C/EBPδ links IL-6 and HIF-1 signaling to promote breast cancer stem cell-associated phenotypes.

Abstract

To improve cancer patient outcome significantly, we must understand the mechanisms regulating stem-like cancer cells, which have been implicated as a cause of metastasis and treatment resistance. The transcription factor C/EBPδ can exhibit pro- and anti-tumorigenic activities, but the mechanisms underlying the complexity of its functions are poorly understood. Here we identify a role for breast cancer cell intrinsic C/EBPδ in promoting phenotypes that have been associated with cancer stem cells (CSCs). While C/EBPδ expression is not abundant in most metastatic breast cancers, our data support a pro-tumorigenic role of C/EBPδ when expressed in subsets of tumor cells and/or through transient activation by the tumor microenvironment or loss of substrate adhesion. Using genetic mouse models and human breast cancer cell lines, we show that deletion or depletion of C/EBPδ reduced expression of stem cell factors and stemnness markers, sphere formation and self-renewal, along with growth of tumors and established experimental metastases in vivo. C/EBPδ is also known as a mediator of the innate immune response, which is enhanced by hypoxia and interleukin-6 (IL-6) signaling, two conditions that also play important roles in cancer progression. Our mechanistic data reveal C/EBPδ as a link that engages two positive feedback loops, in part by directly targeting the IL-6 receptor (IL6RA) gene, and, thus, amplifying IL-6 and HIF-1 signaling. This study provides a molecular mechanism for the synergism of tumor microenvironmental conditions in cancer progression with potential implications for the targeting of CSCs.

• Authors: Kuppusamy Balamurugan, Daniel Mendoza-Villanueva, Shikha Sharan, Glenn H Summers, Lacey E Dobrolecki, Michael T Lewis, Esta Sterneck
• Journal: Oncogene (Oncogene) Vol. 38 Issue 20 Pg. 3765-3780 (05 2019) ISSN: 1476-5594 [Electronic] England
• PMID: 30262865 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• CEBPD protein, human
• F-Box-WD Repeat-Containing Protein 7
• FBXW7 protein, human
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• IL6 protein, human
• IL6R protein, human
• Interleukin-6
• Receptors, Interleukin-6
• CCAAT-Enhancer-Binding Protein-delta

Topics

• Animals
• Breast Neoplasms (metabolism, pathology)
• CCAAT-Enhancer-Binding Protein-delta (genetics, metabolism)
• Cell Line, Tumor
• F-Box-WD Repeat-Containing Protein 7 (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Interleukin-6 (metabolism)
• Lung Neoplasms (genetics, pathology, secondary)
• Mice, Knockout
• Neoplastic Stem Cells (metabolism, pathology)
• Receptors, Interleukin-6 (genetics)
• Signal Transduction (genetics)
• Tumor Microenvironment
• Xenograft Model Antitumor Assays