Research Interests
The focus of my research program over the past decade has been to investigate the role of the domestic dog as a comparative biomedical model with an emphasis on the cytogenetic aspects of
cancer research. The power of a canine model for cancer research lays fundamentally in the unique demographic history of many dog breeds. Domestic dogs are organized into more than 350 phenotypically distinct genetic isolates, termed breeds, which are characterized by unique constellations of morphology, behavior, and susceptibility to naturally occurring diseases, including numerous cancers. Many breeds of dog have been developed by generations of tightly controlled breeding over a relatively short time (100-400 years), during which the restricted gene flow between breeds, combined with moderate to high levels of inbreeding, has resulted in modern dog breeds with
considerably reduced genetic heterogeneity. Genetic investigations of canine diseases may thus be conducted amongst a reduced level of the background noise that is usually associated with investigations of more heterogeneous genomes such as our own. Identifying disease-associated genes (or even gene expression patterns) in dog breeds is therefore likely to be simpler than in human populations.

Cancers in dogs occur spontaneously and so canine tumor genomes are expected to reflect the natural variety of genetic lesions that are observed in human cancer genomes, a feature that is not evident with induced rodent tumors. Furthermore, the pathophysiological similarities between naturally occurring human and dog diseases, combined with recent advances in veterinary medicine, allow the dog to be considered as an ideal second species for comparative and translational research, providing genetic resources and clinical data to fill gaps between fundamental research in rodents and human clinical studies.

Over the past decade my lab has played a pivotal role in developing the molecular cytogenetic resources that are required to support the role of the dog as a model system for genetic studies. These resources include whole chromosome paint probes, bacterial artificial chromosome (BAC) arrays for comparative genomic hybridization analysis, and genome-wide sets of locus specific genomic clones that may be used as single locus probes (SLPs) in multicolor fluorescence in situ
hybridization (FISH) analysis. My lab was responsible for using clones from the 10X coverage BAC library [http://bacpac.chori.org/canine82.htm] for anchoring regions of the emerging canine genome assembly. Following release of the canine genome assembly in late 2005 we have refined our molecular cytogenetic tools further to ensure that they are fully integrated into the assembly. For example, using the genome assembly (http://genome.ucsc.edu/cgibin/
hgGateway?clade=other&org=Dog) we selected a panel of >2,200 dog BAC clones, spaced at 1Mb intervals throughout the dog genome and have assessed each of these clones by multicolor FISH analysis to validate their use as SLPs (Thomas et al 2008). Using these clones we have produced chromosome-specific tiling panels for evaluation of cytogenetic changes in individual cancer cells and also have generated a custom BAC array. With the aid of these genome-integrated cytogenetic resources we are now evaluating numerical and structural chromosome changes in a variety of canine cancers including lymphomas, leukemias, intracranial tumors, osteosarcoma and a variety of soft tissue sarcomas.

A suitable animal model to identify diagnostic and prognostic chromosome aberrations requires the precise set of characteristics that are peculiar to the domestic dog. Specifically, dogs and humans are physiologically similar, share extensive genome homology with a high degree of preserved gene
order, are exposed to the same environmental influences and suffer from similar spontaneous cancers. The underlying hypothesis in our cancer program is that by characterizing chromosome aberrations associated with canine cancers we will identify cancer-associated genes that have thus far remained elusive in studies of human families, populations and tumors.

Of particular interest to the concept of the dog as a suitable model for cancer gene discovery, we have shown that a subset of cytogenetic changes associated with several canine tumors are
evolutionarily conserved between humans and dogs, suggesting a shared ancestral pathogenesis (Breen and Modiano, 2008; Modiano and Breen, 2008). Significantly, we have also identified
aberrant regions of the canine genome for which corresponding changes have not been reported widely in humans. Using the dog and human genome assemblies we are interrogating these regions
for the presence of cancer-associated genes, which have thus far been intractable in studies of human families and tumors.

