The C/EBPδ protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression and associates with good prognosis in breast cancer

Mendoza-Villanueva, Daniel; Balamurugan, Krishnaswamy; Hr, Ali; Kim, SR; Sharan, Shyam K.; Johnson, Randall C.; Merchant, AS; Caldas, Carlos; Landberg, Göran; Sterneck, Esta

doi:10.1038/onc.2016.156

Cited by 23 publications

(28 citation statements)

References 56 publications

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“…It may be argued that chemical inhibitors are non-specific and the effect may not be attributed to a specific gene, however, knockdown of SNAI2 using siRNA transfection resulted in marked reduction in cell growth in TamR cell lines similar to the chemical inhibitors, confirming the importance of the genes in endocrine resistance. In agreement with this, a recent report showed that reduced expression of SNAI2 reduces the aggressiveness of cancer cells [ 33 ].…”

Section: Discussionsupporting

confidence: 83%

Integrative analysis of miRNA and gene expression reveals regulatory networks in tamoxifen-resistant breast cancer

et al. 2016

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Tamoxifen is an effective anti-estrogen treatment for patients with estrogen receptor-positive (ER+) breast cancer, however, tamoxifen resistance is frequently observed. To elucidate the underlying molecular mechanisms of tamoxifen resistance, we performed a systematic analysis of miRNA-mediated gene regulation in three clinically-relevant tamoxifen-resistant breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive cell line. Alterations in the expression of 131 miRNAs in tamoxifen-resistant vs. parental cell lines were identified, 22 of which were common to all TamRs using both sequencing and LNA-based quantitative PCR technologies. Although the target genes affected by the altered miRNA in the three TamRs differed, good agreement in terms of affected molecular pathways was observed. Moreover, we found evidence of miRNA-mediated regulation of ESR1, PGR1, FOXM1 and 14-3-3 family genes. Integrating the inferred miRNA-target relationships, we investigated the functional importance of 2 central genes, SNAI2 and FYN, which showed increased expression in TamR cells, while their corresponding regulatory miRNA were downregulated. Using specific chemical inhibitors and siRNA-mediated gene knockdown, we showed that both SNAI2 and FYN significantly affect the growth of TamR cell lines. Finally, we show that a combination of 2 miRNAs (miR-190b and miR-516a-5p) exhibiting altered expression in TamR cell lines were predictive of treatment outcome in a cohort of ER+ breast cancer patients receiving adjuvant tamoxifen mono-therapy. Our results provide new insight into the molecular mechanisms of tamoxifen resistance and may form the basis for future medical intervention for the large number of women with tamoxifen-resistant ER+ breast cancer.

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Section: Discussionsupporting

confidence: 83%

Integrative analysis of miRNA and gene expression reveals regulatory networks in tamoxifen-resistant breast cancer

et al. 2016

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“…Moreover, C/EBPδ is involved in the regulation of pro-apoptotic gene expression and growth arrest during mammary gland involution [ 19 , 20 ]. In line with these data, C/EBPδ indeed acts as a tumor suppressor in breast cancer [ 21 , 22 , 23 ], ovarian serous carcinoma [ 24 ], cervical carcinoma [ 25 ], leukemia [ 26 ] and hepatocellular carcinoma [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 60%

“…C/EBPδ has been found to negatively affect tumor growth by inducing growth arrest and differentiation [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. Recently, however, C/EBPδ was also suggested to drive tumor progression and/or metastasis in certain tumor types [ 29 , 30 , 31 , 32 ], suggesting that C/EBPδ may either suppress or promote tumor progression in a context specific manner.…”

Section: Discussionmentioning

confidence: 99%

CCAAT/Enhancer-Binding Protein Delta (C/EBPδ): A Previously Unrecognized Tumor Suppressor that Limits the Oncogenic Potential of Pancreatic Ductal Adenocarcinoma Cells

Hartl

Duitman

Aberson

et al. 2020

Cancers

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CCAAT/enhancer-binding protein δ (C/EBPδ) is a transcription factor involved in growth arrest and differentiation, which has consequently been suggested to harbor tumor suppressive activities. However, C/EBPδ over-expression correlates with poor prognosis in glioblastoma and promotes genomic instability in cervical cancer, hinting at an oncogenic role of C/EBPδ in these contexts. Here, we explore the role of C/EBPδ in pancreatic cancer. We determined C/EBPδ expression in biopsies from pancreatic cancer patients using public gene-expression datasets and in-house tissue microarrays. We found that C/EBPδ is highly expressed in healthy pancreatic ductal cells but lost in pancreatic ductal adenocarcinoma. Furthermore, loss of C/EBPδ correlated with increased lymph node involvement and shorter overall survival in pancreatic ductal adenocarcinoma patients. In accordance with this, in vitro experiments showed reduced clonogenic capacity and proliferation of pancreatic ductal adenocarcinoma cells following C/EBPδ re-expression, concurrent with decreased sphere formation capacity in soft agar assays. We thus report a previously unrecognized but important tumor suppressor role of C/EBPδ in pancreatic ductal adenocarcinoma. This is of particular interest since only few tumor suppressors have been identified in the context of pancreatic cancer. Moreover, our findings suggest that restoration of C/EBPδ activity could hold therapeutic value in pancreatic ductal adenocarcinoma, although the latter claim needs to be substantiated in future studies.

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“…Previously, we reported that abundant C/EBPδ expression is associated with estrogen receptor (ER)+ BC and low tumor grade, and that C/EBPδ attenuates proliferation and motility of ER+ MCF-7 cells in culture 27 . When assessed in vivo, however, CEBPD -silenced MCF-7 tumors grew significantly more slowly than controls and mice therefore survived longer (Fig.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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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 (CSC). 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 feed-back 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 micro-environmental conditions in cancer progression with potential implications for the targeting of cancer stem cells.

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The C/EBPδ protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression and associates with good prognosis in breast cancer

Cited by 23 publications

References 56 publications

Integrative analysis of miRNA and gene expression reveals regulatory networks in tamoxifen-resistant breast cancer

Integrative analysis of miRNA and gene expression reveals regulatory networks in tamoxifen-resistant breast cancer

CCAAT/Enhancer-Binding Protein Delta (C/EBPδ): A Previously Unrecognized Tumor Suppressor that Limits the Oncogenic Potential of Pancreatic Ductal Adenocarcinoma Cells

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

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