CD44-P185HER2 INTERACTION IN OVARIAN CANCER PROGRESSION

Summary

Principal Investigator: LILLY BOURGUIGNON
Abstract: Both CD44 and p185HER2 confer the malignant properties of abnormal cell growth, migration and invasion. Furthermore, CD44 forms a complex with p185HER2 and these two molecules closely interact with a number of signaling molecules, thereby activating cytoskeleton function and tumor-specific phenotypes. In this continuation research proposal, we plan to test the hypothesis that CD44-p185HER2 interaction with specific signaling molecules (e g Vav2, Grb2, c-Src kinase and AKT) promotes the concomitant activation of multiple signaling pathways leading to cytoskeleten changes, tumor cell-specific behaviors (e.g. tumor cell growth, survival, invasion and migration) and ovarian cancer progression. To test this hypothesis, we plan to use a variety of biochemical, molecular biological techniques and immunohistochemical staining to elucidate CD44-p185HER2 interaction with the various signaling molecules. We will evaluate the functional ramifications of these interactions with respect to cytoskeleton changes and tumor cell-specific behaviors (e.g. tumor cell growth, survival, migration and invasion). In addition, we plan to analyze the co-expression of CD44v-p185HER2 and various signaling molecules (e.g. Vav2, c-Src and/or AKT) in human ovarian carcinoma tissues obtained from ovarian cancer patients using immunohistochemistry. We will also employ a novel signaling perturbation strategy to impair CD44-p185HER2 interaction with Racl/Ras signaling and c- Src/AKT activation by constructing a number of Vav2/Grb2 and c-Src/AKT dominant negative mutants Finally, we will establish a therapeutic antisense and ribozyme gene therapy procedures to specifically inhibit the mRNA encoding selected CD44 isoforms (and/or p185HER2) in order to effectively block the expression of these CD44 isoforms (and/or p185HER2) involved in Racl/Ras signaling, c-Src/AKT activation and the downstream oncogenic signaling events (e g cytoskeleton changes, tumor cell growth, survival, migration and invasion) These studies may identify useful structure/function-related markers for ovarian cancer detection and prognosis. We believe that the new information obtained from this proposal may establish the CD44-p185HER2 complex and associated signaling molecules as important tumor markers for the early detection and evaluation of oncogenic potential, as well as allow the development of new drug targets to inhibit CD44-p185HER2-mediated ovarian cancer progression.
Funding Period: 1999-04-01 - 2010-01-31
more information: NIH RePORT

Top Publications

  1. pmc Hyaluronan-CD44 interaction promotes microRNA signaling and RhoGTPase activation leading to tumor progression
    Lilly Y W Bourguignon
    Department of Medicine, University of California at San Francisco, and Endocrine Unit 111N2, VA Medical Center, San Francisco, CA USA
    Small Gtpases 3:53-9. 2012
  2. pmc Interaction of low molecular weight hyaluronan with CD44 and toll-like receptors promotes the actin filament-associated protein 110-actin binding and MyD88-NFκB signaling leading to proinflammatory cytokine/chemokine production and breast tumor invasion
    Lilly Y W Bourguignon
    Department of Medicine, University of California, San Francisco, USA
    Cytoskeleton (Hoboken) 68:671-93. 2011
  3. pmc Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells
    L Y W Bourguignon
    San Francisco Veterans Affairs Medical Center and Department of Medicine, University of California at San Francisco and Endocrine Unit 111N2, San Francisco, CA 94121, USA
    Oncogene 31:149-60. 2012
  4. pmc Role of hyaluronan-mediated CD44 signaling in head and neck squamous cell carcinoma progression and chemoresistance
    Steven J Wang
    Department of Otolaryngology Head and Neck Surgery, University of California at San Francisco, San Francisco, California 94115, USA
    Am J Pathol 178:956-63. 2011
  5. pmc Hyaluronan-CD44 interaction promotes c-Src-mediated twist signaling, microRNA-10b expression, and RhoA/RhoC up-regulation, leading to Rho-kinase-associated cytoskeleton activation and breast tumor cell invasion
    Lilly Y W Bourguignon
    Department of Medicine, Endocrine Unit 111N, University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121, USA
    J Biol Chem 285:36721-35. 2010
  6. pmc Reduction of hyaluronan-CD44-mediated growth, migration, and cisplatin resistance in head and neck cancer due to inhibition of Rho kinase and PI-3 kinase signaling
    Carlos Torre
    Department of Otolaryngology Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94121, USA
    Arch Otolaryngol Head Neck Surg 136:493-501. 2010
  7. pmc Hyaluronan-mediated CD44 interaction with p300 and SIRT1 regulates beta-catenin signaling and NFkappaB-specific transcription activity leading to MDR1 and Bcl-xL gene expression and chemoresistance in breast tumor cells
    Lilly Y W Bourguignon
    Department of Medicine, Endocrine Unit 111N2, University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, CA 94121, USA
    J Biol Chem 284:2657-71. 2009
  8. pmc Matrix metalloproteinase-9 facilitates glial scar formation in the injured spinal cord
    Jung Yu C Hsu
    Department of Neurological Surgery, University of California, San Francisco, California 94143, USA
    J Neurosci 28:13467-77. 2008
  9. pmc The role of CD44 in cutaneous inflammation
    Mona Man
    Department of Dermatology, University of California School of Medicine, San Francisco, CA, USA
    Exp Dermatol 18:962-8. 2009
  10. pmc CD44 variant isoforms in head and neck squamous cell carcinoma progression
    Steven J Wang
    Department of Otolaryngology Head and Neck Surgery, University of California San Francisco, Veterans Affairs Medical Center, USA
    Laryngoscope 119:1518-30. 2009

