Abstract LB-343: Defining mechanisms of endocrine resistance in breast cancer using whole exome sequencing

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL About 70% of breast cancers are estrogen receptor positive (ER+) and current treatments target either ER activity (Tamoxifen and Fulvestrant) or the production of estrogen (aromatase inhibitors). These treatments have led to significant increases in disease-free and overall survival, but after initial response to these agents, many ER+ cancers progress to endocrine resistance. There have been several attempts to understand the molecular mechanisms that lead to acquired resistance, but a clear understanding is still lacking. We hypothesize that endocrine resistant cells in the tumor arise by acquiring compensatory somatic mutations, and that some of these driver mutations responsible for resistance are in oncogenes or tumor suppressor genes. To test this we performed whole exome sequencing on three of MCF7 breast cancer cell sublines that are resistant to either tamoxifen, fulvestrant or exemestane - drugs commonly used in the clinic to treat ER+ breast cancers. An Illumina TruSEQ adaptor-based exonic library was prepared using genomic DNA from the resistant and control cell lines, and multiplexed on an Illumina HiSeq 2000 sequencer (100bp paired-end reads). Reads were aligned to human genome build 19 using BWA, variants were called using SAMTools, somatic mutations in endocrine cell lines were determined with VarScan, and amino acid changes were annotated using ANNOVAR. We have identified several non-synonymous mutations in cancer-relevant genes and are currently working to validate these targets. Studying these genes will increase our understanding of how tumors overcome the requirement for estrogen signaling and ultimately, we hope that comparing tumor profiles of patients with endocrine resistance disease will lead to therapeutics targeted to these secondary mutational lesions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-343. doi:1538-7445.AM2012-LB-343