Tamoxifen inhibits malignant peripheral nerve sheath tumor growth in an estrogen receptor–independent manner

Few therapeutic options are available for malignant peripheral nerve sheath tumors (MPNSTs), the most common malignancy associated with neurofibromatosis type 1 (NF1). Guided by clinical observations suggesting that some NF1-associated nerve sheath tumors are hormonally responsive, we hypothesized that the selective estrogen receptor (ER) modulator tamoxifen would inhibit MPNST tumorigenesis in vitro and in vivo. To test this hypothesis, we examined tamoxifen effects on MPNST cell proliferation and survival, MPNST xenograft growth, and the mechanism by which tamoxifen impeded these processes. We found that 1–5 μM 4-hydroxy-tamoxifen induced MPNST cell death, whereas 0.01–0.1 μM 4-hydroxy-tamoxifen inhibited mitogenesis. Dermal and plexiform neurofibromas, MPNSTs, and MPNST cell lines expressed ERβ and G-protein-coupled ER-1 (GPER); MPNSTs also expressed estrogen biosynthetic enzymes. However, MPNST cells did not secrete 17β-estradiol, exogenous 17β-estradiol did not stimulate mitogenesis or rescue 4-hydroxy-tamoxifen effects on MPNST cells, and the steroidal antiestrogen ICI-182,780 did not mimic tamoxifen effects on MPNST cells. Further, ablation of ERβ and GPER had no effect on MPNST proliferation, survival, or tamoxifen sensitivity, indicating that tamoxifen acts via an ER-independent mechanism. Consistent with this hypothesis, inhibitors of calmodulin (trifluoperazine, W-7), another known tamoxifen target, recapitulated 4-hydroxy-tamoxifen effects on MPNST cells. Tamoxifen was also effective in vivo, demonstrating potent antitumor activity in mice orthotopically xenografted with human MPNST cells. We conclude that 4-hydroxy-tamoxifen inhibits MPNST cell proliferation and survival via an ER-independent mechanism. The in vivo effectiveness of tamoxifen provides a rationale for clinical trials in cases of MPNSTs

Perinatal Epidermal Growth Factor Receptor Blockade Prevents Peripheral Nerve Disruption in a Mouse Model Reminiscent of Benign World Health Organization Grade I Neurofibroma

Benign peripheral nerve tumors called neurofibromas are a major source of morbidity for patients with neurofibromatosis type 1. Some neurofibroma Schwann cells aberrantly express the epidermal growth factor receptor (EGFR). In a mouse model in which the CNPase promoter drives expression of human EGFR in Schwann cells, nerves develop hypertrophy, mast cell accumulation, collagen deposition, disruption of axon-glial interactions, characteristics of neurofibroma and are hypoalgesic. Administration of the EGFR antagonist cetuximab (IMC-C225) for 2 weeks beginning at birth in CNPase-hEGFR mice normalized all pathologies at 3 months of age as evaluated by hotplate testing or histology and by electron microscopy. Mast cell chemoattractants brain-derived neurotrophic factor, monocyte chemoattractant protein-1, and transforming growth factor-β1, which may account for mast cell accumulation and fibrosis, were reduced by cetuximab. Later treatment was much less effective. A birth to 2-week pulse of cetuximab blocked hEGFR phosphorylation and Schwann cell proliferation in perinatal mutant nerve, so CNPase-hEGFR Schwann cell numbers correlate with the cetuximab effect. A >250-fold enlarged population of EGFR(+)/p75(+) cells was detected in newborn Nf1(+/−) mouse nerves. These results suggest the existence of an EGFR(+) cell enriched in the perinatal period capable of driving complex changes characteristic of neurofibroma formation