Identification of novel gene amplifications in breast cancer and coexistence of gene amplification with an activating mutation of PIK3CA.
To identify genetic events that characterize cancer progression, we conducted a comprehensive genetic evaluation of 161 primary breast tumors. Similar to the "mountain-and-hill" view of mutations, gene amplification also shows high- and low-frequency alterations in breast cancers. The frequently amplified genes include the well-known oncogenes ERBB2, FGFR1, MYC, CCND1, and PIK3CA, whereas other known oncogenes that are amplified, although less frequently, include CCND2, EGFR, FGFR2, and NOTCH3. More importantly, by honing in on minimally amplified regions containing three or fewer genes, we identified six new amplified genes: POLD3, IRAK4, IRX2, TBL1XR1, ASPH, and BRD4. We found that both the IRX2 and TBL1XR1 proteins showed higher expression in the malignant cell lines MCF10CA1h and MCF10CA1a than in their precursor, MCF10A, a normal immortalized mammary epithelial cell line. To study oncogenic roles of TBL1XR1, we performed knockdown experiments using a short hairpin RNA approach and found that depletion of TBL1XR1 in MCF10CA1h cells resulted in reduction of cell migration and invasion as well as suppression of tumorigenesis in mouse xenografts. Intriguingly, our mutation analysis showed the presence of activation mutations in the PIK3CA gene in a subset of tumors that also had DNA copy number increases in the PIK3CA locus, suggesting an additive effect of coexisting activating amino acid substitution and dosage increase from amplification. Our gene amplification and somatic mutation analysis of breast primary tumors provides a coherent picture of genetic events, both corroborating and novel, offering insight into the genetic underpinnings of breast cancer progression.
Kadota
Mitsutaka
M
Laboratory of Population Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
Sato
Misako
M
Duncan
Beverly
B
Ooshima
Akira
A
Yang
Howard H
HH
Diaz-Meyer
Natacha
N
Gere
Sheryl
S
Kageyama
Shun-Ichiro
S
Fukuoka
Junya
J
Nagata
Takuya
T
Tsukada
Kazuhiro
K
Dunn
Barbara K
BK
Wakefield
Lalage M
LM
Lee
Maxwell P
MP
D001483:Base Sequence; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D005784:Gene Amplification; D018628:Gene Dosage; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D009857:Oncogenes; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
D018398:Homeodomain Proteins; C501595:IRX2 protein, human; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C473691:TBL1XR1 protein, human; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human
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