Candidate tumor-suppressor genes on chromosome arm 8p in early-onset and high-grade breast cancers

Armes, Jane E.; Hammet, Fleur; Silva, Melanie de; Ciciulla, John; Ramus, Susan J.; Soo, Wee Kheng; Mahoney, Alexis; Yarovaya, Natalia; Henderson, Michael A.; Gish, Kurt; Hutchins, Anne-Marie; Price, Gareth; Venter, Deon J.

doi:10.1038/sj.onc.1207740

Cited by 94 publications

(80 citation statements)

References 31 publications

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“…8 Given that the risk of false deletion calling mainly depends on the thickness, which is identical in our present study in breast cancer and our previous study in prostate cancer, we strongly feel that the same scoring criteria are justified. This is also supported by the concordance of our data with 2 previous FISH studies reporting 8p deletion in 39% of 60 14 and 45% of 65 10 analyzed breast cancers using a FISH probe either in the same area or in an adjacent area located only 5.5 megabases telomeric to our FISH probe. Our findings are also in the range of studies using alternative methods for deletion analysis.…”

Section: Discussionsupporting

confidence: 82%

“…[5][6][7][8][9] One of these is deletion of 8p, which is also found in breast cancer. Studies using classical comparative genomic hybridization in 65 -77 patients, 10,11 array-based copy number screening assays in 32 -71 patients, 10,12,13 fluorescence In Situ hybridization (FISH) analysis in 60 -65 patients, 10,14 or loss of heterozygosity (LOH) analysis in 60 -782 patients 15,16 reported 8p deletions in 18-71 % of breast cancers. 8p deletion typically involves extended areas or even the entire 8p arm, with several putative tumor suppressor genes which are located in this region.…”

Section: Introductionmentioning

confidence: 99%

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8p deletion is strongly linked to poor prognosis in breast cancer

Lebok

Mittenzwei

Kluth

et al. 2015

Cancer Biology & Therapy

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Deletions of chromosome 8p occur frequently in breast cancers, but analyses of its clinical relevance have been limited to small patient cohorts and provided controversial results. A tissue microarray with 2,197 breast cancers was thus analyzed by fluorescence in-situ hybridization using an 8p21 probe in combination with a centromere 8 reference probe. 8p deletions were found in 50% of carcinomas with no special type, 67% of papillary, 28% of tubular, 37% of lobular cancers and 56% of cancers with medullary features. Deletions were always heterozygous. 8p deletion was significantly linked to advanced tumor stage (P < 0.0001), high-grade (P < 0.0001), high tumor cell proliferation (Ki67 Labeling Index; P < 0.0001), and shortened overall survival (P < 0.0001). For example, 8p deletion was seen in 32% of 290 grade 1, 43% of 438 grade 2, and 65% of 427 grade 3 cancers. In addition, 8p deletions were strongly linked to amplification of MYC (P < 0.0001), HER2 (P < 0.0001), and CCND1 (p D 0.001), but inversely associated with ER receptor expression (p D 0.0001). Remarkably, 46.5% of 8p-deleted cancers harbored amplification of at least one of the analyzed genes as compared to 27.5% amplifications in 8p-non-deleted cancers (P < 0.0001). In conclusion, 8p deletion characterizes a subset of particularly aggressive breast cancers. As 8p deletions are easy to analyze, this feature appears to be highly suited for future DNA based prognostic breast cancer panels. The strong link of 8p deletion with various gene amplifications raises the possibility of a role for regulating genomic stability.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

8p deletion is strongly linked to poor prognosis in breast cancer

Lebok

Mittenzwei

Kluth

et al. 2015

Cancer Biology & Therapy

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“…We also found evidence that loss of SFRP function contributes to the activation of Wnt signalling in CRC cells . That SFRP1 is located in a chromosomal region that is frequently deleted in breast cancer (8p12 -p11.1) suggests that SFRP1 may also play a tumour suppressor role during mammary tumorigenesis (Ugolini et al, 1999(Ugolini et al, , 2001Armes et al, 2004). Consistent with that idea, we have previously found that SFRP1 is methylated in several breast cancer cell lines (Suzuki et al, 2002), and two other groups recently reported frequent SFRP1 methylation in both primary and cultured breast cancer cells (Lo et al, 2006;Veeck et al, 2006).…”

