Description of research

My research focuses on identifying and characterizing genes that regulate breast tumorigenesis.

Tumorigenesis is the multistep process by which normal cells are transformed into cancer cells by the activation of oncogenes and the inactivation of tumor suppressor genes. A central goal of cancer research is identifying and characterizing genes that drive tumorigenesis. The discovery of these critical genes in prior investigations has allowed the development of new therapeutic agents that have reduced both cancer morbidity and mortality. However, identifying these genes in human cancers is confounded by the inherent genomic instability of cancer cells, therefore novel techniques to identify genes with functional links to tumor initiation and development are essential.

In order to identify functionally important tumor suppressor genes I conducted the first human whole genome in vivo RNA interference (RNAi) screen. Using this approach, I identified several novel candidate breast tumor suppressor genes, including leukemia inhibitory factor receptor (LIFR). My further research demonstrated that LIFR is a key novel tumor suppressor, whose expression is significantly decreased in a large percentage of human cancers including breast, lung, hepatocellular and gastrointestinal tumors. My research validated LIFR as a previously unidentified tumor suppressor, and also demonstrated the power of whole genome in vivo RNAi screens as a method for identifying novel genes regulating tumorigenesis.

My ongoing research includes further characterizing additional novel tumor suppressor genes identified in my RNAi screen. I am also conducting in vivo RNAi screens to identify tumor suppressor genes that specifically mediate transformation of ERBB2 amplified breast cells, as well as screens to identify genes that inhibit metastasis formation.   

My current research continues my previous work conducted at the Institute of Cancer Research U.K., identifying modifiers of drug sensitivity using high-throughput RNAi and small molecule inhibitor screens.

I hope identifying and characterizing novel mechanisms of tumor and metastasis suppression will facilitate the translation of this knowledge into useful therapeutic strategies through the rational application of drugs that target the pathways deregulated by loss of suppressor gene function, reducing breast cancer morbidity and mortality.

Highlights/Discoveries

  • Performance of the first human whole genome in vivo RNAi screen. Screening the entire human genome allowed the identification of new and unanticipated tumor suppressor functions and enabled an unbiased assessment of tumor suppressor function on a global scale.
  • Discovery of a novel tumor suppressor gene, LIFR. LIFR deregulation may drive the transformation of a significant proportion of human cancers. Characterizing the mechanism by which LIFR suppresses tumorigenesis should lead to the development of new therapeutic approaches for the treatment of LIFR deficient tumors.
  • Discovery of CDK10 as an important determinant of sensitivity to anti-endocrine agents. This research identified a subgroup of patients with low CDK10 expressing, ER positive breast cancer who may not benefit from anti-endocrine therapy, suggesting that alternative therapeutic options may be required for treatment of these patients.
  • Discovery of the PDK1 pathway as a target for tamoxifen sensitization. This research indicated that PDK1 pathway inhibitors could enhance the therapeutic response of ER positive breast tumors to anti-endocrine therapy.