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Article ; Online: ALK-activating homologous mutations in LTK induce cellular transformation.

Roll, J Devon / Reuther, Gary W

PloS one

2012 Volume 7, Issue 2, Page(s) e31733

Abstract: Leukocyte tyrosine kinase (LTK) is a receptor tyrosine kinase reported to be overexpressed in human leukemia. Though much regarding the function of LTK remains unknown, it shares a high degree of similarity with anaplastic lymphoma kinase (ALK), which is ...

Abstract	Leukocyte tyrosine kinase (LTK) is a receptor tyrosine kinase reported to be overexpressed in human leukemia. Though much regarding the function of LTK remains unknown, it shares a high degree of similarity with anaplastic lymphoma kinase (ALK), which is found mutated in human cancer. In order to determine if LTK has transforming potential, we created two LTK mutants, F568L and R669Q, that correspond to two well-characterized activating mutations of ALK (F1174L and R1275Q). LTK-F568L, but not wildtype LTK or LTK-R669Q, transformed hematopoietic cells to cytokine independence. LTK-F568L exhibited a stronger ability to induce loss of contact inhibition and anchorage-independent growth of epithelial cells compared to LTK-R669Q, while wildtype LTK was non-transforming in the same cells. Likewise, LTK-F568L induced greater neurite outgrowth of PC12 cells than R669Q, while wildtype LTK could not. Correlating with transforming activity, LTK-F568L displayed significantly enhanced tyrosine phosphorylation compared to wildtype LTK and LTK-R668Q and induced activation of various signaling proteins including Shc, ERK and the JAK/STAT pathway. Expression of wildtype LTK or LTK-R669Q generally led to weaker activation of signaling proteins than expression of LTK-F568L, or no activation at all. Thus, mutating LTK at residue F568, and to a lesser extent at R669, activates the receptor tyrosine kinase, inducing cell signaling that results in transforming properties. These studies suggest that aberrant activation of LTK may contribute to neoplastic cell growth.
MeSH term(s)	Anaplastic Lymphoma Kinase ; Cell Transformation, Neoplastic/genetics ; Contact Inhibition ; Enzyme Activation ; Epithelial Cells ; Humans ; Mutation/physiology ; Phosphorylation ; Receptor Protein-Tyrosine Kinases/genetics ; Receptor Protein-Tyrosine Kinases/metabolism ; Signal Transduction
Chemical Substances	ALK protein, human (EC 2.7.10.1) ; Anaplastic Lymphoma Kinase (EC 2.7.10.1) ; LTK protein, human (EC 2.7.10.1) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2012-02-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0031733
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Article ; Online: CRLF2 and JAK2 in B-progenitor acute lymphoblastic leukemia: a novel association in oncogenesis.

Roll, J Devon / Reuther, Gary W

Cancer research

2010 Volume 70, Issue 19, Page(s) 7347–7352

Abstract: Expression of cytokine receptor-like factor 2 (CRLF2) has recently been shown to be upregulated as well as mutated in populations of B-progenitor acute lymphoblastic leukemia (B-ALL), including Down syndrome (DS-ALL) patients, lacking recurring ... ...

Abstract	Expression of cytokine receptor-like factor 2 (CRLF2) has recently been shown to be upregulated as well as mutated in populations of B-progenitor acute lymphoblastic leukemia (B-ALL), including Down syndrome (DS-ALL) patients, lacking recurring chromosomal translocations. Increased CRLF2 expression associates with JAK2 mutation, a combination that transforms hematopoietic cells, suggesting that mutant JAK2 and CRLF2 may cooperate to contribute to B-ALL formation. Importantly, elevated CRLF2 expression correlates with poor outcome in high-risk B-ALL patients. Therefore, CRLF2 may provide a new prognostic marker for high-risk B-ALL, and inhibition of CRLF2/JAK2 signaling may represent a therapeutic approach for this population of ALL patients.
MeSH term(s)	Animals ; Humans ; Janus Kinase 2/genetics ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Receptors, Cytokine/genetics
Chemical Substances	CRLF2 protein, human ; Receptors, Cytokine ; Janus Kinase 2 (EC 2.7.10.2)
Language	English
Publishing date	2010-08-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-10-1528
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Article ; Online: Dysregulation of the epigenome in human breast cancer: contributions of gene-specific DNA hypermethylation to breast cancer pathobiology and targeting the breast cancer methylome for improved therapy.