Section: Genetics and Genomicssupporting

confidence: 63%

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

et al. 2008

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Although mutation of APC or CTNNB1 (b-catenin) is rare in breast cancer, activation of Wnt signalling is nonetheless thought to play an important role in breast tumorigenesis, and epigenetic silencing of Wnt antagonist genes, including the secreted frizzled-related protein (SFRP) and Dickkopf (DKK) families, has been observed in various tumours. In breast cancer, frequent methylation and silencing of SFRP1 was recently documented; however, altered expression of other Wnt antagonist genes is largely unknown. In the present study, we found frequent methylation of SFRP family genes in breast cancer cell lines (SFRP1, 7 out of 11, 64%; SFRP2, 11 out of 11, 100%; SFRP5, 10 out of 11, 91%) and primary breast tumours (SFRP1, 31 out of 78, 40%; SFRP2, 60 out of 78, 77%; SFRP5, 55 out of 78, 71%). We also observed methylation of DKK1, although less frequently, in cell lines (3 out of 11, 27%) and primary tumours (15 out of 78, 19%). Breast cancer cell lines express various Wnt ligands, and overexpression of SFRPs inhibited cancer cell growth. In addition, overexpression of a b-catenin mutant and depletion of SFRP1 using small interfering RNA synergistically upregulated transcriptional activity of T-cell factor/lymphocyte enhancer factor. Our results confirm the frequent methylation and silencing of Wnt antagonist genes in breast cancer, and suggest that their loss of function contributes to activation of Wnt signalling in breast carcinogenesis. British Journal of Cancer (2008) Wnt ligands are secreted proteins that bind to transmembrane receptors in the Frizzled (Fz) family. During normal developmental processes, the resultant Wnt signalling plays essential roles in the regulation of cell proliferation, patterning and fate determination (Cadigan and Nusse, 1997). The binding of Wnt to Fz leads to dephosphorylation and stabilisation of b-catenin, enabling it to be translocated into the nucleus, where it interacts with members of the T-cell factor/lymphocyte enhancer factor (TCF/LEF) family of transcription factors to stimulate the expression of target genes. This signalling pathway is strongly implicated in tumorigenesis; indeed, the first mammalian Wnt isoform was identified based on its ability to promote mouse mammary tumorigenesis (Polakis, 2000). In addition, aberrant nuclear and cytoplasmic localisation of b-catenin is frequently observed in human breast cancer (Lin et al, 2000;Ryo et al, 2001;Chung et al, 2004). In contrast to colorectal cancer (CRC), however, mutation of APC, AXIN or CTNNB1 (b-catenin) is rare in breast cancer, indicating that other mechanisms are responsible for the activation of b-catenin. These mechanisms could include increased expression of Wnt ligand (Huguet et al, 1994;Dale et al, 1996;Bui et al, 1997) and/or the loss of Wnt antagonists.Several classes of secreted Wnt antagonists are known, including the Cerberus, Wnt inhibitory factor 1, secreted frizzled-related protein (SFRP) and the Dickkopf (DKK) families (Kawano and Kypta, 2003). The SFRP family is comprised of five secreted glycopr...

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“…Mutations in this gene have been associated with aneuploidy and several forms of cancer (24). DUSP4 encodes a dual-specificity phosphatase of the activated mitogen-activated protein kinases ERK1 and ERK2, which play an essential role in mitogen-regulated growth factor signal transduction (25). These findings seem to be in line with our earlier findings that the main functional difference between insensitive and sensitive cells is the lack of cell cycle arrest in relatively sensitive cells (17).…”

Section: Discussionsupporting

confidence: 82%

Microarray Analysis of Bleomycin-Exposed Lymphoblastoid Cells for Identifying Cancer Susceptibility Genes

Cloos

Boer²,

Snel³

et al. 2006

Molecular Cancer Research

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The uncovering of genes involved in susceptibility to the sporadic cancer types is a great challenge. It is well established that the way in which an individual deals with DNA damage is related to the chance to develop cancer. Mutagen sensitivity is a phenotype that reflects an individual's susceptibility to the major sporadic cancer types, including colon, lung, and head and neck cancer. A standard test for mutagen sensitivity is measuring the number of chromatid breaks in lymphocytes after exposure to bleomycin. The aim of the present study was to search for the pathways involved in mutagen sensitivity. Lymphoblastoid cell lines of seven individuals with low mutagen sensitivity were compared with seven individuals with a high score. RNA was isolated from cells exposed to bleomycin (4 hours) and from unexposed cells.

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Candidate tumor-suppressor genes on chromosome arm 8p in early-onset and high-grade breast cancers

Cited by 94 publications

References 31 publications

8p deletion is strongly linked to poor prognosis in breast cancer

8p deletion is strongly linked to poor prognosis in breast cancer

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

Microarray Analysis of Bleomycin-Exposed Lymphoblastoid Cells for Identifying Cancer Susceptibility Genes

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