In Vivo Role of Six1 in Mammary Gland Tumorigenesis

摘要

14. ABSTRACT Homeobox transcription factor Six1 has been associated with tumorigenesis and metastasis in a number of organ systems and has been implicated in proliferation, survival, and migration during normal development. Our research is aimed at utilizing mouse models to understand in the role of Six1 in the onset and progression of breast cancer. Most significantly, we have determined that Six1 is sufficient to induce tumor formation in the mammary glands of mice genetically engineered to inducibly overexpress the gene. The latency for tumor formation is between 12-24 months and the tumors that arise in these animals are very aggressive and have morphological features of an epithelial to mesenchymal transition (EMT), a phenomenon that has recently been suggested to contribute to metastasis, and stem cell origin. Molecular analysis of these tumors has revealed activation of the Wnt signaling pathway, a pathway implicated in maintaining EMT and a stem cell fate that may contribute to tumorigenesis. Additionally, we have discovered that our inducible mouse model allows for leaky transcription of Six1 in the uninduced state. Interestingly, animals from this group acquire tumors at an increased frequency compared to those animals that are induced to express Six1, suggesting that even low levels of Six1 are capable, and may even be more efficient at initiating tumorigenesis compared to higher Six1 levels. These compelling results in combination with similar findings in our experiments involving Six1 in combination with PyMT have led to more studies to dissect the role of Six1 levels and its cofactors in breast cancer initiation and progression.