Genetic deletion of sphingosine kinase 1 suppresses mouse breast tumor development in an HER2 transgenic model

Aberrant sphingolipid metabolism has been reported to promote breast cancer progression. Sphingosine kinase 1 (SphK1) is a key metabolic enzyme for the formation of pro-survival S1P from pro-apoptotic ceramide. The role of SphK1 in breast cancer has been well studied in estrogen receptor (ER)-positive breast cancer; however, its role in human epidermal growth factor 2 (HER2)-positive breast cancer remains unclear. Here, we show that genetic deletion of SphK1 significantly reduced mammary tumor development with reduced tumor incidence and multiplicity in the MMTV-neu transgenic mouse model. Gene expression analysis revealed significant reduction of claudin-2 (CLDN2) expression in tumors from SphK1 deficient mice, suggesting that CLDN2 may mediate SphK1's function. It is remarkable that SphK1 deficiency in HER2-positive breast cancer model inhibited tumor formation by the different mechanism from ER-positive breast cancer. In vitro experiments demonstrated that overexpression of SphK1 in ER-/PR-/HER2+ human breast cancer cells enhanced cell proliferation, colony formation, migration and invasion. Furthermore, immunostaining of SphK1 and CLDN2 in HER2-positive human breast tumors revealed a correlation in high-grade disease. Taken together, these findings suggest that SphK1 may play a pivotal role in HER2-positive breast carcinogenesis. Targeting SphK1 may represent a novel approach for HER2-positive breast cancer chemoprevention and/or treatment.

[1]  R. Schiff,et al.  Targeting HER2 for the treatment of breast cancer. , 2015, Annual review of medicine.

[2]  S. Goodison,et al.  Angiogenin promotes tumoral growth and angiogenesis by regulating matrix metallopeptidase-2 expression via the ERK1/2 pathway , 2014, Oncogene.

[3]  Mårten Fernö,et al.  Claudin‐2 is an independent negative prognostic factor in breast cancer and specifically predicts early liver recurrences , 2014, Molecular oncology.

[4]  S. Goodison,et al.  Targeting Plasminogen Activator Inhibitor-1 Inhibits Angiogenesis and Tumor Growth in a Human Cancer Xenograft Model , 2013, Molecular Cancer Therapeutics.

[5]  H. Furuya,et al.  The Impact of Sphingosine Kinase-1 in Head and Neck Cancer , 2013, Biomolecules.

[6]  Y. Hannun,et al.  Effect of sphingosine kinase 1 inhibition on blood pressure , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[7]  R. O'Regan,et al.  The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy , 2012, Chemotherapy research and practice.

[8]  E. Mallon,et al.  Expression of sphingosine 1-phosphate receptor 4 and sphingosine kinase 1 is associated with outcome in oestrogen receptor negative breast cancer , 2012, British Journal of Cancer.

[9]  A. Ikari,et al.  Increase in claudin-2 expression by an EGFR/MEK/ERK/c-Fos pathway in lung adenocarcinoma A549 cells. , 2012, Biochimica et biophysica acta.

[10]  Z. Dong,et al.  Claudin-2 Promotes Breast Cancer Liver Metastasis by Facilitating Tumor Cell Interactions with Hepatocytes , 2012, Molecular and Cellular Biology.

[11]  H. Furuya,et al.  Sphingolipids in cancer , 2011, Cancer and Metastasis Reviews.

[12]  J. Jung,et al.  The expression of claudin-1, claudin-2, claudin-3, and claudin-4 in gastric cancer tissue. , 2011, The Journal of surgical research.

[13]  P. Schirmacher,et al.  Claudins and tricellulin in fibrolamellar hepatocellular carcinoma , 2011, Virchows Archiv.

[14]  X. Chen,et al.  Claudin-2 Expression Increases Tumorigenicity of Colon Cancer Cells: Role of Epidermal Growth Factor Receptor Activation , 2011, Oncogene.

[15]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[16]  Jonathan Chernoff,et al.  Faculty Opinions recommendation of COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. , 2011 .

[17]  Y. Hannun,et al.  A Role of Sphingosine Kinase 1 in Head and Neck Carcinogenesis , 2011, Cancer Prevention Research.

[18]  Marc Vidal,et al.  COT/MAP3K8 drives resistance to RAF inhibition through MAP kinase pathway reactivation , 2010, Nature.

[19]  Y. Fujiwara,et al.  Sphingosine 1-Phosphate Receptor 4 Uses HER2 (ERBB2) to Regulate Extracellular Signal Regulated Kinase-1/2 in MDA-MB-453 Breast Cancer Cells* , 2010, The Journal of Biological Chemistry.

