C/EBPdelta Links Hypoxia And Inflammation To The Promotion Of Cancer Stem Cell Characteristics And Is a Target For HDAC Inhibitors

Wednesday, September 24, 2014 — Poster Session IV
10:00 a.m. –12:00 p.m.	FAES Academic Center	NCI	CANCER-3

Authors

• B Balamurugan Kuppusamy
• G Glenn Summers
• S Sharan
• E Sterneck

Abstract

Breast cancer associated mortality is due to metastases. Hypoxia and inflammation are common in the tumor microenvironment and play a key role in tumor progression. We have shown that the transcription factor CCAAT/enhancer binding protein delta (CEBPD) augments metastasis in a mouse model of breast cancer; and that CEBPD promotes hypoxia adaptation and inflammatory signaling by inhibiting expression of the tumor suppressor FBXW7. Hypoxia and inflammation also promote the development of cancer stem cells (CSCs), a sub-population of tumor cells that drive tumorigenesis, promote metastasis and drug resistance. Here, we show that the CEBPD-FBXW7 pathway supports CSC features of human and mouse breast tumor cells specifically under hypoxia and inflammatory conditions. Because CEBPD can interact with histone deactylases (HDACs), we tested the effect of HDAC inhibitors (HDACi) that are in clinical trials for breast cancer. HDACi inhibited CEBPD expression but induced FBXW7 expression, and reduced mammosphere formation specifically under hypoxia, which was partially rescued by FBXW7 knockdown. These results suggest a therapeutic benefit of HDACi through activation of FBXW7 and inhibition of CEBPD followed by reduction in CSCs. Our future investigations will explore drug combinations with HDACi to maximize the effectiveness of the FBXW7 tumor suppressor pathway.

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