Abstract B1-23: Early growth response (EGR1) is a critical regulator of cellular metabolism and predicts increased responsiveness to antiestrogens in breast cancer

Abstract

Abstract Breast cancer is the most commonly diagnosed cancer in women and about 1 million new cases per year are diagnosed worldwide. About 70% of all breast cancers are estrogen receptor alpha positive (ER+). Antiestrogens (e.g., Tamoxifen or Faslodex) or aromatase inhibitors (e.g., Letrozole) are often used to treat ER+ breast cancers. However, resistance to these therapies (endocrine resistance) is prevalent in the clinic and the underlying mechanisms remain unclear. We have recently shown that the oncogene MYC is overexpressed in ER+ breast cancer and up-regulates glucose and glutamine uptake in endocrine resistant breast cancer cells, which suggests that the metabolomic profile of endocrine resistant breast cancer cells may contain features that are distinct from sensitive cells. In this study, to identify the biochemical pathways that are differentially regulated in endocrine resistance in breast cancer cells, we have analyzed gene expression data and untargeted metabolite profiles of ER+ MCF7-derived breast cancer cells that are antiestrogen sensitive (LCC1) or antiestrogen resistant (LCC9) under basal conditions. Glycolysis and glutamine-dependent pathways were increased in endocrine resistant cells. Integration of the transcriptomics and metabolomics data predicted an essential role for a gene-metabolite network associated with early growth response (EGR1) and glutamine metabolism in endocrine resistant cells. EGR1 is an immediate-early gene induced by E2, growth factors, or stress signals, and has been reported to exhibit both tumor suppressor and promoter activities, based on cellular context. While EGR1 mediated signaling is important for the normal development of female reproductive organs, its precise role in breast cancer remains unknown. EGR1 gene expression and protein levels were significantly higher in LCC1 cells compared with LCC9 cells. Kaplan-Meier survival curves with gene expression data obtained from ER+ human breast tumors treated with endocrine therapy show that higher EGR1 expression is associated with a more favorable prognosis: GSE17705 [HR=0.38 (0.21-0.69); p=0.00083], GSE6532 (ER+ samples on GPL96 platform) [HR=0.55 (0.34-0.9); p=0.017]. In GSE20181, pre-treatment vs 90 days post-treatment comparisons show significantly increased levels of EGR1 expression (p<0.0001) only in the responder group. Interestingly, in both LCC1 and LCC9 cells, EGR1 overexpression increased ER protein levels and cell proliferation while EGR1 knockdown decreased ER protein levels and cell proliferation. Therefore, to understand the precise role of down-regulated EGR1 in regulating cellular metabolism and survival in endocrine resistance, we compared metabolite profiles in LCC9 cells following knockdown or overexpression of EGR1. Several major biochemical pathways such as glycolysis, lipid metabolism, glutathione, and polyamine metabolism were shown to be regulated by EGR1 in LCC9 cells. Collectively, these findings indicate that down-regulated EGR1 is an important regulator of the aberrant cellular metabolic pathways specific to endocrine resistance. Furthermore, high levels of EGR1 may serve as a favorable prognostic marker in endocrine treatment strategies in breast cancer. Citation Format: Ayesha N. Shajahan-Haq, Lu Jin, Amrita K. Cheema, Simina M. Boca, Yuriy Gusev, Krithika Bhuvaneshwar, Diane M. Demas, Habtom Ressom, Ryan Michalek, Xi Chen, Jianhua Xuan, Subha Madhavan, Robert Clarke. Early growth response (EGR1) is a critical regulator of cellular metabolism and predicts increased responsiveness to antiestrogens in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-23.