[20]  R. Schiff,et al.  Sphingosine Kinase 1 Induces Tolerance to Human Epidermal Growth Factor Receptor 2 and Prevents Formation of a Migratory Phenotype in Response to Sphingosine 1-Phosphate in Estrogen Receptor-Positive Breast Cancer Cells , 2010, Molecular and Cellular Biology.

[21]  Y. Hannun,et al.  Role for sphingosine kinase 1 in colon carcinogenesis , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[22]  T. Karn,et al.  Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer , 2008, Breast Cancer Research and Treatment.

[23]  G. Kim,et al.  Down‐regulation of claudin‐2 in breast carcinomas is associated with advanced disease , 2008, Histopathology.

[24]  Yusuf A. Hannun,et al.  Principles of bioactive lipid signalling: lessons from sphingolipids , 2008, Nature Reviews Molecular Cell Biology.

[25]  S. Milstien,et al.  Autocrine and paracrine roles of sphingosine-1-phosphate , 2007, Trends in Endocrinology & Metabolism.

[26]  Robert D. Cardiff,et al.  Insights from transgenic mouse models of ERBB2-induced breast cancer , 2007, Nature Reviews Cancer.

[27]  J. Mackey,et al.  Prognostic significance of human epidermal growth factor receptor positivity for the development of brain metastasis after newly diagnosed breast cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  S. Milstien,et al.  Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. , 2006, Biochimica et biophysica acta.

[29]  Korey R. Johnson,et al.  ©2005 FASEB The FASEB Journal express article 10.1096/fj.05-4331fje. Published online November 30, 2005. Sphingosine kinase 1 is up-regulated in colon carcinogenesis , 2022 .

[30]  Y. Soini.  Expression of claudins 1, 2, 3, 4, 5 and 7 in various types of tumours , 2005, Histopathology.

[31]  R. Proia,et al.  Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720* , 2004, Journal of Biological Chemistry.

[32]  Y. Soini.  Claudins 2, 3, 4, and 5 in Paget's disease and breast carcinoma. , 2004, Human pathology.

[33]  J. P. Hobson,et al.  Role of Sphingosine-1-phosphate Phosphatase 1 in Epidermal Growth Factor-induced Chemotaxis* , 2004, Journal of Biological Chemistry.

[34]  Brian D. Lee,et al.  Discovery and evaluation of inhibitors of human sphingosine kinase. , 2003, Cancer research.

[35]  Sarah Spiegel,et al.  Sphingosine-1-phosphate: an enigmatic signalling lipid , 2003, Nature Reviews Molecular Cell Biology.

[36]  J. P. Hobson,et al.  Sphingosine kinase type 1 promotes estrogen-dependent tumorigenesis of breast cancer MCF-7 cells. , 2002, Experimental cell research.

[37]  C. Hudis,et al.  Celecoxib, a selective cyclooxygenase 2 inhibitor, protects against human epidermal growth factor receptor 2 (HER-2)/neu-induced breast cancer. , 2002, Cancer research.

[38]  Korey R. Johnson,et al.  PKC-dependent Activation of Sphingosine Kinase 1 and Translocation to the Plasma Membrane , 2002, The Journal of Biological Chemistry.

[39]  J. Isola,et al.  Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. , 2002, Cancer research.

[40]  Y. Yarden,et al.  Untangling the ErbB signalling network , 2001, Nature Reviews Molecular Cell Biology.

[41]  T. Sakaguchi,et al.  Claudins regulate the intestinal barrier in response to immune mediators. , 2000, Gastroenterology.

[42]  K. Seibert,et al.  Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor. , 2000, Cancer research.

[43]  S. Ritland,et al.  Genetic modulation of neu proto-oncogene-induced mammary tumorigenesis. , 1998, Cancer research.

[44]  N. Hynes,et al.  ErbB‐2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling , 1997, The EMBO journal.

[45]  R. Cardiff,et al.  Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[46]  W. McGuire,et al.  HER-2/neu amplification predicts poor survival in node-positive breast cancer. , 1990, Cancer research.

[47]  P. Jolicoeur,et al.  Stochastic appearance of mammary tumors in transgenic mice carrying the MMTV/c-neu oncogene , 1989, Cell.

[48]  P. Leder,et al.  Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene , 1988, Cell.

[49]  A. Jemal,et al.  Cancer statistics, 2016 , 2016, CA: a cancer journal for clinicians.

[50]  H. Furuya,et al.  Involvement of Sphingosine Kinases/Sphingosine-1-Phosphate (S1P)/S1P Receptors in Breast Cancer Subtypes , 2013 .

[51]  V. Natarajan,et al.  Sphingosine kinase localization in the control of sphingolipid metabolism. , 2011, Advances in enzyme regulation.

[52]  Abderrahman Ouban,et al.  Claudins in human cancer: a review. , 2010, Histology and histopathology.