CD44/VARIANT CYTOSKELETON IN BREAST CANCER PROGRESSION

Summary

Principal Investigator: LILLY BOURGUIGNON
Abstract: It is now certain that oncogenic signaling and cytoskeleton function are directly involved in breast cancer progression. Our laboratory has determined that overexpression of CD44 variant (CD44v) isoforms [hyaluronan (HA) receptors] appears to confer the malignant properties of increased growth, migration and invasion on breast epithelial cells. In this continuation research proposal, we plan to test the hypothesis that the interaction between CD44v isoforms (CD44v3, CD44v10 and CD44v6/7) and specific signaling activators [e.g. RhoGEFs/RacGEF (Tiam1) and c-Src kinase] plays an important role in HA-mediated oncogenic signaling such as the RhoA-activated ROK pathway, Tiam1-regulated Rac1-PKNgamma kinase pathway and c-Src-induced cortactin and Gab-1/PI3 kinase-AKT pathways. These activation events induce various tumor cell-specific behaviors (e.g. cellular acidification, ECM degradation, cytoskeleton function, tumor cell growth/survival, migration and invasion) leading to breast cancer progression. To test this hypothesis, we plan to use a variety of biochemical, molecular biological techniques and immunohistochemical staining to elucidate HA-CD44v isoform interaction with the various signaling molecules. We will evaluate the functional ramifications of these interactions with respect to specific downstream effector functions (e.g. NHE1-related acidic pH enzyme activation, ankyrin/cortactin-actin binding and PI3 kinase/AKT-mediated biological activities) required for ECM degradation, cytoskeleton function and metastatic tumor cell properties. In addition, we plan to analyze the co-expression of CD44v isoforms and various signaling molecules (e.g. RhoGEF, Tiam1, ROK, PKNgamma and c-Src) in human breast carcinoma tissues obtained from breast cancer patients using immunocytochemistry. We will also employ novel signaling perturbation strategies to impair HA-CD44v isoform-mediated oncogenic signaling by constructing dominant-negative mutants of certain signaling molecules (e.g. ROK, PKNgamma, c-Src, and cortactin). Finally, we will develop therapeutic antisense and small interference RNAs (siRNAs) specifically targeting CD44 in order to effectively block CD44 expression, inhibit HA-mediated downstream oncogenic signaling events and block breast tumor progression. We believe that the information obtained from this proposal has particularly important clinical utility and could establish CD44v isoforms and associated signaling molecules (e.g. RhoGEF, Tiam1, ROK, PKNgamma and c-Src) as important tumor markers for early detection and evaluation of oncogenic potential, as well as allow the development of new drug targets to inhibit breast tumor metastasis and cancer progression.
Funding Period: ----------------1995 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. 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
  2. ncbi The inhibition of miR-21 promotes apoptosis and chemosensitivity in ovarian cancer
    John K Chan
    Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco School of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero Street, Box 1702, San Francisco, CA 94143, USA Electronic address
    Gynecol Oncol 132:739-44. 2014
  3. pmc Selective matrix (hyaluronan) interaction with CD44 and RhoGTPase signaling promotes keratinocyte functions and overcomes age-related epidermal dysfunction
    Lilly Y W Bourguignon
    Department of Medicine, University of California San Francisco and VA Medical Center, United States Electronic address
    J Dermatol Sci 72:32-44. 2013
  4. pmc Hyaluronan-CD44v3 interaction with Oct4-Sox2-Nanog promotes miR-302 expression leading to self-renewal, clonal formation, and cisplatin resistance in cancer stem cells from head and neck squamous cell carcinoma
    Lilly Y W Bourguignon
    Endocrine Unit 111N2, Department of Medicine, University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121, USA
    J Biol Chem 287:32800-24. 2012
  5. 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
  6. pmc Hyaluronan-CD44 interaction promotes c-Jun signaling and miRNA21 expression leading to Bcl-2 expression and chemoresistance in breast cancer cells
    Liqun Chen
    San Francisco Veterans Affairs Medical Center and Department of Medicine, University of California at San Francisco and Endocrine Unit 111N2, 4150 Clement Street, San Francisco, CA 94121, USA
    Mol Cancer 13:52. 2014
  7. 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
  8. 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
  9. 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
  10. 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

Scientific Experts

  • LILLY BOURGUIGNON
  • Steven J Wang
  • Liqun Chen
  • John K Chan
  • Carlos Torre
  • Mona Man
  • Jung Yu C Hsu
  • Kevin Blansit
  • Christine Earle
  • Tuyen Kiet
  • Gabriel Wong
  • Alexander Sherman
  • Weiliang Xia
  • Peter M Elias
  • Kenneth R Feingold
  • Wenyan Man
  • Yan Wu
  • Mao Qiang Man
  • Christine L Cun
  • Haoqian Zhang
  • Karine Peyrollier
  • Christen M Adams
  • Linda J Noble-Haeusslein
  • Zena Werb
  • Thomas Fandel

Detail Information

Publications26

  1. 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...
  2. ncbi The inhibition of miR-21 promotes apoptosis and chemosensitivity in ovarian cancer
    John K Chan
    Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco School of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero Street, Box 1702, San Francisco, CA 94143, USA Electronic address
    Gynecol Oncol 132:739-44. 2014
    ..MicroRNAs have been implicated in tumorigenesis, drug resistance, and prognosis in cancer. We investigated the role of microRNA-21 (miR-21) in regulating ovarian cancer drug resistance...
  3. pmc Selective matrix (hyaluronan) interaction with CD44 and RhoGTPase signaling promotes keratinocyte functions and overcomes age-related epidermal dysfunction
    Lilly Y W Bourguignon
    Department of Medicine, University of California San Francisco and VA Medical Center, United States Electronic address
    J Dermatol Sci 72:32-44. 2013
    ....
  4. pmc Hyaluronan-CD44v3 interaction with Oct4-Sox2-Nanog promotes miR-302 expression leading to self-renewal, clonal formation, and cisplatin resistance in cancer stem cells from head and neck squamous cell carcinoma
    Lilly Y W Bourguignon
    Endocrine Unit 111N2, Department of Medicine, University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121, USA
    J Biol Chem 287:32800-24. 2012
    ..All of these events are critically important for the acquisition of cancer stem cell properties, including self-renewal, clonal formation, and chemotherapy resistance in HA-CD44v3-activated head and neck cancer...
  5. 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...
  6. pmc Hyaluronan-CD44 interaction promotes c-Jun signaling and miRNA21 expression leading to Bcl-2 expression and chemoresistance in breast cancer cells
    Liqun Chen
    San Francisco Veterans Affairs Medical Center and Department of Medicine, University of California at San Francisco and Endocrine Unit 111N2, 4150 Clement Street, San Francisco, CA 94121, USA
    Mol Cancer 13:52. 2014
    ..This novel HA/CD44-mediated c-Jun signaling pathway and miR-21 production provide a new drug target for the future intervention strategies to treat breast cancer. ..
  7. 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...
  8. 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...
  9. 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
    ....
  10. 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...
  11. 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
    ....
  12. 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...
  13. 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
    ....
  14. 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...
  15. 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...
  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 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...
  18. 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
    ....
  19. 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...
  20. 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...
  21. 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...
  22. 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
    ....
  23. 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...
  24. 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...
  25. 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
    ....
  26. 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
    ....