A relatively few major cell fate regulatory pathways appear to be critical for i) embryonic and fetal development as well as for ii) tumor initiation and progression. With a focus on breast cancer and a goal of improved cancer treatment or even cancer prevention, our laboratory is interested in understanding how major cell fate regulatory factors function in tumor initiation. In 1999 the laboratory reported the first successful use of epithelial cells as a host for oncogene isolation by a technique termed expression cloning, where cDNA libraries are expressed in an indicator line, and transforming oncogenes are therefore identified by their phenotype (Foster KW et al., Cell Growth & Differentiaton). We now utilize a spectrum of models, including very basic epithelial models of in vitro transformation and more complex mouse models, including genetic and carcinogen-induced mouse models of cancer (e.g., Foster KW et al., Oncogene 2005; Li X et al., Oncogene 2006). Observations made in these models are ultimately correlated with gene or protein expression patterns and/or with clinical outcome in patients (e.g., Pandya A et al., Clin Cancer Res 2004; Liu Z et al., Cancer Biol & Ther 2009). Zinc finger transcription factors (ZFTFs) such as Kruppel-like factor (KLF4) and Gli1 are major regulators of pluripotency and are attractive as early mediators (initiators) of the malignant process in tumors such as the breast and skin. For example, we found that induction of KLF4 in the skin results in a rapid-onset, single gene model of cutaneous squamous cell carcinoma (Foster, K.W. et al., Oncogene 2005). Many reports now support the idea that these ZFTFs have important functions in tumor initiation and cancer cell fate. For example, KLF4 was more recently identified as one of the four “Yamanaka factors” that together are sufficient to Induce the Pluripotent Stem cell fate (IPS cells). These same factors have important roles in relevant cell biological processes such as the epithelial-mesenchymal transition and cancer stem cell features. Using in vitro transformation of cultured RK3E epithelial cells and/or transgenic mouse models we identified several small molecules that selectively block the activity of KLF4 (e.g., retinoids, γ-secretase inhibitors) or Gli1 (e.g., rapamycin or its analogues). Additionally, more recent studies have identified specific microRNAs (miRs) that are candidate downstream effectors (e.g., microRNA-206), indicating that specific antago-miRs may be useful for cancer treatment or prevention. We envision accomplishing novel cancer prevention or cancer therapy strategies in a physiologically-relevant mouse model and then translating the strategy to patients.
Dr. Ruppert was recruited to WVU in 2008 as the first recipient of the Jo and Ben Statler Chair in Breast Cancer Research. Our laboratory is located in the newly built Erma Byrd Biomedical Research Building, within walking distance of over 50 other research laboratories working in related areas of biomedicine. Our academic home is the Department of Biochemistry (Michael Schaller, Chair). Among other responsibilities, Dr. Ruppert serves as Director of the MD PhD Program at the WVU School of Medicine. Students in the Ruppert Laboratory can enter one of several Graduate Programs at the Health Sciences Center including the Cancer Cell Biology or Biochemistry Graduate Programs. Within the Mary Babb Randolph Cancer Center Dr. Ruppert serves as Co-Director of the Breast Cancer Research Program. This provides the opportunity to interact with approximately one dozen other laboratories that share an interest in breast cancer research. The resulting academic environment is both robust and interactive.