title: Distinct breast cancer stem/progenitor cell populations require either HIF1α or loss of PHD3 to expand under hypoxic conditions.
abstract: The heterogeneous nature of breast cancer is a result of intrinsic tumor complexity and also of the tumor microenvironment, which is known to be hypoxic. We found that hypoxia expands different breast stem/progenitor cell populations (cells with increased aldehyde dehydrogenase activity (Aldefluor+), high mammosphere formation capacity and CD44+CD24-/low cells) both in primary normal epithelial and tumor cells. The presence of the estrogen receptor (ER) limits hypoxia-dependent CD44+CD24-/low cell expansion.We further show that the hypoxia-driven cancer stem-like cell enrichment results from a dedifferentiation process. The enhanced mammosphere formation and Aldefluor+ cell content observed in breast cancer cells relies on hypoxia-inducible factor 1α (HIF1α). In contrast, the CD44+CD24-/low population expansion is HIF1α independent and requires prolyl hydroxylase 3 (PHD3) downregulation, which mimics hypoxic conditions, leading to reduced CD24 expression through activation of NFkB signaling. These studies show that hypoxic conditions expand CSC populations through distinct molecular mechanisms. Thus, potential therapies that combine current treatments for breast cancer with drugs that target CSC should take into account the heterogeneity of the CSC subpopulations.
authors.affiliation: Cell Biology and Stem Cells Unit, CIC bioGUNE, Derio, Spain.
authors.forename: Oihana
authors.initials: O
authors.lastname: Iriondo
authors.affiliation: Cell Biology and Stem Cells Unit, CIC bioGUNE, Derio, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Rábano
authors.affiliation: Cell Biology and Stem Cells Unit, CIC bioGUNE, Derio, Spain.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Domenici
authors.affiliation: Cell Biology and Stem Cells Unit, CIC bioGUNE, Derio, Spain.
authors.forename: Onintza
authors.initials: O
authors.lastname: Carlevaris
authors.affiliation: Servicio de Radiodiagnóstico Preteimagen, Bilbao, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: López-Ruiz
authors.affiliation: Department of Pathology, Galdakao-Usansolo Hospital, Galdakao, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Zabalza
authors.affiliation: Cell Biology and Stem Cells Unit, CIC bioGUNE, Derio, Spain.
authors.forename: Edurne
authors.initials: E
authors.lastname: Berra
authors.affiliation: Cell Biology and Stem Cells Unit, CIC bioGUNE, Derio, Spain.
authors.forename: Maria dM
authors.initials: Md
authors.lastname: Vivanco
mesh_terms: D000328:Adult; D017209:Apoptosis; D001940:Breast / Q000166:cytology / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D051927:CD24 Antigen; C497442:HIF1A protein, human; D018960:Hyaluronan Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
keywords: PHD3; breast cancer; estrogen receptor; hypoxia; stem cells