Biomarkers for detection and prognosis of breast cancer identified by a functional hypermethylome screen

Jeschke, Jana; Neste, Leander Van; Glöckner, Sabine C.; Dhir, Mashaal; Calmon, Marília Freitas; Deregowski, Valérie; Criekinge, Wim Van; Vlassenbroeck, Ilse; Koch, Alexander; Chan, Timothy A.; Cope, Leslie; Hooker, Craig M.; Schuebel, Kornel; Gabrielson, Edward; Winterpacht, Andreas; Baylin, Stephen B.; Herman, James G.; Ahuja, Nita

doi:10.4161/epi.20445

Cited by 60 publications

(58 citation statements)

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“…To characterize the vast amount of DNA methylation data generated, comprehensive functional approaches have been initiated and novel tumor suppressor genes and pathways as well as biomarkers for early detection and prognosis prediction of cancer have been discovered. [2][3][4][5][6][7][8][9][10][11] Neurofilament heavy polypeptide (NEFH) has been identified as a candidate DNA hypermethylated gene within the functional breast cancer hypermethylome, a comprehensive approach to define genome-wide functional methylation changes in breast cancer that is based on whole transcriptome expression arrays on breast cancer cell lines after pharmacological inhibition of DNA methylation. 6 NEFH encodes the neurofilament heavy polypeptide and assembles along with neurofilament medium polypeptide (NEFM) and neurofilament light polypeptide (NEFL) into 10 nm filamentous structures known as neurofilaments.…”

Section: Introductionmentioning

confidence: 99%

“…[2][3][4][5][6][7][8][9][10][11] Neurofilament heavy polypeptide (NEFH) has been identified as a candidate DNA hypermethylated gene within the functional breast cancer hypermethylome, a comprehensive approach to define genome-wide functional methylation changes in breast cancer that is based on whole transcriptome expression arrays on breast cancer cell lines after pharmacological inhibition of DNA methylation. 6 NEFH encodes the neurofilament heavy polypeptide and assembles along with neurofilament medium polypeptide (NEFM) and neurofilament light polypeptide (NEFL) into 10 nm filamentous structures known as neurofilaments. 12 Neurofilaments are type IV intermediate filaments that are the main structural component of the cytoskeleton in mature neurons 13 determining axon caliber and conductivity for proper neuronal function.…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic silencing of neurofilament genes promotes an aggressive phenotype in breast cancer

et al. 2015

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Neurofilament heavy polypeptide (NEFH) has recently been identified as a candidate DNA hypermethylated gene within the functional breast cancer hypermethylome. NEFH exists in a complex with neurofilament medium polypeptide (NEFM) and neurofilament light polypeptide (NEFL) to form neurofilaments, which are structural components of the cytoskeleton in mature neurons. Recent studies reported the deregulation of these proteins in several malignancies, suggesting that neurofilaments may have a role in other cell types as well. Using a comprehensive approach, we studied the epigenetic inactivation of neurofilament genes in breast cancer and the functional significance of this event. We report that DNA methylation-associated silencing of NEFH, NEFL, and NEFM in breast cancer is frequent, cancer-specific, and correlates with clinical features of disease progression. DNA methylationmediated inactivation of these genes occurs also in multiple other cancer histologies including pancreas, gastric, and colon. Restoration of NEFH function, the major subunit of the neurofilament complex, reduces proliferation and growth of breast cancer cells and arrests them in Go/G1 phase of the cell cycle along with a reduction in migration and invasion. These findings suggest that DNA methylation-mediated silencing of the neurofilament genes NEFH, NEFM, and NEFL are frequent events that may contribute to the progression of breast cancer and possibly other malignancies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Epigenetic silencing of neurofilament genes promotes an aggressive phenotype in breast cancer

et al. 2015

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“…These processes select and support tumor cell subpopulations with distinct phenotypes in proliferation, metastatic/invasive proclivity, and treatment susceptibility that contribute to clinical outcomes. Currently, there is a paucity of biomarkers to identify these subpopulations (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Although detection of genetic heterogeneity may itself be a breast cancer (BCa) prognostic marker (3,(13)(14)(15), the phenotypes manifested from this diversity are context-dependent.…”

