title: Constitutive activation of JAK2 in mammary epithelium elevates Stat5 signalling, promotes alveologenesis and resistance to cell death, and contributes to tumourigenesis.
abstract: 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.
authors.affiliation: Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, UK. mm794@cam.ac.uk
authors.forename: M M
authors.initials: MM
authors.lastname: Caffarel
authors.forename: R
authors.initials: R
authors.lastname: Zaragoza
authors.forename: S
authors.initials: S
authors.lastname: Pensa
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: A R
authors.initials: AR
authors.lastname: Green
authors.forename: C J
authors.initials: CJ
authors.lastname: Watson
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D007774:Lactation / Q000235:genetics; D008297:Male; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D020125:Mutation, Missense; D009368:Neoplasm Transplantation; D011247:Pregnancy; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014183:Transplantation, Heterologous
chemical_list: D050799:STAT5 Transcription Factor; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2