Research Papers:

Distinct breast cancer stem/progenitor cell populations require either HIF1α or loss of PHD3 to expand under hypoxic conditions

Oihana Iriondo, Miriam Rábano, Giacomo Domenici, Onintza Carlevaris, José Antonio López-Ruiz, Ignacio Zabalza, Edurne Berra and Maria dM Vivanco _

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Oncotarget. 2015; 6:31721-31739. https://doi.org/10.18632/oncotarget.5564

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Oihana Iriondo1, Miriam Rábano1, Giacomo Domenici1, Onintza Carlevaris1, José Antonio López-Ruiz2, Ignacio Zabalza3, Edurne Berra1 and Maria dM Vivanco1

1 Cell Biology and Stem Cells Unit, CIC bioGUNE, Derio, Spain

2 Servicio de Radiodiagnóstico Preteimagen, Bilbao, Spain

3 Department of Pathology, Galdakao-Usansolo Hospital, Galdakao, Spain

Correspondence to:

Maria dM Vivanco, email:

Keywords: breast cancer, estrogen receptor, hypoxia, PHD3, stem cells

Received: March 16, 2015 Accepted: August 10, 2015 Published: September 10, 2015


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.

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