Scientific Experts

  • LILLY BOURGUIGNON
  • Steven J Wang
  • Jung Yu C Hsu
  • Carlos Torre
  • Mona Man
  • Jay J Cao
  • Weiliang Xia
  • Kenneth R Feingold
  • Mao Qiang Man
  • Wenyan Man
  • Yan Wu
  • Peter M Elias
  • Andrew Burghardt
  • Bernard P Halloran
  • Patrick A Singleton
  • Thomas J Wronski
  • Pam Kurimoto
  • Benjamin Boudignon
  • Sharmila Majumdar

Detail Information

Publications24

  1. pmc Hyaluronan-CD44 interaction promotes microRNA signaling and RhoGTPase activation leading to tumor progression
    Lilly Y W Bourguignon
    Department of Medicine, University of California at San Francisco, and Endocrine Unit 111N2, VA Medical Center, San Francisco, CA USA
    Small Gtpases 3:53-9. 2012
    ..This new knowledge could serve as groundwork for the future development of new drug targets to inhibit HA/CD44-mediated oncogenic signaling and cancer progression...
  2. pmc Interaction of low molecular weight hyaluronan with CD44 and toll-like receptors promotes the actin filament-associated protein 110-actin binding and MyD88-NFκB signaling leading to proinflammatory cytokine/chemokine production and breast tumor invasion
    Lilly Y W Bourguignon
    Department of Medicine, University of California, San Francisco, USA
    Cytoskeleton (Hoboken) 68:671-93. 2011
    ....
  3. pmc Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells
    L Y W Bourguignon
    San Francisco Veterans Affairs Medical Center and Department of Medicine, University of California at San Francisco and Endocrine Unit 111N2, San Francisco, CA 94121, USA
    Oncogene 31:149-60. 2012
    ..This novel Nanog/Stat-3 signaling pathway-specific mechanism involved in miR-21 production is significant for the formation of future intervention strategies in the treatment of HA/CD44-activated HNSCC...
  4. pmc Role of hyaluronan-mediated CD44 signaling in head and neck squamous cell carcinoma progression and chemoresistance
    Steven J Wang
    Department of Otolaryngology Head and Neck Surgery, University of California at San Francisco, San Francisco, California 94115, USA
    Am J Pathol 178:956-63. 2011
    ..Finally, EGFR-mediated pathways play major roles in the HA/CD44 promotion of chemoresistance in HNSCC. Understanding HA/CD44-mediated signaling pathways may lead to improved treatment of HNSCC...
  5. pmc Hyaluronan-CD44 interaction promotes c-Src-mediated twist signaling, microRNA-10b expression, and RhoA/RhoC up-regulation, leading to Rho-kinase-associated cytoskeleton activation and breast tumor cell invasion
    Lilly Y W Bourguignon
    Department of Medicine, Endocrine Unit 111N, University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121, USA
    J Biol Chem 285:36721-35. 2010
    ..All of these events are critical prerequisite steps for the acquisition of metastatic properties by human breast cancer cells...
  6. pmc Reduction of hyaluronan-CD44-mediated growth, migration, and cisplatin resistance in head and neck cancer due to inhibition of Rho kinase and PI-3 kinase signaling
    Carlos Torre
    Department of Otolaryngology Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94121, USA
    Arch Otolaryngol Head Neck Surg 136:493-501. 2010
    ....
  7. pmc Hyaluronan-mediated CD44 interaction with p300 and SIRT1 regulates beta-catenin signaling and NFkappaB-specific transcription activity leading to MDR1 and Bcl-xL gene expression and chemoresistance in breast tumor cells
    Lilly Y W Bourguignon
    Department of Medicine, Endocrine Unit 111N2, University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, CA 94121, USA
    J Biol Chem 284:2657-71. 2009
    ....
  8. pmc Matrix metalloproteinase-9 facilitates glial scar formation in the injured spinal cord
    Jung Yu C Hsu
    Department of Neurological Surgery, University of California, San Francisco, California 94143, USA
    J Neurosci 28:13467-77. 2008
