Abstract 4169: ERK2 functional chromatin footprints in patient-derived breast tumor cells predict molecular subtype, clinical outcome, and drug response in breast cancers
Authors: Madak-Erdogan Zeynep , El-Ashry Dorraya , Katzenellenbogen Benita S. 
Published: May 2015

Abstract
Increased MAPK pathway activity is a major hallmark of acquired resistance of breast cancers to therapies and disease recurrence, and this oncogenic pathway is targeted in the clinic using MEK inhibitors. However, designing combination therapies is a challenge due to variability in the expression of potential partners of these kinases in different tumor types. For example, we have shown previously in ERα(+) breast cancer cell lines that ERK2 localization to chromatin was dictated by ERα, and that it marked those genes associated with ERα signaling (Madak-Erdogan et al., Mol Cell Biol 31:226-236, 2011). In this study, we hypothesized that in different subtypes of ERα(-) breast tumors, ERK2 might be partnering with different transcription factors, thereby regulating the signaling pathways that control the phenotype of that particular tumor subtype. Furthermore, by identifying new cellular and molecular mechanisms leading to the development of resistance to therapies in specific tumor subtypes, it might be possible to develop combination therapies to improve the clinical effectiveness of treatments of these subtypes. Toward this goal, we obtained ERK2 cistrome information (by ChIP-Seq) from our previously established dissociated primary breast tumor cultures. These cultures represented several different breast cancer subtypes, including Her2 enriched, triple negative (basal), triple negative (Luminal B like), triple negative (claudin low) and triple negative (basal epithelial). We found that tumor-type specific “ERK2 Functional Chromatin Footprints” marked those genes that delineated the subtype of the tumor as well as patient clinical outcome, based on Oncomine and TCGA datasets. In addition, transcription factor binding motif enrichment analysis identified new partners and potential druggable targets for chromatin-associated ERK2. Comparison of the ERK2 cistrome revealed Hedgehog and NRF1 signaling pathways as major pathways associated with MAPK activity in the different tumor subtypes. We then tested several inhibitors targeting these pathways and showed that ERK2 occupancy indeed predicted response to these therapies in different tumors. Our studies reveal that monitoring MAPK activity on chromatin is predictive of patient outcome and tumor response to different therapies. This systems approach can be used to precisely identify the subtype of the tumor, predict outcome, and design personalized therapies, based on the functional partners of ERK2 in a particular breast tumor subtype.
(Supported by grants from The Breast Cancer Research Foundation (BSK), NIH P50 AT006268 (BSK), NIH R01 CA113674 (DEA), and Bankhead Coley Cancer Research Challenge Grant 09BW-04 (DEA))
Citation Format: Zeynep Madak-Erdogan, Dorraya El-Ashry, Benita S. Katzenellenbogen. ERK2 functional chromatin footprints in patient-derived breast tumor cells predict molecular subtype, clinical outcome, and drug response in breast cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4169. doi:10.1158/1538-7445.AM2014-4169