ERalpha-induced C/EBPD inhibits SNAI2 expression and is a marker of good prognosis in breast cancer

Authors

• D Mendoza-Villanueva
• K Balamurugan
• R Ali
• SR Kim
• S Sharan
• R Johnson
• A Merchant
• C Caldas
• G Landberg
• E Sterneck

Abstract

Inflammation and hypoxia are strongly linked to cancer progression. Hypoxia and inflammatory cytokines like IL-6 signal in part through the transcription factor C/EBPD, which drives mesenchymal features and malignant progression of glioblastoma. Here we report a different role for C/EBPD in breast cancer. Previous studies in MMTV-Neu transgenic mice revealed contrasting functions of C/EBPD in reducing mammary tumor multiplicity while promoting metastasis. This study shows that the C/EBPD protein is expressed in normal breast and low-grade oestrogen receptor positive (ER+) cancers, and correlates with longer progressionfree survival of breast cancer patients. Functional studies in cell lines show that ERα promotes C/EBPD protein stability, and that C/EBPD attenuates cell growth, motility and invasiveness by inhibiting expression of the SNAI2 (Slug) transcriptional repressor, leading to expression of CDKN1A (p21CIP1/WAF1). Expression of CEBPD but not CEBPB mRNA in combination with IL6 correlates with lower risk of progression in ER+ breast cancer patients. These findings indicate that C/EBPD attenuates progression of ER+ breast cancer and support a potentially beneficial role for the IL-6 pathway in ER+ breast cancer.

Scientific Focus Area: Cancer Biology

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