Investigating functions of the transcription factor Ets1 in squamous cell carcinoma
Chin, Shu Shien
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The skin epidermis comprised of multilayered keratinocytes provides a protective barrier against mechanical and chemical insults, dehydration and other foreign substances. To establish the barrier function of the skin, keratinocytes in the interfollicular epidermis undergo a tightly controlled program of differentiation. Like other organs in our body, the skin is prone to several diseases including squamous cell carcinoma (SCC). SCC is one of the most common skin diseases and it can progress to malignant and metastatic tumors. One transcription factor that is important for the progression of SCC is Ets1, which is frequently up-regulated in SCC and other cancers. Elevated expression of Ets1 in cancers is associated with poor prognosis, de-differentiation and invasiveness. Although Ets1 appears to have minimal role for epidermal development, its mechanism of action in skin SCC is not well understood. To better understand the molecular mechanism by which Ets1 functions, I have used a Tetracycline inducible bi-transgenic mouse model to examine the roles of Ets1 in pro-oncogenic changes when it is expressed suprabasally in the skin epidermis. Suprabasal over-expression of Ets1 led to dramatic alterations in the skin that were similar to pre-oncogenic transformations observed in SCC. Additional pathways regulated by Ets1 were identified by a global gene profiling experiment that was performed using keratinocytes isolated from the bi-transgenic embryos. Then, to identify the partners with which Ets1 may cooperate during the progression of SCC, I crossed the inducible bi-transgenic mice to different mouse lines that were on an either Mmp13 null or p53 null background. Lastly, I also used the inducible mouse model system to over-express Ets1 in the basal compartment of the skin epidermis. Over-expression of Ets1 in the basal layer is associated with unique changes such as a block in spinous cell differentiation. Some phenotypic features induced by Ets1 over-expression, such as hyper-proliferation, inflammation and angiogenesis, were observed in both bi-transgenic mouse model systems. This suggests a role for Ets1 in regulating these processes during SCC progression. Finally, the work in this thesis has shed light on the signaling pathways and molecular mechanism by which Ets1 regulates during SCC progression.