Genetic Ablation of the Fatty Acid–Binding Protein FABP5 Suppresses HER2-Induced Mammary Tumorigenesis

Abstract

The fatty acid binding protein FABP5 shuttles ligands from the cytosol to the nuclear receptor PPARβ/δ (encoded for by Pparδ), thereby enhancing the transcriptional activity of the receptor. This FABP5/PPARδ pathway is critical for induction of proliferation of breast carcinoma cells by activated EGFR. In this study, we show that FABP5 is highly upregulated in human breast cancers and we provide genetic evidence of the pathophysiological significance of FABP5 in mammary tumorigenesis. Ectopic expression of FABP5 was found to be oncogenic in 3T3 fibroblasts where it augmented the ability of PPARδ to enhance cell proliferation, migration and invasion. To determine whether FABP5 was essential for EGFR-induced mammary tumor growth, we interbred FABP5-null mice with MMTV-ErbB2/HER2 oncomice which spontaneously develop mammary tumors. FABP5 ablation relieved activation of EGFR downstream effector signals, decreased expression of PPARδ target genes that drive cell proliferation, and suppressed mammary tumor development. Our findings establish that FABP5 is critical for mammary tumor development, rationalizing the development of FABP5 inhibitors as novel anticarcinogenic drugs.

Structural Basis for Ligand Regulation of the Fatty Acid-binding Protein 5, Peroxisome Proliferator-activated Receptor β/δ (FABP5-PPARβ/δ) Signaling Pathway

“…Although FABP-bound fatty acid tail mobility has been noted previously via x-ray crystallography (75), our delineation of an active U-conformation versus inactive L-conformer opens up exciting new possibilities for structure-based drug design. The overexpression of FABP5 has been linked to insulin resistance (26), and its signaling is related to cancer cell survival (25), proliferation (29,32), and metastasis (31,33), making the protein an ideal candidate for antagonist development. Theoretically, such compounds could exert their influence via one of several mechanisms of action.…”

Fatty acid binding proteins

“…The role of FABPs in regulating cell proliferation is also seen with FABP5, where levels are up-regulated in breast tumours, promoting proliferation and metastatis in cultured cells, most likely through interactions with PPAR (37). A link between FABP5 and the immune system has also been recently demonstrated in a study investigating the response of lung epithelial cells to infection by influenza virus.…”

Proteomic profiling reveals candidate markers for arsenic-induced skin keratosis

“…The molecular pathogenesis of keratins in skin disorders needs to be further elucidated. The fatty acidbinding protein 5, which was first identified in human epidermal cells, is upregulated in a number of human cancers, including those of prostate (Adamson et al, 2003), bladder (Chen et al, 2011), breast (Levi et al, 2013) and esophagus (Ogawa et al, 2008). Although the mechanisms underlying the upregulation of FABP5 in cancers are incompletely understood, previous studies suggest that FABP5 may promote tumor development.…”