The transcription factor CCAAT/enhancer binding protein delta (CEBPD, C/EBP) is expressed in normal breast epithelial cells and down-regulated in breast cancer tissue and cell lines. In the MMTV-c-Neu mouse mammary tumor model, loss of CEBPD leads to increased tumor incidence but reduced tumor metastasis, suggesting dual functions as a tumor suppressor and tumor promoter.
To investigate the role of CEBPD in human breast cancer, we analyzed tissue microarrays (TMA) by immunostaining. Analysis of 79 breast tumor samples confirmed overall downregulation of CEBPD in cancer but also revealed that CEBPD was expressed in 50% of estrogen receptor (ER) positive (+) breast tumors and associated with longer disease-specific patient survival (P=0.034, log-rank test). Furthermore, CEBPD was correlated with expression of progesterone receptor (PR; P=0.0007). Results from an independent TMA of 292 tumors from patients that were randomized to no adjuvant treatment or two years of tamoxifen (TAM) treatment confirmed that CEBPD expression was an independent good prognostic marker for ER(+) patients (progression-free survival, Multivariate Cox analysis P=0.041). Within the subgroup with high PR labeling, low or no expression of CEBPD was associated with worst prognosis if untreated and associated with significant response to TAM (P=0.034). On the other hand, patients with high CEBPD had better prognosis but did not further benefit from TAM. These data indicate that CEBPD expression is significantly associated with ER/PR(+) breast cancer and has potential as prognostic and/or predictive biomarker.
To investigate the functions of CEBPD we silenced its expression in the ER/PR(+) MCF-7 breast tumor cell line. We found that CEBPD attenuates proliferation and promotes estrogen-dependence. In this cell culture model, CEBPD augmented MCF-7 cell sensitivity to TAM. Furthermore, we found that CEBPD promotes cell-cell adhesion through expression of alpha-catenin. These observations are consistent with a tumor suppressor-like function for CEBPD in ER/PR(+) cancer cells. Currently, we are using ChIP-Seq and mRNA-Seq approaches in MCF-7 cells to identify a CEBPD-dependent gene signature and test its prognostic value in breast cancer gene expression data. Our long-term goal is to contribute to the development of more precise multiparameter predictors of outcome and/or response through the combination of biological assays and analysis of gene expression signatures.
Citation Format: Daniel Y. Mendoza-Villanueva, Suryun Kim, H.Raza Ali, Shikha Sharan, Tapasree R. Sarkar, Carlos Caldas, Goran Landberg, Esta Sterneck. CEBPD (C/EBP) acts as a tumor suppressor in hormone receptor positive breast cancer cells and may serve as biomarker to predict the need for adjuvant therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3464. doi:10.1158/1538-7445.AM2013-3464