Research Abstract:
The goal of my lab is to discover novel mechanisms regulating epithelial cancer development. Currently, we are focused on signaling pathways regulating four processes, hypoxic signaling (hypoxia inducible factor-1a HIF-1), sensing of nutrients/metabolism TSC-1/2, Rheb, mTOR), stem cell fate decisions (Notch system), and cervical carcinogenesis initiated by human papillomavirus (estrogen-HPV16). We have developed in-vivo mouse models of multistage carcinogenesis to test the role of each of these systems in cancer progression and growth.
Hypoxic cells activate a “master regulatory” heterodimeric transcription factor, hypoxia-inducible factor-1 (HIF-1). HIF-1 upregulates several genes important for cancer progression such as vascular endothelial cell growth factor (VEGF), cyclooxygenase-2, glucose transporters and glycolytic enzymes, proteases (MMP2 and urokinase plasminogen activator) and growth factors (endothelin-1). To determine the epithelial biology of gain of HIF-1a function in three distinct epithelia, we created transgenic mouse models of HIF-1a overexpression in skin, cervix, or prostate. Future work will investigate the role of HIF-1a in combination with gain or loss of oncogenes or tumor suppressor genes at each of these sites.
Cells in nutrient-rich environments or stimulated by growth factors activate a pathway PI3K, AKT, TSC-1/2, Rheb, and mTOR (mammalian target of rapamycin) which has been shown to support growth of a variety of human malignancies includeing prostate cancer. mTOR increases ribosome biogenesis and translation of a specific subset of proteins, controlling angiogenesis (VEGF) and cell proliferation (c-myc, cyclin D). We have created transgenic models of mTOR gain of function and are developing models of TSC-1 loss of function to determine the biology of this pathway in mouse prostate.
HPV16 infection and viral persistence cause human cervix cancer. HPV16 initiates premalignant cervical dysplasia, and additional, somatic mutations produce invasive cancer. One such mutation implicated in human cervical carcinogenesis is loss of Notch function We created a unique model of cervical carcinogenesis in HPV16 transgenic mice. We have developed a technique for cervical epithelial cell gene recombination and will now determine the biology of loss of Notch-1 function alone or in combination with HPV16 in cervical carcinogenesis.
Figure Legend: The left panel demonstrates cervical epithelial cells whose floxed beta-galactosidase cDNA has recombined following intrauterine injection of adenovirus expressing Cre recombinase. The middle and right panels are lectin injected skin from a nontransgenic and a transgenic mouse overexpressing a constitutively active HIF-1 mutant transgene.
Selected Publications:
Kaufman B, Scharf O, Arbeit J, et al. Proceedings of the oxygen homeostasis/hypoxia meeting. Cancer Res 2004 64:3350-3356.
Riley RR, Brake T, Duensing S, et al. Dissection of human papillomavirus E6 and E7 function in transgenic mouse models of cervical carcinogenesis. Cancer Res 2003 63:4862-4871.
Arbeit JM. Quiescent hypervascularity mediated by gain of HIF-1a function. Cold Spring Harb Symp Quant Biol 2002 67:133-142.
Elson DA, Thurston G, Huang LE, et al. Induction of hypervascularity without leak or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1a. Genes Dev 2001 15:2520-2532.
Elson DA, Riley RR, Lacy A, et al. Sensitivity of the cervical transformation zone to estrogen-induced squamous carcinogenesis. Cancer Res 2000 60:1267-1275.
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