Abstract 2324: A novel oncogene mediated metabolic gene signature predicts breast cancer outcome

Abstract

Abstract Introduction and Objectives: Breast cancer remains the second most lethal cancer among women in the US, with triple negative breast cancer (TNBC) as the most aggressive subtype with limited treatment options. Trop2, a cell membrane glycoprotein, is overexpressed nearly all epithelial cancers including triple negative breast cancer. In this study, we demonstrate that loss of Trop2 derives downregulation of metabolic genes. Trop2 oncogene-driven metabolic gene signature is highly elevated in breast cancer patients and predicts poor outcome. Methods: Trop2 expression levels in two independent patient cohorts were analyzed with immunohistochemistry. Trop2 was knockdown in TNBC cell line HCC1806 with shRNA and knock-out in HCC1806 with CRISPR Cas9 system. Trop2 downregulation or gene deletion effect was tested in vitro with colony formation and 3D Matrigel invasion assays. The effect of Trop2 downregulation in tumorigenesis was evaluated in vivo by subcutaneous implantation of control and Trop2 knockdown xenografts. Proteomic changes were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Trop2 led to downregulation of TALDO1 associated metabolic cluster genes which expression levels were further investigated in four independent breast cancer cohort. Finally, the correlation of Trop2 oncogene-driven metabolic gene signature with breast cancer outcome was analyzed in 13 independent breast cancer patient datasets. Results: We demonstrate Trop2 is overexpressed in TNBC, and downregulation of Trop2 disrupts TNBC cell and tumor growth. Through whole proteomic profiling, we discovered a novel metabolic cluster that was downregulated in Trop2-depleted breast cancer tumors. The identified oncogene-driven metabolic gene signature is significantly upregulated in TNBC patients across multiple clinical datasets. Our study further reveals that the metabolic gene signature reliably predicts poor survival of breast cancer patients with early stage of the disease. Conclusion: Our study identifies a new five gene metabolic oncogene-driven signature as a prognostic predictor of breast cancer. Citation Format: Merve Aslan, En-Chi Hsu, Fernando J. Garcia Marques, Abel Bermudez, Michelle Shen, Meghan A. Rice, Shiqin Liu, Robert West, Sharon J. Pitteri, Balázs Győrffy, Tanya Stoyanova. A novel oncogene mediated metabolic gene signature predicts breast cancer outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2324.