Materials and methods We refer to Supplementary Methods in Additional file 3 for a detailed description of the therapeutic compound response data, molecular data for the breast cancer cell lines, molecular data for the external breast cancer tumor samples used for validation, classification methods, data integration approach, statistical methods, pathway overrep resentation analysis, and the patient response prediction toolbox for the R project for statistical computing. Data and code deposition Genome copy number data have been deposited at the European Genome phenome Archive , hosted at the EBI. Gene expression data for the cell lines were derived from Affymetrix GeneChip Human Genome U133A and Affymetrix GeneChip Human Exon 1. 0 ST arrays. Raw data are available in ArrayExpress, hosted at the EBI.

RNAseq and exome seq data can be accessed at the GEO, accession number GSE48216. Genome wide methylation data for the cell lines are also available through GEO, accession number GSE42944. Software and data for treatment response prediction are available on Synapse. The software has also been deposited at GitHub. The raw drug response data are available as Additional file 9. Introduction About 80% of primary breast cancer is estrogen receptor alpha positive and proliferates in response to estrogen. E mediates its effect by binding to ER, which in turn regulates transcription of target genes con trolling proliferation and cell survival. Clinically, patients are treated with endocrine agents such as tamoxifen, which competes with E for the ER or aromatase inhibi tors, which block the conversion of androgens to E.

The most effective approach in postmenopausal patients is with AIs, but, as with other treatments, resistance to these agents develops in Brefeldin_A many cases. Studies in model systems indicate that this resistance may often depend on the acquisition of enhanced cross talk between ER and growth factor pathways that allows the disease to cir cumvent the need for steroid hormones. In BC, the PI3K/AKT pathway modulates responses to signals, communicated through the ER and the HER family of receptors. This pathway is important in the clinical sensitivity of BC to antiendocrine therapy. In vitro studies have implicated AKT in the ligand independent phosphorylation of the ER and subsequent resistance to tamoxifen. Similarly, elevated levels of AKT have been shown to change the genome wide binding pattern of ER, effectively altering the ER program. These data suggest that signaling partners downstream of PI3K/AKT may pro vide potential therapeutic targets. One rational possibility is mTOR, which exists in mammalian cells as two protein complexes. mTORC1 and mTORC2.