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confidence: 99%

Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset

Veiseh

Kwon

Borowsky

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Tumor heterogeneity confounds cancer diagnosis and the outcome of therapy, necessitating analysis of tumor cell subsets within the tumor mass. Elevated expression of hyaluronan (HA) and HA receptors, receptor for HA-mediated motility (RHAMM)/HA-mediated motility receptor and cluster designation 44 (CD44), in breast tumors correlates with poor outcome. We hypothesized that a probe for detecting HA-HA receptor interactions may reveal breast cancer (BCa) cell heterogeneity relevant to tumor progression. A fluorescent HA (F-HA) probe containing a mixture of polymer sizes typical of tumor microenvironments (10-480 kDa), multiplexed profiling, and flow cytometry were used to monitor HA binding to BCa cell lines of different molecular subtypes. Formulae were developed to quantify binding heterogeneity and to measure invasion in vivo. Two subsets exhibiting differential binding (HA −/low vs. HA high ) were isolated and characterized for morphology, growth, and invasion in culture and as xenografts in vivo. F-HA-binding amounts and degree of heterogeneity varied with BCa subtype, were highest in the malignant basal-like cell lines, and decreased upon reversion to a nonmalignant phenotype. Binding amounts correlated with CD44 and RHAMM displayed but binding heterogeneity appeared to arise from a differential ability of HA receptor-positive subpopulations to interact with F-HA. HA high subpopulations exhibited significantly higher local invasion and lung micrometastases but, unexpectedly, lower proliferation than either unsorted parental cells or the HA −/low subpopulation. Querying F-HA binding to aggressive tumor cells reveals a previously undetected form of heterogeneity that predicts invasive/metastatic behavior and that may aid both early identification of cancer patients susceptible to metastasis, and detection/therapy of invasive BCa subpopulations.tumor cell heterogeneity | hyaluronan binding | heterogeneity index B reast tumors display substantial heterogeneity driven by genetic and epigenetic mechanisms (1-3). These processes select and support tumor cell subpopulations with distinct phenotypes in proliferation, metastatic/invasive proclivity, and treatment susceptibility that contribute to clinical outcomes. Currently, there is a paucity of biomarkers to identify these subpopulations (3-12). Although detection of genetic heterogeneity may itself be a breast cancer (BCa) prognostic marker (3, 13-15), the phenotypes manifested from this diversity are context-dependent. Therefore, phenotypic markers provide additional powerful tools for biological information required to design diagnostics and therapeutics. Glycomic approaches have enormous potential for revealing tumor cell phenotypic heterogeneity because glycans are themselves highly heterogeneous and their complexity reflects the nutritional, microenvironmental, and genetic dynamics of the tumors (16-18).We used hyaluronan (HA) as a model carbohydrate ligand for probing heterogeneity in glycosaminoglycan-BCa cell receptor interactions. We reasoned this approach...

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“…Creatine kinase (Ckm) has also been detected in the mammary gland . Recently, methylated CKM has been correlated with clinical prognosis in breast cancer patients (Jeschke et al 2012). The expression of the gene encoding cytokeratin 17 was increased by G and GV in myoepithelial cells, as shown by RT-PCR and immunocytochemistry.…”

Section: Discussionmentioning

confidence: 90%

In utero and lactational exposure to vinclozolin and genistein induces genomic changes in the rat mammary gland

Saad

Toullec

Vacher

et al. 2012

Journal of Endocrinology

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Exposure to low doses of environmental estrogens such as bisphenol A and genistein (G) alters mammary gland development. The effects of environmental anti-androgens, such as the fungicide vinclozolin (V), on mammary gland morphogenesis are unknown. We previously reported that perinatal exposure to G, V, and the GV combination causes histological changes in the mammary gland during the peripubertal period, suggesting alterations to the peripubertal hormone response. We now investigate whether perinatal exposure to these compounds alters the gene expression profiles of the developing glands to identify the dysregulated signaling pathways and the underlying mechanisms. G, V, or GV (1 mg/kg body weight per day) was added to diet of Wistar rats, from conception to weaning; female offspring mammary glands were collected at postnatal days (PNDs) 35 and 50. Genes displaying differential expression and belonging to different functional categories were validated by quantitative PCR and immunocytochemistry. At PND35, G had little effect; the slight changes noted were in genes related to morphogenesis. The changes following exposure to V concerned the functional categories associated with development (Cldn1, Krt17, and Sprr1a), carbohydrate metabolism, and steroidogenesis. The GV mixture upregulated genes (Krt17, Pvalb, and Tnni2) involved in muscle development, indicating effects on myoepithelial cells during mammary gland morphogenesis. Importantly, at PND50, cycling females exposed to GV showed an increase in the expression of genes (Csn2, Wap, and Elf5) related to differentiation, consistent with the previously reported abnormal lobuloalveolar development previously described. Thus, perinatal exposure to GV alters the mammary gland hormone response differently at PND35 (puberty) and in animals with established cycles.

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Biomarkers for detection and prognosis of breast cancer identified by a functional hypermethylome screen

Abstract: (2012) Biomarkers for detection and prognosis of breast cancer identified by a functional hypermethylome screen, Epigenetics, 7:7, 701-709,

Cited by 60 publications

References 31 publications

Epigenetic silencing of neurofilament genes promotes an aggressive phenotype in breast cancer

Epigenetic silencing of neurofilament genes promotes an aggressive phenotype in breast cancer

Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset

In utero and lactational exposure to vinclozolin and genistein induces genomic changes in the rat mammary gland

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