Role of Stat5a in Differentiation of Human Breast Cancer
Annual summary rept. 15 May 2007-14 May 2008
THOMAS JEFFERSON UNIV PHILADELPHIA PA
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The Prolactin PRL-Jak2-Stat5 pathway has been described as a key regulator in the normal growth, development, and differentiation of human breast epithelia. Recent evidence from our lab and others has suggested that active Stat5 is a positive predictive marker of prognosis in breast cancer patients and the loss of active Stat5 correlates with a more aggressive disease state. Further, in vitro expression of Stat5 increased differentiation characteristics of human breast cancer cell lines and was able to inhibit invasive characteristics in human breast cancer cell lines. The specific aims of this proposal were designed to further investigate the role of Stat5 in breast cancer progression and metastasis. We hypothesize that active Stat5a suppresses invasion and metastasis of human breast cancer by promoting upregulation of differentiation markers, increasing homotypic adhesion, and inhibiting growth. We aim to test this hypothesis in human breast cancer cell lines both in vitro and in vivo using a novel constitutively active Stat5a construct. We have constructed constitutively active Stat5 mutants and generated adenoviral, lentiviral, and tetracycline-inducible expression systems. We have also generated stable cell lines expressing these constructs. Stable expression of Stat5 in mesenchymal MDA-MB- 231 breast cancer cells does not yield consistent results with those seen in transient expression systems, and it is likely that we are not using an appropriate cell line to study Stat5 signaling. We are in the process of optimizing cell lines and assays to measure Stat5 differentiation in a more relevant setting where Stat5 intracellular regulators are more likely to be present and functioning.
- Medicine and Medical Research