Low SAFB levels are associated with worse outcome in breast cancer patients

Hammerich-Hille, Stephanie; Bardout, Valerie J.; Hilsenbeck, Susan G.; Osborne, C. Kent; Oesterreich, Steffi

doi:10.1007/s10549-008-0297-6

Cited by 30 publications

(25 citation statements)

References 21 publications

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“…This study revealed that decreased expression of SAFB was significantly associated with aggressive cellular characteristics of CRC (e.g., poor cellular differentiation, advanced Dukes stage, advanced TNM stage) and with a poorer outcome of patients, suggesting that SAFB might be a tumor suppressor and a prognostic marker of CRC progression. Consistent with our results, the downregulation of SAFB has been reported to be responsible for the metastasis of prostate cancer and poorer outcomes in patients with breast cancer (13,14).…”

Section: Discussionsupporting

confidence: 92%

“…10), which is involved in inflammation and tumorigenesis and is a source of reactive oxygen species (11,12). Low expression of SAFB is related to the metastasis of prostate cancer and poorer outcomes in patients with breast cancer, which is partly due to the unrestrained activities of the androgen receptor and estrogen receptor a, respectively (13,14). Our preliminary work and a published microarray analysis found that SAFB expression was downregulated in CRC.…”

Section: Introductionmentioning

confidence: 68%

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Downregulation of SAFB Sustains the NF-κB Pathway by Targeting TAK1 during the Progression of Colorectal Cancer

Jiao

Yang

et al. 2017

Clinical Cancer Research

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Purpose: To investigate the role and the underlying mechanism of scaffold attachment factor B (SAFB) in the progression of colorectal cancer (CRC).Experimental Design: SAFB expression was analyzed in the Cancer Outlier Profile Analysis of Oncomine and in 175 paraffinembedded archived CRC tissues. Gene Ontology analyses were performed to explore the mechanism of SAFB in CRC progression. Western blot, RT-PCR, luciferase assay, and chromatin immunoprecipitation (ChIP) were used to detect the regulation of transforming growth factor-b-activated kinase 1 (TAK1) and NF-kB signaling by SAFB. The role of SAFB in invasion, metastasis, and angiogenesis was investigated using in vitro and in vivo assays. The relationship between SAFB and TAK1 was analyzed in CRC tissues.Results: SAFB was downregulated in CRC tissues, and low expression of SAFB was significantly associated with an aggressive phenotype and poorer survival of CRC patients. The downregulation of SAFB activated NF-kB signaling by targeting the TAK1 promoter. Ectopic expression of SAFB inhibited the development of aggressive features and metastasis of CRC cells both in vitro and in vivo. The overexpression of TAK1 could rescue the aggressive features in SAFB-overexpressed cells. Furthermore, the expression of SAFB in CRC tissues was negatively correlated with the expression of TAK1-and NF-kBrelated genes.Conclusions: Our results show that SAFB regulated the activity of NF-kB signaling in CRC by targeting TAK1. This novel mechanism provides a comprehensive understanding of both SAFB and the NF-kB signaling pathway in the progression of CRC and indicates that the SAFB-TAK1-NF-kB axis is a potential target for early therapeutic intervention in CRC progression. Clin Cancer Res; 23(22); 7108-18. Ó2017 AACR.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 68%

Downregulation of SAFB Sustains the NF-κB Pathway by Targeting TAK1 during the Progression of Colorectal Cancer

Jiao

Yang

et al. 2017

Clinical Cancer Research

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“…The same region was recently linked to hereditary breast cancer in Swedish families; however, this study did not identify germ line mutations in the coding regions of SAFB1 and SAFB2 (20). We have recently reported that SAFB1/SAFB2 protein expression was frequently lost in breast tumors and that this was associated with worse overall survival (21). Mouse embryonic fibroblasts deficient in SAFB1 showed a lack of contact inhibition, increased foci formation, and increased oncogene-induced anchorage-independent growth.…”

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confidence: 78%

SAFB1 Mediates Repression of Immune Regulators and Apoptotic Genes in Breast Cancer Cells

