| First Author | Caffarel MM | Year | 2012 |
| Journal | Cell Death Differ | Volume | 19 |
| Issue | 3 | Pages | 511-22 |
| PubMed ID | 21941370 | Mgi Jnum | J:203080 |
| Mgi Id | MGI:5524193 | Doi | 10.1038/cdd.2011.122 |
| Citation | Caffarel MM, et al. (2012) Constitutive activation of JAK2 in mammary epithelium elevates Stat5 signalling, promotes alveologenesis and resistance to cell death, and contributes to tumourigenesis. Cell Death Differ 19(3):511-22 |
| abstractText | Signalling through the janus kinase (JAK)/signal transducer and activator of transcription (Stat) pathway is required at different stages of mammary gland development, and this pathway is frequently hyper-activated in cancer, including tumours of the breast. Stats 3, 5 and 6 have important roles in the differentiation and survival of mammary alveolar cells, but somewhat paradoxically, both Stat3 and 5 can have oncogenic activity in the mammary gland. Constitutive activation of JAK2 could be anticipated to result in hyper-activation of Stats 1, 3, 5 and 6 with concomitant cell transformation, although the outcome is difficult to envisage, particularly since Stats 3 and 5 play opposing roles in normal mammary gland development. Here, we show that expression of a constitutively active JAK2 mutant, JAK2 V617F, leads to hyper-activation of Stat5 in mammary epithelial cells (MECs), and transgenic mice expressing JAK2 V617F specifically in the mammary gland exhibit accelerated alveologenesis during pregnancy and delayed post-lactational regression. Overexpressing JAK2 V617F in MECs in vitro results in elevated proliferation and resistance to cell death. Furthermore, constitutively active JAK2 enhances anchorage-independent cell growth in the presence of a co-operating oncogene and accelerates tumourigenesis in a xenograft model. Taken together, our results provide insights into signalling downstream of constitutively active JAK2 and could be important for understanding the molecular mechanisms of breast tumourigenesis. |
