Epigenetic inactivation of the secreted frizzled-related protein-5 ( SFRP5 ) gene in human breast cancer is associated with unfavorable prognosis

Abstract

Disruption of the Wnt pathway is thought to be crucial in the development of human cancer. Pathway inhibitory members of the secreted frizzled-related protein (SFRP) family were found to be downregulated due to epigenetic inactivation in various malignancies. To date, only SFRP1 has been studied in human breast cancer and we questioned whether other SFRP genes may be implicated in the pathogenesis of this disease as well. An initial real-time polymerase chain reaction analysis of SFRP5 expression in normal human tissues (n = 9) revealed weak expression in most tissues, including breast. Malignant mammary cell lines showed further SFRP5 expression loss in five of six cases. Consistently, in matched pairs of primary breast tumor/normal breast tissue, this downregulation (>5-fold) could be confirmed (n = 8/13; 62%). We identified promoter methylation as the predominant mechanism of SFRP5 gene silencing since SFRP5 promoter methylation correlated significantly with loss of SFRP5 expression in cell lines (P = 0.040) and primary tumors (P = 0.003). Moreover, cancerous cell lines re-expressed SFRP5 messenger RNA following treatment with DNA-demethylating drugs. Of 168 primary breast carcinomas, 73% harbored a methylated SFRP5 promoter, whereas 27% were unaffected by epigenetic alteration. Most interestingly, SFRP5 methylation was associated with reduced overall survival (OS) (P = 0.045) and was an independent risk factor affecting OS in a multivariate Cox proportional hazard model (hazard ratio): 4.55; 95% confidence interval: 1.01-20.56; P = 0.049). In conclusion, SFRP5 is a target of epigenetic inactivation in human breast cancer, supporting the hypothesis of its role as tumor suppressor gene. SFRP5 methylation may be a novel DNA-based biomarker potentially useful in clinical breast cancer management.

Prodigiosin inhibits Wnt/β-catenin signaling and exerts anticancer activity in breast cancer cells

“…Wnt ligands and FZD receptors are expressed in human breast cancer cell lines and primary tumors (30)(31)(32)(33). Multiple negative regulators of Wnt/β-catenin signaling, such as SFRP1, SFRP2, SFRP5, WIF1, DKK1, and DKK3, are down-regulated in many breast tumors (34)(35)(36)(37)(38)(39). Although Wnt/β-catenin pathway mutations are rarely detected in breast tumors, elevated levels of nuclear and/or cytoplasmic β-catenin are frequently found and are associated with poor prognosis (40).…”

Secreted frizzled related proteins: Implications in cancers

“…Apart from SFRP1 and SFRP2, various studies also reported SFRP5 expression to be downregulated and epigenetically inactivated in breast cancer and this trend dictated a poor overall survival [62]. The expression of the molecule was rescued when cells were treated with DNAdemethylating drugs, confirming the methylation-based silencing of another SFRP tumour suppressor in breast cancer.…”

Methylated SFRP1,2 and CD25 Expression in Acute Myeloid Leukemia Play an Important Role in the Pathogenesis of the Disease and in Turn in its Treatment

“…While none of the control samples showed hypermethylation. Veeck et al stated that hypermethylation of SFRP-1 associated with poor prognosis in breast cancer patients [20,21]. SFRP gene promoter hypermethylation has been demonstrated in different hematopoietic malignancies like acute lymphoblastic leukemia (ALL) and Multiple myeloma (MM).…”