Abstract 1508: Integration of transcriptomic and metabolomic data reveals a central role for EGR1 in regulating survival and cellular metabolism in endocrine-resistant breast cancer

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA Breast cancer is the most commonly diagnosed cancer in women. About 70% of all breast cancers are estrogen receptor alpha positive (ER+) and are treated with antiestrogens. However, endocrine resistance is prevalent in the clinic and the underlying mechanisms remain unclear. MYC is overexpressed in endocrine resistant ER+ breast cancers, which suggests that the metabolomic profile of endocrine resistant breast cancers may contain features that are distinct from sensitive cells. We integrated data from transcriptomics and metabolomics analysis of ER+ MCF7-derived breast cancer cells that are antiestrogen sensitive (LCC1) or resistant (LCC9; resistant to ICI182,780). To validate our model, we tested a gene-metabolite network associated with EGR1 (early growth response 1), which was significantly higher in LCC1 cells compared with LCC9 cells. In ER+ human breast tumors treated with endocrine therapy, higher EGR1 expression was associated with a more favorable prognosis. In both LCC1 and LCC9 cell lines, compared to respective controls, knockdown of EGR1 decreased cell proliferation, ERα and MYC protein levels while overexpression of EGR1 did not change these. Comparison of metabolite profiles in LCC9 cells following knockdown or overexpression of EGR1 showed interruption of several biochemical pathways such as glycolysis, lipid metabolism, glutathione, and polyamine metabolism. Treatment with tolfenamic acid (TOL), a nonsteroidal anti-inflammatory drug (NSAID) known to target EGR1, decreased EGR1 protein levels and had an additive effect with ICI182,780 in inhibiting cell proliferation 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, and targeting EGR1 may be an effective therapeutic approach in inhibiting growth of these tumors. Furthermore, high levels of EGR1 may serve as a favorable prognostic marker in some endocrine resistant tumors. Citation Format: Ayesha N. Shajahan-Haq, Amrita Cheema, Lu Jin, Simina Boca, Yuriy Gusev, Krithika Bhuvaneshwar, Diane Demas, Kristopher Raghavan, Subha Madhavan, Robert Clarke. Integration of transcriptomic and metabolomic data reveals a central role for EGR1 in regulating survival and cellular metabolism in endocrine-resistant breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1508.