Oncogene-mediated metabolic gene signature predicts breast cancer outcome

Merve Aslan,En-Chi Hsu,Abel Bermudez,Robert West,Balázs Győrffy,James D Brooks,Michelle Shen,Sharon J Pitteri,Meredith West,Tanya Stoyanova,Chiyuan Amy Zhang,Meghan A Rice,Fernando J Garcia-Marques,Shiqin Liu

doi:10.1038/s41523-021-00341-6

Abstract

Breast cancer remains the second most lethal cancer among women in the United States and triple-negative breast cancer is the most aggressive subtype with limited treatment options. Trop2, a cell membrane glycoprotein, is overexpressed in almost all epithelial cancers. In this study, we demonstrate that Trop2 is overexpressed in triple-negative breast cancer (TNBC), and downregulation of Trop2 delays TNBC cell and tumor growth supporting the oncogenic role of Trop2 in breast cancer. Through proteomic profiling, we discovered a metabolic signature comprised of TALDO1, GPI, LDHA, SHMT2, and ADK proteins that were downregulated in Trop2-depleted breast cancer tumors. The identified oncogene-mediated metabolic gene signature is significantly upregulated in TNBC patients across multiple RNA-expression clinical datasets. Our study further reveals that the metabolic gene signature reliably predicts poor survival of breast cancer patients with early stages of the disease. Taken together, our study identified a new five-gene metabolic signature as an accurate predictor of breast cancer outcome.

Highlights

Breast cancer is the most common noncutaneous cancer among women and the second leading cause of cancer-associated deaths in women in the United States[1]
We further investigated the correlation of the 5-gene metabolic signature, summarized as a table from STRING analysis (Fig. 5a), with clinical outcomes to test whether this signature was associated with overall survival in early-stage breast cancer. mRNA expression levels of the 5-gene metabolic signature were analyzed in breast cancer patients with tumor stages I–III from the METABRIC dataset (Fig. 5b)
Trop[2] is elevated across epithelial cancers and commonly acts as an oncogene that promotes tumor growth and metastasis[18,19,30,31,32,33,34,35,36,37,38,39,40,41,42]. Consistent with these findings, here we demonstrate that Trop[2] protein levels are elevated in Triple-negative breast cancer (TNBC) when compared to estrogen receptor (ER)+ and human epidermal growth receptor type 2 (HER2)+ patients

Summary

INTRODUCTION

Breast cancer is the most common noncutaneous cancer among women and the second leading cause of cancer-associated deaths in women in the United States[1]. Proteomic profiling of TNBC tumors with decreased levels of Trop[2] via knockdown strategies revealed that several known oncogenic proteins and a metabolic cluster of proteins composed of TALDO1, GPI, LDHA, SHMT2, and ADK are significantly decreased. Consistent with this result, the expression levels of the identified oncogenes and five metabolic genes (TALDO1, GPI, LDHA, SHMT2, and ADK) are elevated in TNBC patients when compared to ER+ patient samples across multiple clinical datasets. The 5-gene metabolic signature (TALDO1, GPI, LDHA, SHMT2, and ADK) correlates with poor overall and disease-free survival in 12 different mRNA expression clinical datasets These findings demonstrate that the oncogene-mediated 5-gene.

RESULTS

DISCUSSION

Findings

METHODS