRP1 and chemoresistance is limited. A pan-cancer analysis suggested that SFRPs are strongly correlated with patient survival, but there is an inconsistency between family members and cancer types [17]. A systematic review and meta-analysis of the SFRP family also revealed that SFRP1 hypermethylation was significantly associated with cancer risk [18].…”

Section: Introductionmentioning

confidence: 99%

Epigenetics of SFRP1: The Dual Roles in Human Cancers

Baharudin

Tieng

Lee

et al. 2020

Cancers

View full text Add to dashboard Cite

Secreted frizzled-related protein 1 (SFRP1) is a gene that belongs to the secreted glycoprotein SFRP family. SFRP1 has been classified as a tumor suppressor gene due to the loss of expression in various human cancers, which is mainly attributed by epigenetic inactivation via DNA methylation or transcriptional silencing by microRNAs. Epigenetic silencing of SFRP1 may cause dysregulation of cell proliferation, migration, and invasion, which lead to cancer cells formation, disease progression, poor prognosis, and treatment resistance. Hence, restoration of SFRP1 expression via demethylating drugs or over-expression experiments opens the possibility for new cancer therapy approach. While the role of SFRP1 as a tumor suppressor gene is well-established, some studies also reported the possible oncogenic properties of SFRP1 in cancers. In this review, we discussed in great detail the dual roles of SFRP1 in cancers—as tumor suppressor and tumor promoter. The epigenetic regulation of SFRP1 expression will also be underscored with additional emphasis on the potentials of SFRP1 in modulating responses toward chemotherapeutic and epigenetic-modifying drugs, which may encourage the development of novel drugs for cancer treatment. We also present findings from clinical trials and patents involving SFRP1 to illustrate its clinical utility, extensiveness of each research area, and progression toward commercialization. Lastly, this review provides directions for future research to advance SFRP1 as a promising cancer biomarker.

show abstract

“…Thus, a restoration of the SFRP1 expression through epigenetic drugs or the natural compound flavonoid epigallocatechin-3-gallate (EGCG), as it was shown in our recent study, could be a new therapeutic option for β-catenin mutant pediatric liver cancers (Godeke et al 2013). In contrast to other studies, the reduced SFRP1 gene expression in our HB patient cohort was not associated to the DNA methylation status (Vincent and Postovit 2017;Kaur et al 2012). Several patient samples showed a SFRP1 downregulation without a concomitant methylation of the promoter.…”

Section: Discussionmentioning

confidence: 43%

“…Moreover, it was previously shown that the dickkopf WNT signaling pathway inhibitor 1 (DKK1) is upregulated in HB patient samples, which might represent negative feedback mechanisms (Wirths et al 2003). On the contrary, among the known WNT antagonists, the secreted frizzled-related protein 1 (SFRP1) is often downregulated in various cancer entities, which indicates that SFRP1 has tumor-suppressive functions (Vincent and Postovit 2017). Under physiological conditions, SFRP1 inactivates the canonical and non-canonical WNT/β-catenin pathway by directly binding to WNT proteins or the frizzled receptor (Kawano and Kypta 2003).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of SFRP1 is a protumorigenic event in hepatoblastoma and correlates with beta-catenin mutations

Regel

Eichenmüller

Mahajan

et al. 2020

J Cancer Res Clin Oncol

View full text Add to dashboard Cite

Background Hepatoblastoma (HB) and pediatric hepatocellular carcinoma (HCC) are the most common malignant liver tumors in childhood. Both tumor types exhibit genetic and epigenetic alterations in the WNT/β-catenin signaling pathway, which is a key regulator of liver progenitor cells in embryonic development. The tumors demonstrate a high rate of β-catenin mutations and gene expression changes of several WNT antagonists. However, the role of the WNT inhibitory factor secreted frizzled-related protein 1 (SFRP1) has not been addressed in pediatric liver cancer so far. Results In our study, we investigated the gene expression level, DNA methylation status and functional relevance of SFRP1 in HB cell lines and in pediatric liver tumor patient samples. SFRP1 was downregulated due to DNA promoter methylation in all tested HB cell lines. Overexpression of SFRP1 in HB cell lines diminished tumor cell proliferation, colony formation and migration potential. In addition, the SFRP1-expressing HB cell lines showed reduced WNT/β-catenin signaling pathway activity and decreased expression of WNT target genes. To evaluate the utility of SFRP1 as a biomarker in pediatric liver cancer, we determined the gene expression level and DNA methylation status of SFRP1 in 45 pediatric liver tumor patient samples. The correlation analysis of different clinical parameters and tumor characteristics revealed a significant correlation of reduced SFRP1 expression with the presence of mutant β-catenin. The methylation status of SFRP1 was furthermore associated to a pediatric liver tumor type with HCC-like characteristics, TERT mutations and an older age at diagnosis. Conclusion Altogether, our data demonstrate that the epigenetic suppression of the WNT/β-catenin antagonist SFRP1 has an important impact on the malignant behavior of HB cells. Although SFRP1 methylation is a common event in HCC-like pediatric liver tumors, its potential as a prognostic or diagnostic biomarker needs to be further investigated.

show abstract

A pan-cancer analysis of secreted Frizzled-related proteins: re-examining their proposed tumour suppressive function

Cited by 43 publications

References 39 publications

Ductal Carcinoma In Situ Progression in Dog Model of Breast Cancer

Ductal Carcinoma In Situ Progression in Dog Model of Breast Cancer

Epigenetics of SFRP1: The Dual Roles in Human Cancers

Downregulation of SFRP1 is a protumorigenic event in hepatoblastoma and correlates with beta-catenin mutations

Contact Info

Product

Resources

About