Sandhu, Rupninder / Roll, J Devon / Rivenbark, Ashley G / Coleman, William B

The American journal of pathology

2014 Volume 185, Issue 2, Page(s) 282–292

Abstract: Triple-negative breast cancers (including basal-like and claudin-low molecular subtypes) represent 20% to 25% of all breast cancers, but disproportionately contribute to breast cancer-associated death. We have identified a novel fundamental biological ... ...

Abstract	Triple-negative breast cancers (including basal-like and claudin-low molecular subtypes) represent 20% to 25% of all breast cancers, but disproportionately contribute to breast cancer-associated death. We have identified a novel fundamental biological property of triple-negative breast cancers: most triple-negative breast cancers express aberrant DNA hypermethylation due to overexpression of DNA methyltransferase 3b (and hyperactivity of the DNA methyltransferase enzymes). DNA methyltransferase 3b overexpression occurs secondary to loss of miRNA-mediated post-transcriptional regulation. The resulting hyperactivity of DNA methyltransferase 3b produces concurrent DNA methylation-dependent silencing of numerous critical gene targets (including tumor suppressors and pro-apoptotic genes) and resistance to cytotoxic chemotherapy. This observation presents new opportunities for development of innovative treatment strategies on the basis of the epigenome as a novel therapeutic target in triple-negative breast cancers. Epigenetic therapy represents a new principle in cancer treatment in which restoration of critical molecular pathways occurs secondary to reexpression of silenced genes that encode negative mediators of cancer cell growth.
MeSH term(s)	Apoptosis/genetics ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA (Cytosine-5-)-Methyltransferases/metabolism ; DNA Methylation ; DNA, Neoplasm/genetics ; DNA, Neoplasm/metabolism ; Drug Resistance, Neoplasm ; Epigenesis, Genetic ; Female ; Humans ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism ; DNA Methyltransferase 3B
Chemical Substances	DNA, Neoplasm ; Tumor Suppressor Proteins ; DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37)
Language	English
Publishing date	2014-12-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2014.12.003
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Article ; Online: ALK-activating homologous mutations in LTK induce cellular transformation.

J Devon Roll / Gary W Reuther

PLoS ONE, Vol 7, Iss 2, p e

2012 Volume 31733

Abstract	Leukocyte tyrosine kinase (LTK) is a receptor tyrosine kinase reported to be overexpressed in human leukemia. Though much regarding the function of LTK remains unknown, it shares a high degree of similarity with anaplastic lymphoma kinase (ALK), which is found mutated in human cancer. In order to determine if LTK has transforming potential, we created two LTK mutants, F568L and R669Q, that correspond to two well-characterized activating mutations of ALK (F1174L and R1275Q). LTK-F568L, but not wildtype LTK or LTK-R669Q, transformed hematopoietic cells to cytokine independence. LTK-F568L exhibited a stronger ability to induce loss of contact inhibition and anchorage-independent growth of epithelial cells compared to LTK-R669Q, while wildtype LTK was non-transforming in the same cells. Likewise, LTK-F568L induced greater neurite outgrowth of PC12 cells than R669Q, while wildtype LTK could not. Correlating with transforming activity, LTK-F568L displayed significantly enhanced tyrosine phosphorylation compared to wildtype LTK and LTK-R668Q and induced activation of various signaling proteins including Shc, ERK and the JAK/STAT pathway. Expression of wildtype LTK or LTK-R669Q generally led to weaker activation of signaling proteins than expression of LTK-F568L, or no activation at all. Thus, mutating LTK at residue F568, and to a lesser extent at R669, activates the receptor tyrosine kinase, inducing cell signaling that results in transforming properties. These studies suggest that aberrant activation of LTK may contribute to neoplastic cell growth.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Mutations in the transmembrane and juxtamembrane domains enhance IL27R transforming activity.

