title: CAMK1D amplification implicated in epithelial-mesenchymal transition in basal-like breast cancer.
abstract: 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.
authors.affiliation: Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway.
authors.forename: Anna
authors.initials: A
authors.lastname: Bergamaschi
authors.forename: Young H
authors.initials: YH
authors.lastname: Kim
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Kwei
authors.forename: Yoon
authors.initials: Y
authors.lastname: La Choi
authors.forename: Melanie
authors.initials: M
authors.lastname: Bocanegra
authors.forename: Anita
authors.initials: A
authors.lastname: Langerød
authors.forename: Wonshik
authors.initials: W
authors.lastname: Han
authors.forename: Dong-Young
authors.initials: DY
authors.lastname: Noh
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.forename: Stefanie S
authors.initials: SS
authors.lastname: Jeffrey
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Pollack
mesh_terms: 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
chemical_list: C517601:CAMK1D protein, human; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1