We have identified several regions of the canine genome that become aberrant in a variety of canine cancers (listed above). Interestingly, many of these recurent aberrations have been shown to be breed specific suggestive of an inherited component. My lab has recruited over 700 patient tumor samples, representing a variety of cancers that have been used to generate tumor DNA, tumor RNA, pathology materials, primary cell cultres etc, all of which we are actively using for ongoing projects. In addition, I have established several collaborations with several major human cancer research labs, in which we are being provided human specimens and are evaluating these samples by human aCGH analysis and dog-directed cytogenetic profiling.

Recent Accomplishments and Honors
1986 Sir W. H. Tate University Undergraduate Scholarship for outstanding achievement in Science
2004 Faculty Professional Research and Development Award (NCSU).
2006 Pfizer Award for Excellence in Veterinary Research (NCSU).
2006 NCSU Alumni Outstanding Research Award
2007 Asa Mays Award for Excellence in Canine Health Research

Training
University of Liverpool, U.K. B.Sc. (Hons) 1987 Genetics
University of Liverpool, U.K. PhD 1990 Genetics/Cytogenetics
Medical Research Council, U.K. PostDoc 1990-1992 Molecular Cytogenetics

Publications
Schatzberg, S.J., Olby, N.J., Breen, M., Anderson, L.V.B., Langford, C.F., Dickens, H.F., Wilton, S.D., Zeiss, C.J.,
Binns, M.M., Kornegay, J.N.,Morris, G., Sharp, N.J.H. (1999). Molecular analysis of a spontaneous dystrophin
knockout dog. Neuromuscular Disorders 9:289-295.
Thomas, R., Breen, M., Langford, C.F., and Binns, M.M. (1999). Zoo-FISH analysis of dog chromosome 5: of conserved
synteny with human and cat chromosomes. Cytogenetics and Cell Genetics 87:4-10.
Breen, M., Bullerdiek, J and Langford, C.F. (1999). The DAPI banded karyotype of the domestic dog (Canis familiaris)
generated using chromosome specific paint probes. Chromosome Research 7:401-406.
Breen, M., Thomas, R., Binns, M.M., Carter, N.P. and Langford, C.F (1999). Reciprocal chromosome painting reveals
detailed regions of synteny between the karyotypes of the domestic dog (Canis familiaris) and human. Genomics
61:145-155.
Dunn, K.A., Thomas, R., Binns, M.M., Breen, M. (2000). Comparative Genomic Hybridisation (CGH) in Dogs -
Application to the study of a Canine Glial Tumour Cell Line. The Veterinary Journal 160: 77-82.
Thomas, R., Breen, M., Deloukas, P., Holmes, N.G. and Binns, M.M (2001). An integrated physical, comparative and
radiation-hybrid map of dog chromosome five. Mammalian Genome 12: 371-375.
Breen M., Jouquand S., Renier C., Mellersh C.S., Hitte C., Holmes N.G. et al. (2001). Chromosome-specific single locus
FISH probes allow anchorage of an 1,800 marker integrated radiation-hybrid/ linkage map of the domestic dog (Canis
familiaris) genome to all chromosomes. Genome Research 11:1784-1795.
Thomas, R., Smith, K.C., Ostrander, E.A., Galibert, F., Breen, M. (2003). Chromosome aberrations in canine multicentric
lymphomas detected with comparative genomic hybridisation and a panel of single locus probes. British Journal of
Cancer 89:1530-1537.
Lingaas, F., Comstock, K.E., Kirkness E.F., Srensen, A., Aarskaug, T., Hitte, C., Nickerson, M,L, Moe, L, Schmidt,
L.S., Thomas, R., Breen, M., Galibert, F., Zbar, B., Ostrander, E.A. A Mutation in the Canine BHD Gene is Associated
with Hereditary Multifocal Renal Cystadenocarcinoma and Nodular Dermatofibrosis in the German Shepherd Dog.
