The role of signal transducer and activator of transcription 5 (Stat5) in mammary gland development and tumorigenesis.

摘要

With over 184,000 reported cases in 2008 in the US, breast cancer is one of the most common types of cancer diagnosed in women, with over 40,000 of these cases resulting in deaths each year. The initiation and progression of human breast cancer is a multi-step process involving alterations to the genome and proteome, dysregulation of the tissue microenvironment, and a loss of cellular control mechanisms regulated by hormonal factors. The development of new transgenic systems to model these steps in cancer development have led to a greater understanding of how these variations in normal cellular control can contribute to neoplastic transformation of mammary epithelial cells. There is increasing evidence that the upregulation and activation of the prolactin-induced Jak2/Stat5 pathway may be involved in the initiation of a subset human breast cancer. In this dissertation, I describe the generation and analysis of a novel bi-transgenic, doxycycline-inducible mouse model system to investigate the role of Stat5 in both normal mammary gland development as well as tumorigenesis. Using this model system, I can demonstrate that this transcription factor plays an important biological role in the survival of mammary epithelial cells. My studies provide experimental evidence in vivo and in cell culture models that Stat5 regulates the expression of the pro-survival gene Akt1 in a unique manner. It binds to various consensus sites within the Akt1 gene, and it activates the transcription of Akt1 through a mammary-specific promoter. The conditional overexpression of Stat5 during the early phases of post-lactational involution leads to a sustained expression of total and phosphorylated Akt1, and this transcriptional cascade is sufficient to override pro-apoptotic signals that are activated by Stat3 and its downstream targets, p50 and p55. Since inhibition of programmed cell death is one hallmark of cancer, my studies might provide evidence that a sustained expression and activation of Stat5 may contribute to neoplastic transformation, and this transcription factor could therefore serve as a target for preventing the initiation of breast cancer.