Regulation of syndecan 1 in by n-3 PUFA

Summary

Principal Investigator: IRIS EDWARDS
Abstract: DESCRIPTION (provided by applicant): Human population studies and experimental animal models indicate that fatty acid saturation may be a key factor in determining whether a particular fat promotes or inhibits the development of breast cancer. The proposed studies address mechanisms at the cellular level that may account for the reported divergent effects of different fatty acids. The major focus is on cell surface proteoglycans (PGly) as important mediators of tumorigenic potential. The overall hypothesis is that PGly metabolism represents a level of regulation of the tumorigenic potential of mammary cells that is modified by dietary fatty acids. Specific hypotheses are .that n-3 polyunsaturated fatty acids (PUFA) enhance the expression of the PGly, syndecan 1 and that this regulation is mediated by the peroxisome proliferators receptor (PPAR) gamma transcriptional pathway. The resulting increase in syndecan 1 inhibits the tumorigenic potential of the cells by decreasing growth and increasing apoptosis. A unique feature of the studies is the use of low density lipoproteins (LDL) and the LDL receptor pathway to deliver fatty acids to the cells. Since LDL receptors are upregulated in tumor cells, this pathway is likely to represent a major route for delivery of fatty acids in vivo. Studies will use LDL obtained from African green monkeys fed dietary fats proposed to have opposite effects in human breast cancer: n-6 PUFA (tumor promoting) and n-3 PUFA (tumor inhibiting). Four Specific Aims are proposed. In Aim 1, studies will examine metabolism of the LDL by non-tumorigenic mammary cells and breast cancer cell lines and compare delivery of PUFA to cell membranes by LDL and non LDL-receptor dependent pathways. In Aim 2, the emphasis will be effects of LDL-delivered PUFA on the cell surface PGly, syndecan 1. Using biochemical, molecular biologic and immunologic techniques, studies will examine effects of LDL on syndecan synthesis, structure and gene regulation in non-tumorigenic and tumorigenic breast cells. In addition, using a transgenic mouse model engineered to produce n-3 PUFA;studies will examine syndecan 1 expression in an enhanced in vivo n-3 PUFA environment. In Aim 3, studies will investigate the involvement of the PPARy transcriptional pathway in the n-3 PUFA regulation of syndecan 1. In Aim 4, using syndecan 1-transfected cells we will test the hypothesis that increased production of syndecan 1 has a significant effect on cell growth and apoptosis. Data will provide important new information on mechanisms by which intake of specific dietary fats may affect the metabolism and behavior of both non-tumorigenic and tumorigenic human breast cells and provide rationale for dietary modifications aimed at breast cancer risk reduction or survival.
Funding Period: 2005-09-23 - 2010-06-30
more information: NIH RePORT

Top Publications

  1. pmc Fatty acid metabolites in rapidly proliferating breast cancer
    JOSEPH T O'FLAHERTY
    Department of Internal Medicine, Wake Forest School of Medicine, Winston Salem, North Carolina, United States of America
    PLoS ONE 8:e63076. 2013
  2. pmc 15-Lipoxygenase-1-mediated metabolism of docosahexaenoic acid is required for syndecan-1 signaling and apoptosis in prostate cancer cells
    Yunping Hu
    Department of Pathology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
    Carcinogenesis 34:176-82. 2013
  3. pmc 15-lipoxygenase metabolites of docosahexaenoic acid inhibit prostate cancer cell proliferation and survival
    JOSEPH T O'FLAHERTY
    Department of Internal Medicine Wake Forest School of Medicine, Winston Salem, NC, USA
    PLoS ONE 7:e45480. 2012
  4. pmc Omega-3 fatty acids induce apoptosis in human breast cancer cells and mouse mammary tissue through syndecan-1 inhibition of the MEK-Erk pathway
    Haiguo Sun
    Department of Pathology, Wake ForestUniversity School of Medicine, Winston Salem, NC 27157, USA
    Carcinogenesis 32:1518-24. 2011
  5. pmc Endogenous synthesis of n-3 polyunsaturated fatty acids in Fat-1 mice is associated with increased mammary gland and liver syndecan-1
    Haiguo Sun
    Department of Pathology, Wake Forest School of Medicine, Winston Salem, North Carolina, United States of America
    PLoS ONE 6:e20502. 2011
  6. pmc Syndecan-1-dependent suppression of PDK1/Akt/bad signaling by docosahexaenoic acid induces apoptosis in prostate cancer
    Yunping Hu
    Department of Pathology, Wake Forest University School of Medicine, Winston Salem, NC, USA
    Neoplasia 12:826-36. 2010
  7. pmc Decorin suppresses prostate tumor growth through inhibition of epidermal growth factor and androgen receptor pathways
    Yunping Hu
    Department of Pathology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
    Neoplasia 11:1042-53. 2009
  8. pmc Multi-targeted therapy of cancer by omega-3 fatty acids
    Isabelle M Berquin
    Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, United States
    Cancer Lett 269:363-77. 2008
  9. pmc In vivo and in vitro regulation of syndecan 1 in prostate cells by n-3 polyunsaturated fatty acids
    Iris J Edwards
    Department of Pathology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
    J Biol Chem 283:18441-9. 2008
  10. pmc Peroxisome proliferator-activated receptor gamma-mediated up-regulation of syndecan-1 by n-3 fatty acids promotes apoptosis of human breast cancer cells
    Haiguo Sun
    Department of Pathology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
    Cancer Res 68:2912-9. 2008

