Abstract
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.
Highlights
Resistance to endocrine therapy is a major clinical problem for the management of estrogen receptor positive (ER+) breast cancers
Comparing LCC1 and LCC9 cell lines yielded 4,010 unique differentially expressed genes (DEGs), 46 unique m/z values for metabolites from the Metabolomics Shared Resources Core (MSRC) analysis conducted at Georgetown University Medical Center and 12 identified metabolites from the Metabolon analysis at an false discovery rate (FDR) threshold of 0.01 for the first two analyses, respectively; 0.05 for the third analysis. (Figure 1A and 1B)
Silencing of early growth response 1 (EGR1) was accompanied by high levels of glycerol and multiple monoacylglycerols such as 1-myristoylglycerol that may reflect an increase in complex lipid hydrolysis
Summary
Resistance to endocrine therapy is a major clinical problem for the management of estrogen receptor positive (ER+) breast cancers. ER+ tumors comprise 70% of all breast cancer cases. Antiestrogens such as tamoxifen, ICI 182,780/faslodex/fulvestrant (ICI) or aromatase inhibitors (AI) are widely used endocrine therapies but little is known about the complex cellular pathways that contribute to resistance [1, 2]. Deregulation of metabolic pathways regulated by oncogenes such as MYC has been implicated in endocrine resistant breast cancer [3,4,5]. Within our genemetabolite integrated model, we selected to further study the role of EGR1 (early growth response 1), a gene that is known to be deregulated in some cancers [6]
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