title: Hypoxia-inducible factor 1 is activated by dysregulated cyclin E during mammary epithelial morphogenesis.
abstract: Increased cyclin E expression has been identified in human tumors of diverse histologies, and in studies of primary breast cancers, high cyclin E is associated with poor prognosis. We have studied dysregulated cyclin E in epithelial tissues using organotypic cultures of human mammary epithelial cells and a murine model. We unexpectedly discovered that dysregulated cyclin E impairs normal acinar morphogenesis in vitro, and this is associated with the induction of p21(Cip1), p27(Kip1), and cellular senescence. Cyclin E-induced morphogenesis arrest is dependent upon hypoxia-inducible factor 1α (HIF-1α), which itself is induced by high cyclin E both in cultured mammary acini and in mammary epithelial tissues in a mouse model of deregulated cyclin E expression. We next determined that E2F activity directly regulates and is required for induction of HIF1A by cyclin E. Additionally, we found that cyclin E deregulation in mammary acini decreases, in an E2F-independent manner, expression of the EGLN1 prolyl hydroxylase that regulates HIF-1α degradation within the VHL ubiquitin ligase pathway. Together, our findings reveal a direct link between cyclin E and HIF-1 activities in mammary epithelial cells and implicate HIF-1 as a mediator of proliferation-independent phenotypes associated with high cyclin E expression in some human breast cancers.
authors: Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors: Tanushri
authors: T
authors: Sengupta
authors: Gathi
authors: G
authors: Abraham
authors: Yanfei
authors: Y
authors: Xu
authors: Bruce E
authors: BE
authors: Clurman
authors: Alex C
authors: AC
authors: Minella
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002453:Cell Cycle; D002460:Cell Line; D016922:Cellular Senescence; D047369:Chromatin Immunoprecipitation; D019927:Cyclin E / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis* / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis* / Q000378:metabolism; D050684:E2F Transcription Factors / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000166:cytology*; D042361:Mammary Glands, Human / Q000166:cytology*; D051379:Mice; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050684:E2F Transcription Factors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D050760:Cyclin-Dependent Kinase Inhibitor p27