EGR1 regulates cellular metabolism and survival in endocrine resistant breast cancer

Ayesha N. Shajahan-Haq, Simina M. Boca, Lu Jin, Krithika Bhuvaneshwar, Yuriy Gusev, Amrita K. Cheema, Diane D. Demas, Kristopher S. Raghavan, Ryan Michalek, Subha Madhavan, Robert Clarke

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)96865-96884
Number of pages20
JournalOncotarget
Volume8
Issue number57
DOIs
StatePublished - 2017
Externally publishedYes

Bibliographical note

Funding Information:
This work was partly supported by Public Health Service grants U54-CA149147 and U01-CA184902 to RC and R01CA201092 to ANSH. Technical services were provided by the following shared resources at Georgetown University Medical Center: Genomics and Epigenomics, Metabolomics, Flow Cytometry and Tissue Culture Core Shared Resources that were funded through Public Health Service award 1P30-CA-51008 (Lombardi Comprehensive Cancer Center Support Grant).

Publisher Copyright:
© Shajahan-Haq et al.

Keywords

  • Breast cancer
  • Endocrine resistance
  • Metabolomics
  • Transcriptomics

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