Essential functions of the Janus kinase 2 (Jak2) during mammary gland development and tumorigenesis

Excerpt

Jak2 is a hormone-receptor-coupled kinase that mediates the tyrosine phosphorylation and activation of signal transducers and activators of transcription (Stat). The biological relevance of Jak/Stat signaling in hormone-responsive adult tissues is difficult to investigate since Jak2 deficiency leads to embryonic lethality [1‐3]. We therefore generated various Jak2 conditional knockout models to study essential functions of Jak2 during particular stages of mammary gland development and during neoplastic transformation in a Her2/neu-overexpressing breast cancer model. Our experiments show that Jak2 is essential for mammogenesis in virgin, pregnant, and postpartum females [4]. In addition to its pivotal role for mammary epithelial cell proliferation, specification, and differentiation, we demonstrate that this kinase is indispensable for the prolactin-mediated activation of Stat5 and the maintenance of functionally differentiated alveolar cells during lactation. A primary focus of our current research is to examine how Jak/Stat signaling cascades are altered in breast cancer models that initiate tumorigenesis through overexpression of growth factor receptors, in particular ErbB2 (Her2/neu). The uniqueness of our model design enables us to genetically modify Jak/Stat signaling both prior to growth factor-mediated neoplastic transformation (cancer prevention) and during particular stages of the progressing disease (cancer therapy). …