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Restoring Endocrine Response in Breast Cancer Cells by Inhibition of the Sphingosine Kinase-1 Signaling Pathway

Signal Transduction Laboratory (O.S., E.V., P.X.), Division of Human Immunology, Institute of Medical and Veterinary Science and Department of Medicine, University of Adelaide, South Australia 5005, Australia; and Signal Transduction Laboratory (L.W., M.A.V., P.X.), Centenary Institute and Sydney Medical School, The University of Sydney, Newtown, New South Wales 2042, Australia

Address all correspondence and requests for reprints to: Associate Professor Pu Xia, Signal Transduction Laboratory, Centenary Institute, Locked Bag No. 6, Newtown, New South Wales 2042, Australia. E-mail: p.xia{at}centenary.org.au.

We previously demonstrated that sphingosine kinase-1 (SphK1) is an important mediator in the cytoplasmic signaling of estrogens, including Ca²⁺ mobilization, ERK1/2 activation, and the epidermal growth factor receptor transactivation. Here we report for the first time that SphK1 activity is causally associated with endocrine resistance in MCF-7 human breast cancer cells. Enforced overexpression of human SphK1 in MCF-7 cells resulted in enhanced cell proliferation and resistance to tamoxifen-induced cell growth arrest and apoptosis. Tamoxifen-resistant (TamR) MCF-7 cells selected by prolonged exposure to 4-hydroxytamoxifen, exhibited higher levels in SphK1 expression and activity, compared with the control cells. Inhibition of SphK1 activity by either specific pharmaceutical inhibitors or the dominant-negative mutant SphK1^G82D restored the antiproliferative and proapoptotic effects of tamoxifen in the TamR cells. Furthermore, silencing of SphK1, but not SphK2, expression by the specific small interference RNA also restored the tamoxifen responsiveness in the TamR cells. Thus, blockade of the SphK1 signaling pathway may reprogram cellular responsiveness to tamoxifen and abrogate antiestrogen resistance in human breast cancer cells.