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.