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Sphingosine Kinase Transmits Estrogen Signaling in Human Breast Cancer Cells

Signal Transduction Laboratory, Division of Human Immunology, Hanson Institute, Institute of Medical and Veterinary Science and University of Adelaide, Adelaide, South Australia 5000, Australia

Address all correspondence and requests for reprints to: Pu Xia, Signal Transduction Laboratory, Division of Human Immunology, Institute of Medical and Veterinary Science, Frome Road, Adelaide, South Australia 5000, Australia. E-mail: pu.xia{at}imvs.sa.gov.au.

Current understanding of cytoplasmic signaling pathways that mediate estrogen action in human breast cancer is incomplete. Here we report that treatment with 17ß-estradiol (E₂) activates a novel signaling pathway via activation of sphingosine kinase (SphK) in MCF-7 breast cancer cells. We found that E₂ has dual actions to stimulate SphK activity, i.e. a rapid and transient activation mediated by putative membrane G protein-coupled estrogen receptors (ER) and a delayed but prolonged activation relying on the transcriptional activity of ER. The E₂-induced SphK activity consequently activates downstream signal cascades including intracellular Ca²⁺ mobilization and Erk1/2 activation. Enforced expression of human SphK type 1 gene in MCF-7 cells resulted in increases in SphK activity and cell growth. Moreover, the E₂-dependent mitogenesis were highly promoted by SphK overexpression as determined by colony growth in soft agar and solid focus formation. In contrast, expression of SphK^G82D, a dominant-negative mutant SphK, profoundly inhibited the E₂-mediated Ca²⁺ mobilization, Erk1/2 activity and neoplastic cell growth. Thus, our data suggest that SphK activation is an important cytoplasmic signaling to transduce estrogen-dependent mitogenic and carcinogenic action in human breast cancer cells.

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Ligands:   17β-Estradiol

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