Lambert, Que T / Pradhan, Anuradha / Roll, J Devon / Reuther, Gary W

The Biochemical journal

2011 Volume 438, Issue 1, Page(s) 155–164

Abstract: Cytokines and their receptors regulate haemopoiesis by controlling cellular growth, survival and differentiation. Thus it is not surprising that mutations of cytokine receptors contribute to the formation of haemopoietic disorders, including cancer. We ... ...

Abstract	Cytokines and their receptors regulate haemopoiesis by controlling cellular growth, survival and differentiation. Thus it is not surprising that mutations of cytokine receptors contribute to the formation of haemopoietic disorders, including cancer. We recently identified transforming properties of IL27R, the ligand-binding component of the receptor for interleukin-27. Although wild-type IL27R exhibits transforming properties in haemopoietic cells, in the present study we set out to determine if the transforming activity of IL27R could be enhanced by mutation. We identified three mutations of IL27R that enhance its transforming activity. One of these mutations is a phenylalanine to cysteine mutation at residue 523 (F523C) in the transmembrane domain of the receptor. The two other mutations identified involve deletions of amino acids in the cytoplasmic juxtamembrane region of the receptor. Expression of each of these mutant IL27R proteins led to rapid cytokine-independent transformation in haemopoietic cells. Moreover, the rate of transformation induced by these mutants was significantly greater than that induced by wild-type IL27R. Expression of these IL27R mutants also induced enhanced activation of JAK (Janus kinase)/STAT (signal transducer and activator of transcription) signalling compared with wild-type. An activating deletion mutation of IL27R enhanced homodimerization of the receptor by a mechanism that may involve disulfide bonding. These transforming IL27R mutants displayed equal or greater transforming activity than bona fide haemopoietic oncogenes such as BCR-ABL (breakpoint cluster region-Abelson murine leukaemia viral oncogene homologue) and JAK2-V617F. Since IL27R is expressed on haemopoietic stem cells, lymphoid cells and myeloid cells, including acute myeloid leukaemia blast cells, mutation of this receptor has the potential to contribute to a variety of haemopoietic neoplasms.
MeSH term(s)	Amino Acid Sequence ; Animals ; Blotting, Western ; Cell Membrane ; Cell Transformation, Neoplastic ; Cells, Cultured ; Dimerization ; Flow Cytometry ; Fusion Proteins, bcr-abl/metabolism ; Humans ; Janus Kinase 1/metabolism ; Kidney/cytology ; Kidney/metabolism ; Mice ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Mutation/genetics ; Myeloid Cells/metabolism ; Myeloid Cells/pathology ; Protein Structure, Tertiary ; Receptors, Cytokine/genetics ; Receptors, Cytokine/metabolism ; Receptors, Interleukin/genetics ; Receptors, Interleukin/metabolism ; STAT Transcription Factors/metabolism ; Sequence Homology, Amino Acid
Chemical Substances	IL27RA protein, human ; Il27ra protein, mouse ; Receptors, Cytokine ; Receptors, Interleukin ; STAT Transcription Factors ; Fusion Proteins, bcr-abl (EC 2.7.10.2) ; JAK1 protein, human (EC 2.7.10.2) ; Janus Kinase 1 (EC 2.7.10.2)
Language	English
Publishing date	2011-06-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BJ20110351
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Article ; Online: DNMT3b overexpression contributes to a hypermethylator phenotype in human breast cancer cell lines.

Roll, J Devon / Rivenbark, Ashley G / Jones, Wendell D / Coleman, William B

Molecular cancer

2008 Volume 7, Page(s) 15

Abstract: Background: DNA hypermethylation events and other epimutations occur in many neoplasms, producing gene expression changes that contribute to neoplastic transformation, tumorigenesis, and tumor behavior. Some human cancers exhibit a hypermethylator ... ...

