Role of Splicing Factors in Breast Cancer

Summary

Principal Investigator: OLGA ANCZUKOW-CAMARDA
Abstract: DESCRIPTION (provided by applicant): Cancer cells often display aberrant profiles of alternative splicing, leading to the production of protein isoforms that can increase cell proliferation, migration, and apoptotic resistance. My long-term goal is to establish an independent research lab, where I will elucidate molecular mechanisms by which alternative splicing misregulation plays a role in cancer by altering the expression of various oncogenes and tumor-suppressor genes. Importantly, these findings will translate into the development of novel therapeutic strategies. The K99/R00 career award will help in achieving this goal by advancing my training in: antisense oligonucleotide technologies under the guidance of my primary mentor Dr. Adrian Krainer;next-generation sequencing under the co-mentorship of Dr. Michael Schatz;and metastatic breast cancer models under the co-mentorship of Dr. Mikala Egeblad. This training will complement my previous expertise in breast cancer research and RNA splicing mechanisms. The very stimulating scientific environment at Cold Spring Harbor Laboratory will not only provide me with the expertise and facilities necessary for the completion of the mentored phase of this project, but will also prepare me to transition smoothly into an independent faculty position. During the K99 mentored phase, I will define the role of splicing factors and splicing misregulation in breast cancer. In the subsequent R00 independent phase, I will indentify oncogenic splicing events that could constitute therapeutic targets to pursue during my future independent research. We have previously demonstrated that overexpression of the splicing factor SRSF1 can transform human mammary epithelial cells in vitro and in vivo. We have also shown that SRFS1 levels are directly regulated by the MYC oncoprotein. However, additional splicing factors are also overexpressed in human breast tumors, suggesting that they may also play a role in breast cancer. In Aim 1, during the K99 phase, I will determine the role of specific splicing factors in breast cancer using relevant cell and animal models that mimic the biological context in which the tumors arise. This includes: (i) identifying changes in alternative splicing events underlying splicing-factor- mediated transformation by next-generation RNA-sequencing in 3-D cultures of human mammary epithelial cells;and (ii) defining the metastatic potential of these oncogenic splicing factors using in vivo mouse models. In Aim 2, during the K99 phase, I will determine the role of MYC in the regulation of alternative splicing in breast cancer, by identifying changes in both splicing-factor expression and in alternative splicing profiles by next-generation RNA-sequencing in a MYC-inducible cell culture system. In Aim 3, during the R00 phase, I will determine the role of splicing factors in acquisition of resistance to tyrosine kinase inhibitors in breast cancer, by identifying changes in splicing-factor levels and i alternative splicing events. Finally, starting in the K99 phase and leading into the R00 phase, I will determine the therapeutic potential of using antisense oligonucleotides to modulate specific oncogenic alternative splicing events identified in Aims 1-3. The proposed research will identify not only splicing factors involved in breast cancer but also their regulators and specific targets. This plan will establish the basis for my independent research program, in which I plan to contribute to the development of new cancer therapies based on modulating the expression and activity of splicing factors or their targets.
Funding Period: 2013-09-01 - 2015-08-31
more information: NIH RePORT

Research Grants

  1. Mechanisms of Esophageal Carcinogenesis
    Anil K Rustgi; Fiscal Year: 2013
  2. Molecular Pathogenesis of Basal-like Breast Cancer
    Richard J Baer; Fiscal Year: 2013
  3. South Carolina Cancer Disparities Community Network -- II
    James R Hebert; Fiscal Year: 2013
  4. ROLES AND REGULATION OF P53
    Carol Prives; Fiscal Year: 2013
  5. Specialized Program of Research Excellence
    Jennifer Rubin Grandis; Fiscal Year: 2013
  6. Signaling and Progression in Prostate Cancer
    Dan Theodorescu; Fiscal Year: 2013
  7. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
  8. SPORE in Soft Tissue Sarcoma
    Samuel Singer; Fiscal Year: 2013
  9. Proteolytic matriptase-prostasin axis in breast cancer
    Karin List; Fiscal Year: 2013
  10. Role of 11q23 Chromosome Abnormalities in the Causation of Acute Leukemia
    Carlo M Croce; Fiscal Year: 2013

Detail Information

Research Grants30

  1. Mechanisms of Esophageal Carcinogenesis
    Anil K Rustgi; Fiscal Year: 2013
    ..abstract_text> ..
  2. Molecular Pathogenesis of Basal-like Breast Cancer
    Richard J Baer; Fiscal Year: 2013
    ..e., metastasis, and develop strategies for therapy. ..
  3. South Carolina Cancer Disparities Community Network -- II
    James R Hebert; Fiscal Year: 2013
    ....
  4. ROLES AND REGULATION OF P53
    Carol Prives; Fiscal Year: 2013
    ..The projects are even more interdependent and interactive than before and as a result much of the proposed research cannot be done effectively without the support of this program. ..
  5. Specialized Program of Research Excellence
    Jennifer Rubin Grandis; Fiscal Year: 2013
    ..abstract_text> ..
  6. Signaling and Progression in Prostate Cancer
    Dan Theodorescu; Fiscal Year: 2013
    ..The long-term objective is to translate our understanding of prostate cancer progression mechanisms into the identification of new drug targets and pre-clinical models that recapitulate key aspects of the human disease. ..
  7. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  8. SPORE in Soft Tissue Sarcoma
    Samuel Singer; Fiscal Year: 2013
    ..abstract_text> ..
  9. Proteolytic matriptase-prostasin axis in breast cancer
    Karin List; Fiscal Year: 2013
    ..The combination of state-of-the art mouse genetics with 2D and 3D cell culture based assays encompasses an innovative strategy for studying human cancerous disease, and may offer new avenues for diagnosis and therapy of breast cancer. ..
  10. Role of 11q23 Chromosome Abnormalities in the Causation of Acute Leukemia
    Carlo M Croce; Fiscal Year: 2013
    ..abstract_text> ..
  11. INTEGRATIVE PATHOPHYSIOLOGY OF SOLID TUMORS
    Rakesh K Jain; Fiscal Year: 2013
    ..abstract_text> ..
  12. Interrogating Epigenetic Changes in Cancer Genomes
    Tim H M Huang; Fiscal Year: 2013
    ..abstract_text> ..
  13. The Biology of Prostate Cancer Skeletal Metastases
    EVAN TODD KELLER; Fiscal Year: 2013
    ..This combination of investigators, projects and cores result in a highly synergistic Program that will continue to provide cutting-edge research on PCa bone metastases. ..
  14. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..
  15. Model-based predictions of responses RTK Pathway therapies
    Joe W Gray; Fiscal Year: 2013
    ..abstract_text> ..
  16. Exploiting synthetic-lethal interactions to target triple-negative breast cancers
    Dai Horiuchi; Fiscal Year: 2013
    ..If successful, the proposed research will not only expand our knowledge on MYC biology but will also provide novel therapeutic concepts to be tested again patients with TN tumors. ..
  17. CENTER FOR BIOMEDICAL RESEARCH
    Timothy Turner; Fiscal Year: 2013
    ..abstract_text> ..