Targets of genome copy number reduction in primary breast cancers identified by integrative genomics.
The identification of specific oncogenes and tumor suppressor genes in regions of recurrent aneuploidy is a major challenge of molecular cancer research. Using both oligonucleotide single-nucleotide polymorphism and mRNA expression arrays, we integrated genomic and transcriptional information to identify and prioritize candidate cancer genes in regions of increased and decreased chromosomal copy number in a cohort of primary breast cancers. Confirming the validity of this approach, several regions of previously-known copy number (CN) alterations in breast cancer could be successfully reidentified. Focusing on regions of decreased CN, we defined a prioritized list of eighteen candidate genes, which included ARPIN, FBN1, and LZTS1, previously shown to be associated with cancers in breast or other tissue types, and novel genes such as P29, MORF4L1, and TBC1D5. One such gene, the RUNX3 transcription factor, was selected for further study. We show that RUNX3 is present at reduced CNs in proportion to the rest of the tumor genome and that RUNX3 CN reductions can also be observed in a breast cancer series from a different center. Using tissue microarrays, we demonstrate in an independent cohort of over 120 breast tissues that RUNX3 protein is expressed in normal breast epithelium but not fat and stromal tissue, and widely down-regulated in the majority of breast cancers (>85%). In vitro, RUNX3 overexpression suppressed the invasive potential of MDA-MB-231 breast cancer cells in a matrigel assay. Our results demonstrate the utility of integrative genomic approaches to identify novel potential cancer-related genes in primary tumors. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.
Chen
Wei
W
Agenica Research, Singapore 169610, Republic of Singapore.
Salto-Tellez
Manuel
M
Palanisamy
Nallasivam
N
Ganesan
Kumaresan
K
Hou
Qingsong
Q
Tan
Lay Keng
LK
Sii
Lang Hiong
LH
Ito
Kosei
K
Tan
Benita
B
Wu
Jeanie
J
Tay
Andrew
A
Tan
Kok Chai
KC
Ang
Erik
E
Tan
Bien Keem
BK
Tan
Puay Hoon
PH
Ito
Yoshiaki
Y
Tan
Patrick
P
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D052138:Genes, Neoplasm; D016147:Genes, Tumor Suppressor; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism
D050677:Core Binding Factor Alpha 3 Subunit; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C493729:Runx3 protein, human