Abstract	Background: DNA hypermethylation events and other epimutations occur in many neoplasms, producing gene expression changes that contribute to neoplastic transformation, tumorigenesis, and tumor behavior. Some human cancers exhibit a hypermethylator phenotype, characterized by concurrent DNA methylation-dependent silencing of multiple genes. To determine if a hypermethylation defect occurs in breast cancer, the expression profile and promoter methylation status of methylation-sensitive genes were evaluated among breast cancer cell lines. Results: The relationship between gene expression (assessed by RT-PCR and quantitative real-time PCR), promoter methylation (assessed by methylation-specific PCR, bisulfite sequencing, and 5-aza-2'deoxycytidine treatment), and the DNA methyltransferase machinery (total DNMT activity and expression of DNMT1, DNMT3a, and DNMT3b proteins) were examined in 12 breast cancer cell lines. Unsupervised cluster analysis of the expression of 64 methylation-sensitive genes revealed two groups of cell lines that possess distinct methylation signatures: (i) hypermethylator cell lines, and (ii) low-frequency methylator cell lines. The hypermethylator cell lines are characterized by high rates of concurrent methylation of six genes (CDH1, CEACAM6, CST6, ESR1, LCN2, SCNN1A), whereas the low-frequency methylator cell lines do not methylate these genes. Hypermethylator cell lines coordinately overexpress total DNMT activity and DNMT3b protein levels compared to normal breast epithelial cells. In contrast, most low-frequency methylator cell lines possess DNMT activity and protein levels that are indistinguishable from normal. Microarray data mining identified a strong cluster of primary breast tumors that express the hypermethylation signature defined by CDH1, CEACAM6, CST6, ESR1, LCN2, and SCNN1A. This subset of breast cancers represents 18/88 (20%) tumors in the dataset analyzed, and 100% of these tumors were classified as basal-like, suggesting that the hypermethylator defect cosegregates with poor prognosis breast cancers. Conclusion: These observations combine to strongly suggest that: (a) a subset of breast cancer cell lines express a hypermethylator phenotype, (b) the hypermethylation defect in these breast cancer cell lines is related to aberrant overexpression of DNMT activity, (c) overexpression of DNMT3b protein significantly contributes to the elevated DNMT activity observed in tumor cells expressing this phenotype, and (d) the six-gene hypermethylator signature characterized in breast cancer cell lines defines a distinct cluster of primary basal-like breast cancers.
MeSH term(s)	Antimetabolites, Antineoplastic/pharmacology ; Azacitidine/pharmacology ; Breast/metabolism ; Breast/pathology ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; CpG Islands ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA (Cytosine-5-)-Methyltransferases/metabolism ; DNA Methylation ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Genes, Tumor Suppressor ; Humans ; Phenotype ; Promoter Regions, Genetic/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Cells, Cultured ; DNA Methyltransferase 3B
Chemical Substances	Antimetabolites, Antineoplastic ; DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37) ; Azacitidine (M801H13NRU)
Language	English
Publishing date	2008-01-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2091373-4
ISSN	1476-4598 ; 1476-4598
ISSN (online)	1476-4598
ISSN	1476-4598
DOI	10.1186/1476-4598-7-15
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Article ; Online: Dysregulation of the epigenome in triple-negative breast cancers: basal-like and claudin-low breast cancers express aberrant DNA hypermethylation.

Roll, J Devon / Rivenbark, Ashley G / Sandhu, Rupninder / Parker, Joel S / Jones, Wendell D / Carey, Lisa A / Livasy, Chad A / Coleman, William B

Experimental and molecular pathology

2013 Volume 95, Issue 3, Page(s) 276–287

Abstract: A subset of human breast cancer cell lines exhibits aberrant DNA hypermethylation that is characterized by hyperactivity of the DNA methyltransferase enzymes, overexpression of DNMT3b, and concurrent methylation-dependent silencing of numerous epigenetic ...

