title: High expression of sphingosine 1-phosphate receptors, S1P1 and S1P3, sphingosine kinase 1, and extracellular signal-regulated kinase-1/2 is associated with development of tamoxifen resistance in estrogen receptor-positive breast cancer patients.
abstract: Various studies in cell lines have previously demonstrated that sphingosine kinase 1 (SK1) and extracellular signal-regulated kinase 1/2 (ERK-1/2) interact in an estrogen receptor (ER)-dependent manner to influence both breast cancer cell growth and migration. A cohort of 304 ER-positive breast cancer patients was used to investigate the prognostic significance of sphingosine 1-phosphate (S1P) receptors 1, 2, and 3 (ie, S1P1, S1P2, and S1P3), SK1, and ERK-1/2 expression levels. Expression levels of both SK1 and ERK-1/2 were already available for the cohort, and S1P1, S1P2, and S1P3 levels were established by immunohistochemical analysis. High membrane S1P1 expression was associated with shorter time to recurrence (P=0.008). High cytoplasmic S1P1 and S1P3 expression levels were also associated with shorter disease-specific survival times (P=0.036 and P=0.019, respectively). Those patients with tumors that expressed high levels of both cytoplasmic SK1 and ERK-1/2 had significantly shorter recurrence times than those that expressed low levels of cytoplasmic SK1 and cytoplasmic ERK-1/2 (P=0.00008), with a difference in recurrence time of 10.5 years. Similarly, high cytoplasmic S1P1 and cytoplasmic ERK-1/2 expression levels (P=0.004) and high cytoplasmic S1P3 expression and cytoplasmic ERK-1/2 expression levels (P=0.004) were associated with shorter recurrence times. These results support a model in which the interaction between SK1, S1P1, and/or S1P3 and ERK-1/2 might drive breast cancer progression, and these findings, therefore, warrant further investigation.
authors.affiliation: Institute of Cancer, College of Medical, Veterinary and Life Sciences, Section of Surgery, Division of Cancer Studies and Molecular Pathology, Faculty of Medicine, University of Glasgow, Pathology Department, Western Infirmary, Glasgow G31 2ER, UK.
authors.forename: Carol
authors.initials: C
authors.lastname: Watson
authors.forename: Jaclyn S
authors.initials: JS
authors.lastname: Long
authors.forename: Clare
authors.initials: C
authors.lastname: Orange
authors.forename: Claire L
authors.initials: CL
authors.lastname: Tannahill
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mallon
authors.forename: Liane M
authors.initials: LM
authors.lastname: McGlynn
authors.forename: Susan
authors.initials: S
authors.lastname: Pyne
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Pyne
authors.forename: Joanne
authors.initials: J
authors.lastname: Edwards
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D015996:Survival Rate; D013629:Tamoxifen / Q000627:therapeutic use*; D000099157:Sphingosine Kinase
chemical_list: D018931:Antineoplastic Agents, Hormonal; D008246:Lysophospholipids; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017853:Phosphotransferases (Alcohol Group Acceptor); D020033:Protein Isoforms; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D013629:Tamoxifen; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate