FOXF2 differentially regulates expression of metabolic genes in non-cancerous and cancerous breast epithelial cells.

Pang-Kuo Lo

doi:10.15761/tdm.1000103

Abstract

Forkhead box F2 (FOXF2) functions as a transcription factor and is critically involved in programming organogenesis and regulating epithelial-to-mesenchymal transition (EMT) and cell proliferation. We recently have revealed that FOXF2 can exert distinct functional effects on different molecular subtypes of breast cancer. We found that FOXF2 expression is epigenetically silenced in luminal breast cancers due to its tumor-suppressive role in DNA replication regulation. In contrast, FOXF2 is overexpressed in basal-like triple-negative breast cancers (TNBCs) due to its oncogenic role in promoting EMT. Although our and other studies have shown that FOXF2 dysregulation is critical for tumorigenesis of various tissue types, the role of FOXF2 in metabolic rewiring of cancer remains unknown. In this study, we analyzed our previous microarray data to understand the metabolic role of FOXF2 in non-cancerous and cancerous breast epithelial cells. Our studies showed that in non-cancerous breast epithelial cells FOXF2 can also play a dual role either in tumor suppression or in tumor promotion through regulating expression of tumor-suppressive and oncogenic metabolic genes. Furthermore, we found that FOXF2-regulated metabolic genes are not conserved between non-cancerous and cancerous breast epithelial cells and FOXF2 is involved in metabolic rewiring in breast cancer cells. This is the first report to explore the metabolic function of FOXF2 in breast cancer.

Highlights

Metabolic reprogramming has been recognized as a hallmark of cancer due to its critical role in tumorigenesis [1]
We observed that non-cancerous breast epithelial and basal-like triple-negative breast cancers (TNBCs) cells displayed distinct Forkhead box F2 (FOXF2)-regulated metabolic gene expression signatures, indicating that FOXF2 has different metabolic roles in noncancerous and cancerous breast epithelial cells
Due to the critical role of metabolic rewiring in cancer development, identification of molecular regulators involved in this event is crucial for understanding of cancer metabolism and developing novel therapeutic medicine targeting metabolic vulnerabilities in cancer cells

Summary

Introduction

Metabolic reprogramming has been recognized as a hallmark of cancer due to its critical role in tumorigenesis [1]. Due to the development of microarray technology, genome-wide gene expression profiling has been exploited to molecularly classify heterogeneous breast cancers into at least five subtypes, including normal breast-like, luminal A (ER+ and/or PR ± HER2– with a low Ki67 index), luminal B (ER+ and/or PR ± HER2+ or HER2– with a high Ki67 index), HER2positive (ER–/PR–/HER2+) and basal-like/triple negative (ER–/PR–/ HER2–) [2,3]. Among these molecular subtypes, basal-like triplenegative breast cancer (TNBC), characterized by its lack of ER, PR and HER2, is aggressive and lacks targeted therapies [3]. TNBCs and HER2-positive breast cancers manifest higher glycolytic activity (Warburg effect) and glutamine metabolism compared to luminal breast cancers

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