Abstract	A subset of human breast cancer cell lines exhibits aberrant DNA hypermethylation that is characterized by hyperactivity of the DNA methyltransferase enzymes, overexpression of DNMT3b, and concurrent methylation-dependent silencing of numerous epigenetic biomarker genes. The objective of this study was to determine if this aberrant DNA hypermethylation (i) is found in primary breast cancers, (ii) is associated with specific breast cancer molecular subtypes, and (iii) influences patient outcomes. Analysis of epigenetic biomarker genes (CDH1, CEACAM6, CST6, ESR1, GNA11, MUC1, MYB, SCNN1A, and TFF3) identified a gene expression signature characterized by reduced expression levels or loss of expression among a cohort of primary breast cancers. The breast cancers that express this gene expression signature are enriched for triple-negative subtypes - basal-like and claudin-low breast cancers. Methylation analysis of primary breast cancers showed extensive promoter hypermethylation of epigenetic biomarker genes among triple-negative breast cancers, compared to other breast cancer subclasses where promoter hypermethylation events were less frequent. Furthermore, triple-negative breast cancers either did not express or expressed significantly reduced levels of protein corresponding to methylation-sensitive biomarker gene products. Together, these findings suggest strongly that loss of epigenetic biomarker gene expression is frequently associated with gene promoter hypermethylation events. We propose that aberrant DNA hypermethylation is a common characteristic of triple-negative breast cancers and may represent a fundamental biological property of basal-like and claudin-low breast cancers. Kaplan-Meier analysis of relapse-free survival revealed a survival disadvantage for patients with breast cancers that exhibit aberrant DNA hypermethylation. Identification of this distinguishing trait among triple-negative breast cancers forms the basis for development of new rational therapies that target the epigenome in patients with basal-like and claudin-low breast cancers.
MeSH term(s)	Biomarkers, Tumor/genetics ; Breast/metabolism ; Breast/pathology ; DNA Methylation ; Epigenomics ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Neoplasm Recurrence, Local/genetics ; Neoplasm Recurrence, Local/mortality ; Prognosis ; Promoter Regions, Genetic/genetics ; Receptor, ErbB-2/metabolism ; Receptors, Estrogen/metabolism ; Receptors, Progesterone/metabolism ; Survival Rate ; Triple Negative Breast Neoplasms/classification ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/mortality
Chemical Substances	Biomarkers, Tumor ; Receptors, Estrogen ; Receptors, Progesterone ; Receptor, ErbB-2 (EC 2.7.10.1)
Language	English
Publishing date	2013-09-14
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article
ZDB-ID	207655-x
ISSN	1096-0945 ; 0014-4800
ISSN (online)	1096-0945
ISSN	0014-4800
DOI	10.1016/j.yexmp.2013.09.001
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Article: Dysregulation of the epigenome in triple-negative breast cancers: Basal-like and claudin-low breast cancers express aberrant DNA hypermethylation

Roll, J. Devon / Rivenbark, Ashley G / Sandhu, Rupninder / Parker, Joel S / Jones, Wendell D / Carey, Lisa A / Livasy, Chad A / Coleman, William B

Experimental and molecular pathology. 2013 Dec., v. 95, no. 3

2013

Abstract	A subset of human breast cancer cell lines exhibits aberrant DNA hypermethylation that is characterized by hyperactivity of the DNA methyltransferase enzymes, overexpression of DNMT3b, and concurrent methylation-dependent silencing of numerous epigenetic biomarker genes. The objective of this study was to determine if this aberrant DNA hypermethylation (i) is found in primary breast cancers, (ii) is associated with specific breast cancer molecular subtypes, and (iii) influences patient outcomes. Analysis of epigenetic biomarker genes (CDH1, CEACAM6, CST6, ESR1, GNA11, MUC1, MYB, SCNN1A, and TFF3) identified a gene expression signature characterized by reduced expression levels or loss of expression among a cohort of primary breast cancers. The breast cancers that express this gene expression signature are enriched for triple-negative subtypes — basal-like and claudin-low breast cancers. Methylation analysis of primary breast cancers showed extensive promoter hypermethylation of epigenetic biomarker genes among triple-negative breast cancers, compared to other breast cancer subclasses where promoter hypermethylation events were less frequent. Furthermore, triple-negative breast cancers either did not express or expressed significantly reduced levels of protein corresponding to methylation-sensitive biomarker gene products. Together, these findings suggest strongly that loss of epigenetic biomarker gene expression is frequently associated with gene promoter hypermethylation events. We propose that aberrant DNA hypermethylation is a common characteristic of triple-negative breast cancers and may represent a fundamental biological property of basal-like and claudin-low breast cancers. Kaplan–Meier analysis of relapse-free survival revealed a survival disadvantage for patients with breast cancers that exhibit aberrant DNA hypermethylation. Identification of this distinguishing trait among triple-negative breast cancers forms the basis for development of new rational therapies that target the epigenome in patients with basal-like and claudin-low breast cancers.
Keywords	DNA ; biomarkers ; breast neoplasms ; enzymes ; epigenetics ; gene overexpression ; genes ; humans ; methylation ; patients
Language	English
Dates of publication	2013-12
Size	p. 276-287.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	207655-x
ISSN	1096-0945 ; 0014-4800
ISSN (online)	1096-0945
ISSN	0014-4800
DOI	10.1016/j.yexmp.2013.09.001
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Article ; Online: DNMT3b overexpression contributes to a hypermethylator phenotype in human breast cancer cell lines