Hammerich-Hille

Kaipparettu

Tsimelzon

et al. 2010

Journal of Biological Chemistry

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The scaffold attachment factors SAFB1 and SAFB2 are paralogs, which are involved in cell cycle regulation, apoptosis, differentiation, and stress response. They have been shown to function as estrogen receptor corepressors, and there is evidence for a role in breast tumorigenesis. To identify their endogenous target genes in MCF-7 breast cancer cells, we utilized a combined approach of chromatin immunoprecipitation (ChIP)-on-chip and gene expression array studies. By performing ChIP-on-chip on microarrays containing 24,000 promoters, we identified 541 SAFB1/SAFB2-binding sites in promoters of known genes, with significant enrichment on chromosomes 1 and 6. Gene expression analysis revealed that the majority of target genes were induced in the absence of SAFB1 or SAFB2 and less were repressed. Interestingly, there was no significant overlap between the genes identified by ChIP-on-chip and gene expression array analysis, suggesting regulation through regions outside the proximal promoters. In contrast to SAFB2, which shared most of its target genes with SAFB1, SAFB1 had many unique target genes, most of them involved in the regulation of the immune system. A subsequent analysis of the estrogen treatment group revealed that 12% of estrogen-regulated genes were dependent on SAFB1, with the majority being estrogen-repressed genes. These were primarily genes involved in apoptosis, such as BBC3, NEDD9, and OPG. Thus, this study confirms the primary role of SAFB1/SAFB2 as corepressors and also uncovers a previously unknown role for SAFB1 in the regulation of immune genes and in estrogen-mediated repression of genes. The estrogen receptor ␣ (ER␣)3 plays a pivotal role in both normal and pathophysiological processes, such as osteoporosis and breast cancer (1). The transcriptional activity of ER␣ is not only regulated by its ligand estrogen but also through its interaction with cofactors, which can either enhance (coactivators) or repress (corepressors) its activity (2). Briefly, upon binding of its ligand, ER␣ undergoes major structural rearrangements leading to exposure of binding surfaces that subsequently results in facilitated recruitment of different coactivators, including histone acetyltransferases or histone methyltransferases, and proteins from the SWI/SNF chromatin remodeling complex (3). In the absence of ligand, recruitment of corepressors results in the creation of locally repressed chromatin, subsequently resulting in inhibition of transcription (4).Our group has identified the scaffold attachment factors SAFB1 and SAFB2 as ER␣ corepressors (5, 6). The two proteins are paralogs that share 74% similarity at the amino acid levels, with up to 98% in some functional domains (7). The genes reside in close proximity on chromosome 19p13.3, oriented in a head-to-head orientation, separated by an ϳ500-bp GC-rich promoter (6). The C termini of the proteins harbor a repression domain that can refer repression when transferred to a heterologous DNA-binding protein. This repression domain can be further defined into two ...

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“…SAFB1 mutations were identified in microdissected breast tumours but not in the normal adjacent tissue, and a high loss of heterozygosity (78%) was detected at the SAFB chromosomal locus in invasive breast cancer [111]. Also, low SAFB expression was associated with worse overall survival of breast cancer patients, but did not affect tamoxifen response [112]. Two animal models, MMTV-Wnt-1 oncogenic mice and mice treated with DMBA, were then used to investigate the impact of SAFB1 +/− heterozygosity on the development of mammary tumours [113].…”

Section: Safb Function In Vivo and Possible Roles In Human Diseasementioning

confidence: 98%

The increasing diversity of functions attributed to the SAFB family of RNA-/DNA-binding proteins

Norman

Rivers

Lee

et al. 2016

Biochemical Journal

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RNA-binding proteins play a central role in cellular metabolism by orchestrating the complex interactions of coding, structural and regulatory RNA species. The SAFB (scaffold attachment factor B) proteins (SAFB1, SAFB2 and SAFB-like transcriptional modulator, SLTM), which are highly conserved evolutionarily, were first identified on the basis of their ability to bind scaffold attachment region DNA elements, but attention has subsequently shifted to their RNA-binding and protein-protein interactions. Initial studies identified the involvement of these proteins in the cellular stress response and other aspects of gene regulation. More recently, the multifunctional capabilities of SAFB proteins have shown that they play crucial roles in DNA repair, processing of mRNA and regulatory RNA, as well as in interaction with chromatin-modifying complexes. With the advent of new techniques for identifying RNA-binding sites, enumeration of individual RNA targets has now begun. This review aims to summarise what is currently known about the functions of SAFB proteins.

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Low SAFB levels are associated with worse outcome in breast cancer patients

Cited by 30 publications

References 21 publications

Downregulation of SAFB Sustains the NF-κB Pathway by Targeting TAK1 during the Progression of Colorectal Cancer

Downregulation of SAFB Sustains the NF-κB Pathway by Targeting TAK1 during the Progression of Colorectal Cancer

SAFB1 Mediates Repression of Immune Regulators and Apoptotic Genes in Breast Cancer Cells

The increasing diversity of functions attributed to the SAFB family of RNA-/DNA-binding proteins

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