title: Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ.
abstract: In cultured neuroblastoma cells, hypoxia induces a dedifferentiated phenotype. We tested whether hypoxia-induced dedifferentiation also occurs in vivo in mammary ductal carcinoma in situ with its well-defined lesions and distinct areas of necrosis. Ductal carcinoma in situ cells surrounding the central necrosis have high hypoxia inducible factor-1alpha protein levels, down-regulated estrogen receptor-alpha, and increased expression of the epithelial breast stem cell marker cytokeratin 19; lose their polarization; and acquire an increased nucleus/cytoplasm ratio, hallmarks of poor architectural and cellular differentiation. The hypoxia-induced changes were confirmed in cultured breast cancer cells. We propose that hypoxia-induced dedifferentiation is a mechanism that promotes tumor progression in breast cancer.
authors.affiliation: Department of Laboratory Medicine, Lund University, S-20502 Malmö, Sweden.
authors.forename: Karolina
authors.initials: K
authors.lastname: Helczynska
authors.forename: Asa
authors.initials: A
authors.lastname: Kronblad
authors.forename: Annika
authors.initials: A
authors.lastname: Jögi
authors.forename: Elise
authors.initials: E
authors.lastname: Nilsson
authors.forename: Siv
authors.initials: S
authors.lastname: Beckman
authors.forename: Göran
authors.initials: G
authors.lastname: Landberg
authors.forename: Sven
authors.initials: S
authors.lastname: Påhlman
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002278:Carcinoma in Situ / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D015536:Down-Regulation; D047628:Estrogen Receptor alpha; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007633:Keratins / Q000096:biosynthesis / Q000235:genetics; D009336:Necrosis; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D047628:Estrogen Receptor alpha; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011960:Receptors, Estrogen; D014157:Transcription Factors; D007633:Keratins