Rivenbark Ashley G / Roll J Devon / Jones Wendell D / Coleman William B

Molecular Cancer, Vol 7, Iss 1, p

2008 Volume 15

Abstract: Abstract Background DNA hypermethylation events and other epimutations occur in many neoplasms, producing gene expression changes that contribute to neoplastic transformation, tumorigenesis, and tumor behavior. Some human cancers exhibit a ... ...

Abstract	Abstract Background DNA hypermethylation events and other epimutations occur in many neoplasms, producing gene expression changes that contribute to neoplastic transformation, tumorigenesis, and tumor behavior. Some human cancers exhibit a hypermethylator phenotype, characterized by concurrent DNA methylation-dependent silencing of multiple genes. To determine if a hypermethylation defect occurs in breast cancer, the expression profile and promoter methylation status of methylation-sensitive genes were evaluated among breast cancer cell lines. Results The relationship between gene expression (assessed by RT-PCR and quantitative real-time PCR), promoter methylation (assessed by methylation-specific PCR, bisulfite sequencing, and 5-aza-2'deoxycytidine treatment), and the DNA methyltransferase machinery (total DNMT activity and expression of DNMT1, DNMT3a, and DNMT3b proteins) were examined in 12 breast cancer cell lines. Unsupervised cluster analysis of the expression of 64 methylation-sensitive genes revealed two groups of cell lines that possess distinct methylation signatures: (i) hypermethylator cell lines, and (ii) low-frequency methylator cell lines. The hypermethylator cell lines are characterized by high rates of concurrent methylation of six genes ( CDH1, CEACAM6, CST6, ESR1, LCN2, SCNN1A ), whereas the low-frequency methylator cell lines do not methylate these genes. Hypermethylator cell lines coordinately overexpress total DNMT activity and DNMT3b protein levels compared to normal breast epithelial cells. In contrast, most low-frequency methylator cell lines possess DNMT activity and protein levels that are indistinguishable from normal. Microarray data mining identified a strong cluster of primary breast tumors that express the hypermethylation signature defined by CDH1 , CEACAM6, CST6, ESR1, LCN2 , and SCNN1A . This subset of breast cancers represents 18/88 (20%) tumors in the dataset analyzed, and 100% of these tumors were classified as basal-like, suggesting that the hypermethylator defect cosegregates with poor prognosis breast cancers. Conclusion These observations combine to strongly suggest that: (a) a subset of breast cancer cell lines express a hypermethylator phenotype, (b) the hypermethylation defect in these breast cancer cell lines is related to aberrant overexpression of DNMT activity, (c) overexpression of DNMT3b protein significantly contributes to the elevated DNMT activity observed in tumor cells expressing this phenotype, and (d) the six-gene hypermethylator signature characterized in breast cancer cell lines defines a distinct cluster of primary basal-like breast cancers.
Keywords	Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	616 ; 570
Language	English
Publishing date	2008-01-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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