Basal-like Breast cancer DNA copy number losses identify genes involved in genomic instability, response to therapy, and patient survival
Open Access
- 3 November 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Breast Cancer Research and Treatment
- Vol. 133 (3), 865-880
- https://doi.org/10.1007/s10549-011-1846-y
Abstract
Breast cancer is a heterogeneous disease with known expression-defined tumor subtypes. DNA copy number studies have suggested that tumors within gene expression subtypes share similar DNA Copy number aberrations (CNA) and that CNA can be used to further sub-divide expression classes. To gain further insights into the etiologies of the intrinsic subtypes, we classified tumors according to gene expression subtype and next identified subtype-associated CNA using a novel method called SWITCHdna, using a training set of 180 tumors and a validation set of 359 tumors. Fisher’s exact tests, Chi-square approximations, and Wilcoxon rank-sum tests were performed to evaluate differences in CNA by subtype. To assess the functional significance of loss of a specific chromosomal region, individual genes were knocked down by shRNA and drug sensitivity, and DNA repair foci assays performed. Most tumor subtypes exhibited specific CNA. The Basal-like subtype was the most distinct with common losses of the regions containing RB1, BRCA1, INPP4B, and the greatest overall genomic instability. One Basal-like subtype-associated CNA was loss of 5q11–35, which contains at least three genes important for BRCA1-dependent DNA repair (RAD17, RAD50, and RAP80); these genes were predominantly lost as a pair, or all three simultaneously. Loss of two or three of these genes was associated with significantly increased genomic instability and poor patient survival. RNAi knockdown of RAD17, or RAD17/RAD50, in immortalized human mammary epithelial cell lines caused increased sensitivity to a PARP inhibitor and carboplatin, and inhibited BRCA1 foci formation in response to DNA damage. These data suggest a possible genetic cause for genomic instability in Basal-like breast cancers and a biological rationale for the use of DNA repair inhibitor related therapeutics in this breast cancer subtype.Keywords
This publication has 49 references indexed in Scilit:
- Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancersProceedings of the National Academy of Sciences of the United States of America, 2010
- Allele-specific copy number analysis of tumorsProceedings of the National Academy of Sciences of the United States of America, 2010
- Genome remodelling in a basal-like breast cancer metastasis and xenograftNature, 2010
- Evidence that Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor that Inhibits PI3K SignalingCancer Cell, 2009
- CAMK1D amplification implicated in epithelial–mesenchymal transition in basal‐like breast cancerMolecular Oncology, 2008
- Genomic and transcriptional aberrations linked to breast cancer pathophysiologiesCancer Cell, 2006
- The COSMIC (Catalogue of Somatic Mutations in Cancer) database and websiteBritish Journal of Cancer, 2004
- Repeated observation of breast tumor subtypes in independent gene expression data setsProceedings of the National Academy of Sciences of the United States of America, 2003
- A Gene-Expression Signature as a Predictor of Survival in Breast CancerThe New England Journal of Medicine, 2002
- Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implicationsProceedings of the National Academy of Sciences of the United States of America, 2001