Regulation and function of IKKe in breast cancer initiation and maintenance

Summary

Principal Investigator: William C Hahn
Abstract: The nuclear-factor ?B (NF-?B) family of transcription factors plays a central role in regulating many physiological processes including innate and adaptive immunity. In addition, accumulating evidence suggests that inappropriate activation of NF-?B occurs in many types of human cancers. Although genetic alterations of specific core components of the NF-?B signaling pathway have been identified in a few lymphoid malignancies, the molecular alterations that lead to and the consequences of increased NF-:B activity in the pathogenesis of human cancers remain incompletely understood. In recent work, we have identified the inhibitor of ?B kinase 5 (IKBKE, IKKi IKK5) as amplified and overexpressed in a substantial subset of human breast cancer cell lines and tumors. IKK5 is required for the survival of breast cancer cell lines that harbor IKK5 copy number gain and confers a tumorigenic phenotype when expressed in immortalized human mammary epithelial cells. Breast cancer cell lines and tumors that overexpress IKK5 exhibit increased NF-?B activity, which is essential for their transformed phenotype. These observations classify IKK5 as a breast cancer oncogene and may also explain the increased NF-?B activity previously described in a subset of human breast cancers. Based on these observations, this proposal focuses on investigating the role of IKK5 in breast cancer pathogenesis. Specifically, biochemical, genetic and molecular biological approaches will be applied to identify and characterize which substrates and interacting proteins of this non-canonical IKK are critical for tumorigenicity, to investigate how ubiquitination regulates IKK5 activity and function in breast cancer and to dissect the roles of IKK5 in tumor initiation and maintenance in genetically engineered mice. Investigating the regulation and function of IKK5 in breast cancer development will not only enhance our mechanistic understanding of this non-canonical IKK regulator but will also clarify the role of NF-?B signaling in the development of human epithelial cancers. In addition, these studies will provide a foundation for strategies to target this kinase oncogene therapeutically. PUBLIC HEALTH RELEVANCE: Although significant progress has been made in the diagnosis and treatment of breast cancer, we lack curative targeted therapies for many advanced stage breast cancers. This proposal focuses on deciphering the role of a newly discovered oncogene in breast cancer initiation and maintenance. These biochemical, cell and animal-based studies will not only provide insight into the biology of this kinase oncogene but will serve as a foundation for translational studies for the development of novel therapeutic agents.
Funding Period: 2009-03-01 - 2014-12-31
more information: NIH RePORT

Top Publications

  1. pmc Systematic interrogation of 3q26 identifies TLOC1 and SKIL as cancer drivers
    Daniel Hägerstrand
    1Departments of Medical Oncology and 2Cancer Biology 3Center for Cancer Genome Discovery, Dana Farber Cancer Institute 4Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston 5Broad Institute of Harvard and MIT, Cambridge, Massachusetts and 6Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina
    Cancer Discov 3:1044-57. 2013
  2. pmc RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer
    Violeta Serra
    Experimental Therapeutics, Vall d Hebron Institute of Oncology, Barcelona, Spain
    J Clin Invest 123:2551-63. 2013
  3. pmc Structure and ubiquitination-dependent activation of TANK-binding kinase 1
    Daqi Tu
    Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA
    Cell Rep 3:747-58. 2013
  4. pmc IKKε-mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex
    Alicia Y Zhou
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA
    Cell Rep 3:724-33. 2013
  5. pmc IκB kinase ε phosphorylates TRAF2 to promote mammary epithelial cell transformation
    Rhine R Shen
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
    Mol Cell Biol 32:4756-68. 2012
  6. pmc PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling
    Y Shrestha
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA
    Oncogene 31:3397-408. 2012
  7. pmc Emerging roles for the non-canonical IKKs in cancer
    R R Shen
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA
    Oncogene 30:631-41. 2011
  8. pmc CK1epsilon is required for breast cancers dependent on beta-catenin activity
    So Young Kim
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America
    PLoS ONE 5:e8979. 2010
  9. pmc Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1
    David A Barbie
    Department of Medical Oncology, Dana Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115 USA
    Nature 462:108-12. 2009
  10. pmc Phosphorylation of the tumor suppressor CYLD by the breast cancer oncogene IKKepsilon promotes cell transformation
    Jessica E Hutti
    Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
    Mol Cell 34:461-72. 2009