    ..MMP-9 may thus be a promising therapeutic target to reduce glial scarring during wound healing after spinal cord injury...
  9. pmc The role of CD44 in cutaneous inflammation
    Mona Man
    Department of Dermatology, University of California School of Medicine, San Francisco, CA, USA
    Exp Dermatol 18:962-8. 2009
    ....
  10. pmc CD44 variant isoforms in head and neck squamous cell carcinoma progression
    Steven J Wang
    Department of Otolaryngology Head and Neck Surgery, University of California San Francisco, Veterans Affairs Medical Center, USA
    Laryngoscope 119:1518-30. 2009
    ..The objective of this study was to investigate the role of the CD44 v3, v6, and v10 variant isoforms in head and neck squamous cell carcinoma (HNSCC) tumor progression behaviors...
  11. pmc Hyaluronan-CD44 interaction with protein kinase C(epsilon) promotes oncogenic signaling by the stem cell marker Nanog and the Production of microRNA-21, leading to down-regulation of the tumor suppressor protein PDCD4, anti-apoptosis, and chemotherapy res
    Lilly Y W Bourguignon
    Endocrine Unit, Department of Medicine, University of California at San Francisco, and Veterans Affairs Medical Center, San Francisco, California 94121, USA
    J Biol Chem 284:26533-46. 2009
    ..Thus, this newly discovered HA-CD44 signaling pathway should provide important drug targets for sensitizing tumor cell apoptosis and overcoming chemotherapy resistance in breast cancer cells...
  12. pmc Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression
    Lilly Y W Bourguignon
    Department of Medicine, University of California at San Francisco and Endocrine Unit 111N, VA Medical Center, 4150 Clement Street, San Francisco, CA 94121, USA
    Semin Cancer Biol 18:251-9. 2008
    ..It could also serve as ground work for the future development of new drug targets to inhibit HA/CD44-mediated tumor metastasis and cancer progression...
  13. pmc Hyaluronan-CD44 interaction activates stem cell marker Nanog, Stat-3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells
    Lilly Y W Bourguignon
    Department of Medicine, University of California, San Francisco, and Endocrine Unit, Veterans Affairs Medical Center, San Francisco, California 94121, USA
    J Biol Chem 283:17635-51. 2008
    ....
  14. ncbi Hyaluronan-CD44 interaction with IQGAP1 promotes Cdc42 and ERK signaling, leading to actin binding, Elk-1/estrogen receptor transcriptional activation, and ovarian cancer progression
    Lilly Y W Bourguignon
    Department of Medicine, University of California, and the Endocrine Unit, Veterans Affair Medical Center, San Francisco, California 94121, USA
    J Biol Chem 280:11961-72. 2005
    ....
  15. ncbi Hyaluronan-CD44 promotes phospholipase C-mediated Ca2+ signaling and cisplatin resistance in head and neck cancer
    Steven J Wang
    Department of Otolaryngology Head and Neck Surgery and Endocrine Unit, Department of Medicine, University of California San Francisco, 4150 Clement Street 112B, San Francisco, CA 94121, USA
    Arch Otolaryngol Head Neck Surg 132:19-24. 2006
    ..To investigate whether hyaluronan (HA)-CD44 promotes head and neck squamous cell carcinoma (HNSCC) cisplatin resistance and whether HA-CD44 promotes phospholipase C (PLC)-mediated Ca2+ signaling to alter cisplatin sensitivity in HNSCC...
  16. ncbi Hyaluronan-CD44 interaction stimulates keratinocyte differentiation, lamellar body formation/secretion, and permeability barrier homeostasis
    Lilly Y W Bourguignon
    Department of Medicine, University of California San Francisco and VA Medical Center, San Francisco, California, USA lilly bourguignon ucsf edu
    J Invest Dermatol 126:1356-65. 2006
    ..HA-CD44 signaling could comprise a novel approach to treat skin disorders characterized by abnormalities in differentiation, lipid synthesis, and/or barrier function...
