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 ␤/␦ (PPAR␤/␦), 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-␤1 signals through the ERK and the phophatidylinositol-3-kinase cascades, resulting in activation of the transcription factor NF-B. In turn, NF-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␤/␦ 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 Krüppel-like factor KLF2, suggesting a tumor suppressor activity for this factor.ErbB2 (HER2/neu) is a member of the epidermal growth factor receptor (EGFR) 3 family that also includes EGFR/HER1, HER3/ErbB3, and HER4/ErbB4 (1, 2). ErbB2 is a tyrosine kinase oncogene whose amplification is evident in a large percentage of primary human breast cancers (3), and its occurrence is inversely correlated with long-term survival in human patients (4 -8). ErbB2 lacks a ligand binding domain, and it functions as a heterodimer with other members of the EGFR family that are activated by their cognate ligands heregulins (1, 2). Overexpression of ErbB2 or of ErbB2 in conjunction with other EGFRs or treatment of cells with heregulins result in uncontrolled proliferation, resistance to apoptosis, and increased motility and invasion and can lead to oncogenic transformation (9 -19). Indeed, one of the best characterized animal models of breast cancer is the TgN(MMTVneu)202Mul transgenic mouse, which displays mammary-specific amplification of ErbB2 (20, 21). In the MMTV-neu mouse model, 100% of female mice develop mammary adenocarcinomas that involve the entire epithelium in each gland with a median time for tumor progression at ϳ205 days (22). Ligand-induced heterodimerization of ErbB2 with an EGFR partner activates a complex signaling network that includes kinases such as extracellular signal-regulated kinases (ERK), phophatidylinositol-3-kinase (PI3K), mitogen-activated protein kinase, and protein kinase C (2). However, down-stream events through which heregulins, their receptors, and ...

Fatty acid binding protein 5 (FABP5) delivers ligands from the cytosol directly to the nuclear receptor PPARβ/δ and thus facilitates the ligation and enhances the transcriptional activity of the receptor. We show here that expression levels of both FABP5 and PPARβ/δ are correlated with the tumorigenic potential of prostate cancer cell lines. We show further that FABP5 comprises a direct target gene for PPARβ/δ and thus the binding protein and its cognate receptor are engaged in a positive feedback loop. The observations demonstrate that, similarly to effects observed in mammary carcinomas, activation of the FABP5/PPARβ/δ pathway induces PPARβ/δ target genes involved in cell survival and growth and enhances cell proliferation and anchorage-independent growth in prostate cancer cells. Furthermore, the data show that downregulation of either FABP5 or PPARβ/δ inhibits the growth of the highly malignant prostate cancer PC3M cells. These studies suggest that the FABP5/PPARβ/δ pathway may play a general role in facilitating tumor progression and that inhibition of the pathway may comprise a novel strategy in treatment of cancer.

Ligands that activate the nuclear receptor RXR display potent anticarcinogenic activities but the mechanisms by which these compounds inhibit carcinoma cell growth are poorly understood. While RXR can regulate gene expression due to its intrinsic ligand-activated transcription function, this receptor can also regulate transcription by functioning as a ligand-controlled DNA architectural factor. It was thus reported that apo-RXR self-associates into tetramers and that each dimer within these tetramers can separately bind to an RXR response elements. Hence, DNA-binding by RXR tetramers may bring distant genomic regions into close physical proximity. As ligand-binding induces the dissociation of RXR tetramers into dimers, can alter gene expression by modulating DNA architecture. Here we show that inhibition of mammary carcinoma cell growth by RXR ligands stem from the ability of these compounds to regulate the oligomeric state of RXR and is independent of the direct intrinsic transcriptional activity of the receptor. The data suggest that compounds that trigger dissociation of RXR tetramers may comprise a novel class of anti-carcinogenic agents.

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