Scientific Experts

  • IRIS EDWARDS
  • Yong Q Chen
  • Haiguo Sun
  • JOSEPH T O'FLAHERTY
  • Yunping Hu
  • Rick T Owens
  • Isabelle M Berquin
  • Zhennan Gu
  • Michael P Samuel
  • Rhonda E Wooten
  • Michael J Thomas
  • Steven A Akman
  • L Douglas Case
  • Edward A Levine
  • Yungping Hu
  • David A Horita
  • Martha D Wilson
  • Mark C Willingham
  • Lawrence L Rudel
  • Jansheng Wu
  • Jiansheng Wu
  • Donna Perry

Detail Information

Publications11

  1. pmc Fatty acid metabolites in rapidly proliferating breast cancer
    JOSEPH T O'FLAHERTY
    Department of Internal Medicine, Wake Forest School of Medicine, Winston Salem, North Carolina, United States of America
    PLoS ONE 8:e63076. 2013
    ..However, these metabolites and behaviors have not been identified. We here identify which metabolites among those that stimulate breast cancer cell proliferation in vitro are associated with rapidly proliferating breast cancer...
  2. pmc 15-Lipoxygenase-1-mediated metabolism of docosahexaenoic acid is required for syndecan-1 signaling and apoptosis in prostate cancer cells
    Yunping Hu
    Department of Pathology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
    Carcinogenesis 34:176-82. 2013
    ..These findings demonstrate that 15-LOX-1-mediated metabolism of DHA is required for it to upregulate SDC-1 and trigger the signaling pathway that elicits apoptosis in prostate cancer cells...
  3. pmc 15-lipoxygenase metabolites of docosahexaenoic acid inhibit prostate cancer cell proliferation and survival
    JOSEPH T O'FLAHERTY
    Department of Internal Medicine Wake Forest School of Medicine, Winston Salem, NC, USA
    PLoS ONE 7:e45480. 2012
    ..The DHA metabolites thus slow prostate cancer cell proliferation by engaging the PPARĪ³/syndecan-1 pathway of apoptosis and thereby may contribute to the prostate cancer-suppressing effects of not only 15-LOX but also dietary DHA...
  4. pmc Omega-3 fatty acids induce apoptosis in human breast cancer cells and mouse mammary tissue through syndecan-1 inhibition of the MEK-Erk pathway
    Haiguo Sun
    Department of Pathology, Wake ForestUniversity School of Medicine, Winston Salem, NC 27157, USA
    Carcinogenesis 32:1518-24. 2011
    ..These data elucidate a pathway whereby SDC-1, upregulated by DHA, induces apoptosis in breast cancer cells through inhibition of MEK/Erk/Bad signaling...
  5. pmc Endogenous synthesis of n-3 polyunsaturated fatty acids in Fat-1 mice is associated with increased mammary gland and liver syndecan-1
    Haiguo Sun
    Department of Pathology, Wake Forest School of Medicine, Winston Salem, North Carolina, United States of America
    PLoS ONE 6:e20502. 2011
    ..This was accompanied by higher SDC-1 in mammary glands and livers of Fat-1 mice, thus demonstrating that endogenously synthesized n-3 PUFA may upregulate SDC-1 in the presence of high dietary n-6 PUFA...
  6. pmc Syndecan-1-dependent suppression of PDK1/Akt/bad signaling by docosahexaenoic acid induces apoptosis in prostate cancer
    Yunping Hu
    Department of Pathology, Wake Forest University School of Medicine, Winston Salem, NC, USA
    Neoplasia 12:826-36. 2010
    ..The effect of DHA on PDK1/Akt/Bad signaling was abrogated by SDC-1 siRNA. These findings define a mechanism by which SDC-1-dependent suppression of phosphorylation of PDK1/Akt/Bad mediates n-3 PUFA-induced apoptosis in prostate cancer...
  7. pmc Decorin suppresses prostate tumor growth through inhibition of epidermal growth factor and androgen receptor pathways
    Yunping Hu
    Department of Pathology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
    Neoplasia 11:1042-53. 2009
    ..Those findings highlight the effectiveness of decorin in the presence of a powerful genetic cancer risk and implicate decorin as a potential new agent for prostate cancer therapy by targeting EGFR/AR-PI3K-Akt pathways...
  8. pmc Multi-targeted therapy of cancer by omega-3 fatty acids
    Isabelle M Berquin
    Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, United States
    Cancer Lett 269:363-77. 2008
    ..In this review, we discuss the rationale for using long-chain n-3 PUFAs in cancer prevention and treatment and the challenges that such approaches pose in the design of clinical trials...
  9. pmc In vivo and in vitro regulation of syndecan 1 in prostate cells by n-3 polyunsaturated fatty acids
    Iris J Edwards
    Department of Pathology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
    J Biol Chem 283:18441-9. 2008
    ..These findings indicate that syndecan 1 is up-regulated by n-3 fatty acids by a transcriptional pathway involving PPARgamma. This mechanism may contribute to the chemopreventive properties of n-3 fatty acids in prostate cancer...
  10. pmc Peroxisome proliferator-activated receptor gamma-mediated up-regulation of syndecan-1 by n-3 fatty acids promotes apoptosis of human breast cancer cells
    Haiguo Sun
    Department of Pathology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
    Cancer Res 68:2912-9. 2008
    ..This provides a novel mechanism for the chemopreventive effects of n-3 PUFA in breast cancer...
  11. ncbi Dietary fat-gene interactions in cancer
    Yong Q Chen
    Cancer Biology, Wake Forest University School of Medicine, Medical Center Blvd, Winston Salem, NC 27157, USA
    Cancer Metastasis Rev 26:535-51. 2007
    ..The purpose of this review is to present a more cohesive view of dietary fat-gene interactions, and outline a working hypothesis of the intricate connection between fat, genes and cancer...