CAMK1D amplification implicated in epithelial-mesenchymal transition in basal-like breast cancer.
Breast cancer exhibits clinical and molecular heterogeneity, where expression profiling studies have identified five major molecular subtypes. The basal-like subtype, expressing basal epithelial markers and negative for estrogen receptor (ER), progesterone receptor (PR) and HER2, is associated with higher overall levels of DNA copy number alteration (CNA), specific CNAs (like gain on chromosome 10p), and poor prognosis. Discovering the molecular genetic basis of tumor subtypes may provide new opportunities for therapy. To identify the driver oncogene on 10p associated with basal-like tumors, we analyzed genomic profiles of 172 breast carcinomas. The smallest shared region of gain spanned just seven genes at 10p13, including calcium/calmodulin-dependent protein kinase ID (CAMK1D), functioning in intracellular signaling but not previously linked to cancer. By microarray, CAMK1D was overexpressed when amplified, and by immunohistochemistry exhibited elevated expression in invasive carcinomas compared to carcinoma in situ. Engineered overexpression of CAMK1D in non-tumorigenic breast epithelial cells led to increased cell proliferation, and molecular and phenotypic alterations indicative of epithelial-mesenchymal transition (EMT), including loss of cell-cell adhesions and increased cell migration and invasion. Our findings identify CAMK1D as a novel amplified oncogene linked to EMT in breast cancer, and as a potential therapeutic target with particular relevance to clinically unfavorable basal-like tumors.
Bergamaschi
Anna
A
Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway.
Kim
Young H
YH
Kwei
Kevin A
KA
La Choi
Yoon
Y
Bocanegra
Melanie
M
Langerød
Anita
A
Han
Wonshik
W
Noh
Dong-Young
DY
Huntsman
David G
DG
Jeffrey
Stefanie S
SS
Børresen-Dale
Anne-Lise
AL
Pollack
Jonathan R
JR
D001943:Breast Neoplasms / Q000473:pathology*; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000032:analysis / Q000235:genetics*; D002448:Cell Adhesion / Q000235:genetics; D049109:Cell Proliferation; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D004847:Epithelial Cells / Q000473:pathology*; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D059630:Mesenchymal Stem Cells / Q000145:classification / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis
C517601:CAMK1D protein, human; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1