Human Molecular Genetics 12:3043-3053.
Tiret, L., Blot, S., Kessler, J.L., Gaillot, H., Breen, M., Panthier, J.J. (2003). Mapping of the cnm locus in Labrador
retrievers, a canine homologue of the human autosomal forms of the centronuclear myopathy. Human Genetics
113:297-306.
Thomas, R, Bridge, W., Benke, K., Breen, M. (2003). Isolation, characterization and chromosomal localization of 25
cancer related canine genes. Cytogenetic and Genome Research 102:249-253.
Thomas, R., Fiegler, H., Ostrander, E.A., Galibert, F., Carter, N.P., Breen, M. (2003). A canine cancer-gene microarray
for CGH analysis of canine tumors. Cytogenetic and Genome Research 102: 254-260.
Fosmire, S.P, Dickerson, E.B., Scott, A., Bianco, S.R., Pettengill, M., Meylemans, H., Padilla, M., Frazer-Abel, A. A.,
Akhtar, N., Getzy, D.M., Wojcieszyn, J., Breen, M., Helfand, S.C., Modiano, J.F. (2004). Canine malignant
hemangiosarcoma as a model of primitive angiogenic endothelium. Lab Invest 84, 562-572.
Akhtar, N, Padilla, M.L., Dickerson, E.B., Steinberg, H., Breen, M., Auerbach, R., Helfand, S.C. (2004). Interleuikin-12
inhibits tumor growth in a novel angiogenesis canine hemangiosarcoma xenograft model. Neoplasia 6, 106-116.
Breen, M., Hitte, C., Lorentzen, T., et al (2004). An integrated 4300 marker FISH/RH map of the canine genome. BMC
Genomics 6:65:1-11
Kennerly, E., Thomson, S, Olby, N., Breen, M., Gibson, G. (2004). Comparison of regional gene expression differences
ion the brains of the domestic dog and human. Human Genomics 1 (6) 435-443.
Dickerson, E.B., Thomas, R, Fosmire, S.P., Lamerato-Kozicki, A.R., Bianco, S.R., Wojcieszyn, J., Breen, M., Helfand,
S.C., Modiano. J.F. (2005) Mutations of PTEN in canine hemangiosarcoma. Vet. Pathol. 42 618-632.
Thomson, S.A., Kennerly, E., Olby, N., Mickelson, J.R., Hoffmann, D.E., Dickinson, P.J., Gibson, G., Breen. M. (2005)
Microarray analysis of differentially expressed genes of primary tumors in the canine central nervous system. J. Vet.
Path. 42 550-55
Modiano, J.F./Breen, M., Burnett, R.C., Parker, H.G., Inusah, S., Thomas, R., Avery, P.R., Lindblad-Toh, K., Ostrander,
E.A., Cutter, G.C., Avery, A.C. Distinct B and T Cell Lymphoproliferative Disease Prevalence among Dog Breeds
Indicates Heritable Risk. Cancer Research 65 (13): 5654-5661.
Thomas, R., Scott, A., Langford, C.F., Fosmire, S.P., Jubala, C.M., Lorentzen, T.D., Hitte, C., Karlsson, E.K., Kirkness,
E., Ostrander, E.A., Galibert, F., Lindblad-Toh, K, Modiano, J.F., Breen, M. (2005). Construction of a 2Mb resolution
BAC-microarray for CGH analysis of canine tumors. Genome Research 15 1831-1837.
Kerstin Lindblad-Toh, Claire M Wade, Tarjei Mikkelsen, Elinor K Karlsson, David B Jaffe, Michael C Zody, Michele
Clamp, Michael Kamal, Edward J Kulbokas III, Jean L Chang, Evan Mauceli, Xiaohui Xie, Matthew Breen, et al
(2005). Genome Sequence, Comparative Analysis and Haplotype Structure of the Domestic Dog. Nature 438: 803-819.
Modiano JF, Breen M, London CA, Avery AC. Breed Specific Canine Lymphoproliferative Diseases. In The Dog and its
Genome. Ostrander EA, Giger U, Lindblad-Toh K, eds. Cold Spring Harbor Press:Cold Spring Harbor, 2005.
Breen, M. and Thomas, R. Karyotype and Chromosomal Organization. In The Dog and its Genome. Ostrander EA, Giger
U, Lindblad-Toh K, eds. Cold Spring Harbor Press:Cold Spring Harbor, 2005.
Modiano JF and Breen M. Genetic Factors in Cancer Etiology. In Small Animal Clinical Oncology, 4th edition. Withrow
