Basal-like Breast Cancer DNA copy number losses identify genes involved in genomic instability, response to therapy, and patient survival. Homo sapiens

Breast cancer is a heterogeneous disease with known tumor subtypes. In order to gain insight into the underlying etiologies of these disease subtypes, we first classified tumors according to gene expression intrinsic subtype, and second, identified subtype associated tumor genomic DNA copy number alterations (CNA) using a novel method called SWITCHdna. Most tumor subtypes showed specific CNA with Basal-like breast cancers being the most distinct and associated with loss of RB1, BRCA1, 5q11-35, and showed the greatest overall genomic instability. The common Basal-like CNA of loss of a segment of chromosome 5q11-35 contained at least three genes important for DNA repair (RAD17, RAD50, and RAP80), which were predominantly lost in pairs or all three simultaneously. Loss of two or three of these genes was associated with significantly increased genomic instability as defined by the absolute number of CNA, and poor patient survival . RNAi knockdown of RAD17, or RAD17 and RAD50, in an immortalized HMEC line caused increased sensitivity to a PARP inhibitor, or carboplatin. These data suggest mechanisms for genomic instability in Basal-like breast cancers and a biological rationale for the use of DNA repair inhibitor related therapeutics in this aggressive breast cancer subtype. Overall design: 324 Human breast samples by microarray (275 samples from primary sites, 35 from sites of metastasis, and 14 normal tissues). 180 Human breast tumors by aCGH (Illumina).