EGR1 regulates cellular metabolism and survival in endocrine resistant breast cancer
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Ayesha N. Shajahan-Haq1, Simina M. Boca1,2,3,*, Lu Jin1,*, Krithika Bhuvaneshwar1,2,*, Yuriy Gusev1,2, Amrita K. Cheema1, Diane D. Demas1, Kristopher S. Raghavan1, Ryan Michalek4, Subha Madhavan1,2 and Robert Clarke1
1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
2Innovation Center for Biomedical Informatics (ICBI), Georgetown University Medical Center, Washington, DC, USA
3Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown University, Washington, DC, USA
4Metabolon, Inc, Durham, NC, USA
*These authors contributed equally to this work
Ayesha N. Shajahan-Haq, email: firstname.lastname@example.org
Keywords: breast cancer, endocrine resistance, transcriptomics, metabolomics
Received: October 26, 2016 Accepted: May 17, 2017 Published: May 30, 2017
About 70% of all breast cancers are estrogen receptor alpha positive (ER+; ESR1). Many are treated with antiestrogens. Unfortunately, de novo and acquired resistance to antiestrogens is common but the underlying mechanisms remain unclear. Since growth of cancer cells is dependent on adequate energy and metabolites, the metabolomic profile of endocrine resistant breast cancers likely contains features that are deterministic of cell fate. Thus, we integrated data from metabolomic and transcriptomic analyses of ER+ MCF7-derived breast cancer cells that are antiestrogen sensitive (LCC1) or resistant (LCC9) that resulted in a gene-metabolite network associated with EGR1 (early growth response 1). In human ER+ breast tumors treated with endocrine therapy, higher EGR1 expression was associated with a more favorable prognosis. Mechanistic studies showed that knockdown of EGR1 inhibited cell growth in both cells and EGR1 overexpression did not affect antiestrogen sensitivity. Comparing metabolite profiles in LCC9 cells following perturbation of EGR1 showed interruption of lipid metabolism. Tolfenamic acid, an anti-inflammatory drug, decreased EGR1 protein levels and synergized with antiestrogens in inhibiting cell proliferation in LCC9 cells. Collectively, these findings indicate that EGR1 is an important regulator of breast cancer cell metabolism and is a promising target to prevent or reverse endocrine resistance.
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