Detail Information

Publications13

  1. pmc Systematic interrogation of 3q26 identifies TLOC1 and SKIL as cancer drivers
    Daniel Hägerstrand
    1Departments of Medical Oncology and 2Cancer Biology 3Center for Cancer Genome Discovery, Dana Farber Cancer Institute 4Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston 5Broad Institute of Harvard and MIT, Cambridge, Massachusetts and 6Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina
    Cancer Discov 3:1044-57. 2013
    ..Together, these studies identify TLOC1 and SKIL as driver genes at 3q26 and more broadly suggest that cooperating genes may be coamplified in other regions with somatic copy number gain...
  2. pmc RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer
    Violeta Serra
    Experimental Therapeutics, Vall d Hebron Institute of Oncology, Barcelona, Spain
    J Clin Invest 123:2551-63. 2013
    ..These observations provide a strong rationale for the combined use of RSK and PI3K pathway inhibitors to elicit favorable responses in breast cancer patients with activated RSK...
  3. pmc Structure and ubiquitination-dependent activation of TANK-binding kinase 1
    Daqi Tu
    Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA
    Cell Rep 3:747-58. 2013
    ..The structure of TBK1 will facilitate studies of the atypical IKKs in normal and disease physiology and further the development of more specific inhibitors that may be useful as anticancer or anti-inflammatory agents...
  4. pmc IKKε-mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex
    Alicia Y Zhou
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA
    Cell Rep 3:724-33. 2013
    ..Altogether, these observations demonstrate that K63-linked polyubiquitination regulates IKKε activity in both inflammatory and oncogenic contexts and suggests an alternative approach to targeting this breast cancer oncogene...
  5. pmc IκB kinase ε phosphorylates TRAF2 to promote mammary epithelial cell transformation
    Rhine R Shen
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
    Mol Cell Biol 32:4756-68. 2012
    ..Breast cancer cells that depend on IKKε expression for survival are also dependent on TRAF2. This work defines TRAF2 phosphorylation to be one key effector of IKKε-induced mammary epithelial cell transformation...
  6. pmc PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling
    Y Shrestha
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA
    Oncogene 31:3397-408. 2012
    ....
  7. pmc Emerging roles for the non-canonical IKKs in cancer
    R R Shen
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA
    Oncogene 30:631-41. 2011
    ..In this review, we will highlight the mechanisms by which IKKɛ and TBK1 orchestrate pathways involved in inflammation and cancer...
  8. pmc CK1epsilon is required for breast cancers dependent on beta-catenin activity
    So Young Kim
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America
    PLoS ONE 5:e8979. 2010
    ..Aberrant beta-catenin signaling plays a key role in several cancer types, notably colon, liver and breast cancer. However approaches to modulate beta-catenin activity for therapeutic purposes have proven elusive to date...
  9. pmc Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1
    David A Barbie
    Department of Medical Oncology, Dana Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115 USA
    Nature 462:108-12. 2009
    ..These observations indicate that TBK1 and NF-kappaB signalling are essential in KRAS mutant tumours, and establish a general approach for the rational identification of co-dependent pathways in cancer...
  10. pmc Phosphorylation of the tumor suppressor CYLD by the breast cancer oncogene IKKepsilon promotes cell transformation
    Jessica E Hutti
    Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
    Mol Cell 34:461-72. 2009
    ..Together, these observations define IKKepsilon and CYLD as an oncogene-tumor suppressor network that participates in tumorigenesis...
  11. pmc Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit
    Zehua Zhu
    Departments of 1Medical Oncology and 2Cancer Biology, Dana Farber Cancer Institute 3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston 4Broad Institute of Harvard and MIT, Cambridge 5MGH Cancer Center, 6Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, Massachusetts and 7Department of Surgery, Division of Biology and Biomedical Sciences, Washington University, St Louis, Missouri
    Cancer Discov 4:452-65. 2014
    ....