TY - JOUR
T1 - EGR1 regulates cellular metabolism and survival in endocrine resistant breast cancer
AU - Shajahan-Haq, Ayesha N.
AU - Boca, Simina M.
AU - Jin, Lu
AU - Bhuvaneshwar, Krithika
AU - Gusev, Yuriy
AU - Cheema, Amrita K.
AU - Demas, Diane D.
AU - Raghavan, Kristopher S.
AU - Michalek, Ryan
AU - Madhavan, Subha
AU - Clarke, Robert
N1 - Publisher Copyright:
© Shajahan-Haq et al.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Breast cancer
KW - Endocrine resistance
KW - Metabolomics
KW - Transcriptomics
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U2 - 10.18632/oncotarget.18292
DO - 10.18632/oncotarget.18292
M3 - Article
C2 - 29228577
AN - SCOPUS:85029489638
SN - 1949-2553
VL - 8
SP - 96865
EP - 96884
JO - Oncotarget
JF - Oncotarget
IS - 57
ER -