  17. ncbi Hyaluronan-CD44 interaction with leukemia-associated RhoGEF and epidermal growth factor receptor promotes Rho/Ras co-activation, phospholipase C epsilon-Ca2+ signaling, and cytoskeleton modification in head and neck squamous cell carcinoma cells
    Lilly Y W Bourguignon
    Department of Medicine, University of California at San Francisco and Endocrine Unit 111N, Veterans Affairs Medical Center, San Francisco, California 94121, USA
    J Biol Chem 281:14026-40. 2006
    ....
  18. ncbi Hyaluronan and the interaction between CD44 and epidermal growth factor receptor in oncogenic signaling and chemotherapy resistance in head and neck cancer
    Steven J Wang
    Department of Otolaryngology Head and Neck Surgery, Veterans Affairs Medical Center, University of California, San Francisco, USA
    Arch Otolaryngol Head Neck Surg 132:771-8. 2006
    ..We recently determined that HA-CD44 promotes phospholipase C-mediated calcium signaling and cisplatin resistance in HNSCC...
  19. ncbi Hyaluronan-CD44 interaction with neural Wiskott-Aldrich syndrome protein (N-WASP) promotes actin polymerization and ErbB2 activation leading to beta-catenin nuclear translocation, transcriptional up-regulation, and cell migration in ovarian tumor cells
    Lilly Y W Bourguignon
    Department of Medicine, University of California, Endocrine Unit, Veterans Affairs Medical Center, San Francisco, California 94121, USA
    J Biol Chem 282:1265-80. 2007
    ....
  20. ncbi Association of CD44 V3-containing isoforms with tumor cell growth, migration, matrix metalloproteinase expression, and lymph node metastasis in head and neck cancer
    Steven J Wang
    Department of Otolaryngology Head and Neck Surgery, Veterans Affairs Medical Center, University of California, San Francisco, California, USA
    Head Neck 29:550-8. 2007
    ..The objective of this study was to investigate whether CD44 v3-containing isoforms are involved in head and neck squamous cell carcinoma (HNSCC) tumor progression...
  21. ncbi The influence of hyaluronan-CD44 interaction on topoisomerase II activity and etoposide cytotoxicity in head and neck cancer
    Steven J Wang
    Department of Otolaryngology Head and Neck Surgery and Endocrine Unit, Department of Medicine, Veterans Affairs Medical Center, University of California, San Francisco, USA
    Arch Otolaryngol Head Neck Surg 133:281-8. 2007
    ..We recently determined that HA-CD44 interaction promotes PLC-mediated Ca(2+) signaling and cisplatin resistance in HNSCC...
  22. ncbi Hyaluronan-CD44 interaction stimulates Rac1 signaling and PKN gamma kinase activation leading to cytoskeleton function and cell migration in astrocytes
    Lilly Y W Bourguignon
    Department of Medicine, University of California San Francisco, Endocrine Unit 111 N, San Francisco VA Medical Center, San Francisco, CA 94121, USA
    J Neurochem 101:1002-17. 2007
    ..These newly discovered HA/CD44-induced astrocyte function may provide important insight into novel therapeutic treatments for tissue repair following CNS injury...
  23. ncbi Heregulin-mediated ErbB2-ERK signaling activates hyaluronan synthases leading to CD44-dependent ovarian tumor cell growth and migration
    Lilly Y W Bourguignon
    Department of Medicine, University of California at San Francisco, USA
    J Biol Chem 282:19426-41. 2007
    ..Taken together, these findings clearly indicate that HRG activation of ErbB2-ERK signaling modulates HAS phosphorylation/activation and HA production leading to CD44-mediated oncogenic events and ovarian cancer progression...
  24. ncbi Hyaluronan increases RANKL expression in bone marrow stromal cells through CD44
    Jay J Cao
    Division of Endocrinology, Veterans Affairs Medical Center, San Francisco, California 94121, USA
    J Bone Miner Res 20:30-40. 2005
    ..HA stimulation of RANKL is blocked by anti-CD44 antibody and is absent in cells from CD44(-/-) mice. CD44(-/-) mice exhibit thicker cortical bone and a smaller medullary cavity, but indices of bone resorption are not affected...