SJ and Vail DM, eds. Elsevier: New York, 2005.
Modiano JF, Breen M, Lana SE, Ehrhart N, Fosmire SP, Thomas R, Jubala CM, Lamerato-Kozicki AR, Ehrhart EJ,
Schaack J, Duke RC, Cutter GC, Bellgrau D (2006). Naturally occurring translational models for development of cancer
gene therapy. Gene Therapy and Molecular Biology 10, 31-40, 2006
Khanna C, Lindblad-Toh K, Vail D, London C, Bergman P, Barber L, Breen M, Kitchell B, McNeil E, Modiano JF,
Niemi S, Comstock K, Ostrander E, Westmoreland S, Withrow S. (2006). Dogs, cancer, translation and genomics:
a novel comparative opportunity. Nature Biotechnology 24(9):1065-1066.
Modiano JF, Breen M, Valli VEO, Wojcieszyn, J.W, Cutter, G. (2007). Predictive Value of p16 or Rb Inactivation
in a Model of Naturally Occurring Canine non-Hodgkin Lymphoma. Leukemia 21(1): 184-187.
Fosmire SP, Thomas R, Jubala CM, Smith T, Wojcieszyn J, Getzy DM, Valli VEO, Helfand SC, Cutter GC, Breen
M, Modiano JF. Inactivation of p16 cyclin-dependent kinase inhibitor in high-grade canine non-Hodgkin T cell
lymphoma. Vet Path. 44(4): 467-478.
Tarjei S. Mikkelsen, Bronwen Aken, Chris T. Amemiya, Jean L. Chang, Shannon Duke, (et al) Matthew Breen,
Paul B. Samollow, Eric S. Lander, Kerstin Lindblad-Toh. (2007). Genome of the marsupial Monodelphis
domestica reveals lineage-specific innovation in coding and non-coding sequences. Nature 447: 167-177.
Duke, S., Samallow, P., Mauceli, E., Lindblad-Toh, K., Breen, M. (2007). Cytogenetic BAC map of the genome of
Monodelphis domestica.Chromosome Research 15:3610-370.
Davidow, L.S., Breen, M., Samollow, P.B., Duke, S.E., McCarrey, J.R. and Lee, J.T. (2007). The Search for a
Marsupial XIC Reveals a Break with Vertebrate Synteny. Chromosome Research 15:137-146.
WC Kisseberth, P Nadella M Breen, R Thomas, S Duke, CE Kosarek, S Murahari, W Vernau, AC Avery, MJ
Burkhard, and TJ Rosol. (2007). A novel canine lymphoma cell line: A translational and comparative model for
lymphoma research. Leukemia Research 12:1709-1720.
Thomas, R., Duke, S. Bloom, S., Breen, T,Feiste, E., Young, A., Seiser, E., Tsai, Pei Chien, Ellis, P., Langford, C,
Karlsson, E., Mauceli, E., Lindblad-Toh, K., Breen. M. (2007). A cytogenetically characterized, genome anchored
10Mb BAC array for the domestic dog. J. Heredity 98 (5): 474-484
Breen, M. and Modiano, J. (2008). Evolutionarily Conserved Cytogenetic Changes in Hematologic Malignancies of
Dogs and Humans Man and his best friend share more than companionship. Chromosome Research 16:145-154.
Breen. M and Langford, C.F. and. (2008). Comparative Cytogenetics. In: Encyclopedia of Life Sciences. John
Wiley & Sons, Ltd: Chichester http://www.els.net/ [DOI:10.1002/9780470015902. a0005801.pub2]
Breen, M. (2008). Canine Cytogenetics from band to basepair. Cytogenetics and Genome Research (in press).
Modiano, J.F and Breen, M (2008). Shared Pathogenesis of Human and Canine Tumors - an Inextricable Link
Between Cancer and Evolution. Cancer Therapy (in press).
Thomas, R., Duke, S.E., Karlsson, E.K., Evans, A., Ellis, P., Lindblad-Toh, K., Langford, C.F. and Breen, M.
(2008). A genome assembly-integrated dog 1Mb BAC microarray: a cytogenetic resource for canine cancer studies
and comparative genomic analysis. Cytogenetics and Genome Research (in press).

E-mail: matthew_breen@ncsu.edu
Telephone: 919-513-1467
FAX: 919-513-7301
Address: NCSU Raleigh, NC

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