Fatty Acid-binding Protein 5 and PPARβ/δ Are Critical Mediators of Epidermal Growth Factor Receptor-induced Carcinoma Cell Growth

Epidermal growth factors and their receptors (EGFRs) promote breast cancer cell proliferation and can drive tumorigenesis. However, the molecular mechanisms that mediate these effects are incompletely understood. We previously showed that mammary tumor development in the mouse model of breast cancer MMTV-neu, a model characterized by amplification of the EGFR ErbB2 in mammary tissue, correlates with a marked up-regulation of fatty acid-binding protein 5 (FABP5). FABP5 functions to deliver ligands to and enhance the transcriptional activity of the nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta), a receptor whose target genes include genes involved in cell growth and survival. We show here that in MCF-7 mammary carcinoma cells, EGFR signaling directly up-regulates the expression of FABP5. The data demonstrate that treatment of these cells with the EGFR ligand heregulin-beta 1 signals through the ERK and the phophatidylinositol-3-kinase cascades, resulting in activation of the transcription factor NF-kappa B. In turn, NF-kappa B induces the expression of FABP5 through two cognate response elements in the promoter of this gene. The observations further demonstrate that FABP5 and PPAR beta/delta are critical mediators of the ability of EGFR to enhance cell proliferation, indicating that this transcriptional pathway plays a key role in EGFR-induced tumorigenesis. Additional observations indicate that the expression of FABP5 is down-regulated by the Kruppel-like factor KLF2, suggesting a tumor suppressor activity for this factor.