Tamoxifen inhibits the proliferation and survival of malignant peripheral nerve sheath tumor cells via an estrogen receptor‐independent mechanism

Abstract

No effective therapies are available to patients with malignant peripheral nerve sheath tumors (MPNSTs), the most common malignancy associated with neurofibromatosis type 1 (NF1). We have found that 4‐hydroxy‐tamoxifen rapidly induces MPNST cell death at concentrations similar to those promoting breast carcinoma apoptosis while lower concentrations inhibit MPNST mitogenesis. Although MPNSTs and MPNST cell lines express estrogen receptor β(ERβ), G‐protein coupled estrogen receptor‐1 (GPER) and estrogen biosynthetic enzymes, mass spectrometric studies shows no evidence that MPNST cells secrete 17β‐estradiol. Further, exogenous 17β‐estradiol, alone or in combination with forskolin, did not stimulate MPNST mitogenesis and ablation of ERβ and GPER expression by RNA interference likewise had no effect. Tamoxifen also acts via estrogen receptor‐independent means, including inhibition of calmodulin and protein kinase C (PKC) signaling. While the broad spectrum PKC inhibitor GF109203X had no effect, calmodulin inhibitors (trifluoperazine, W‐7) recapitulated 4‐hydroxy‐tamoxifen effects on MPNST cells. We conclude that 4‐hydroxy‐tamoxifen inhibits MPNST cell proliferation and survival via an estrogen receptor‐independent mechanism that may involve calmodulin. These observations suggest that tamoxifen may be effective for the treatment of MPNSTs. Supported by NIH grants NS048353, CA122804.