C/EBPdelta is a candidate tumor suppressor whose protein expression is induced by the estrogen receptor

Wednesday, September 24, 2014 — Poster Session IV
10:00 a.m. –12:00 p.m.	FAES Academic Center	NCI	CANCER-15

* FARE Award Winner

Authors

• D Mendoza-Villanueva
• S Kim
• H Raza Ali
• S Sharan
• T Sarkar
• C Caldas
• G Landberg
• E Sterneck

Abstract

The estrogen receptor (ER) is well characterized as a driver of proliferation and metastasis of luminal breast cancers (BC). Here we show that ER also promotes expression of the transcription factor C/EBPdelta (CEBPD) and that CEBPD has tumor-suppressor activity in ER+ BC/cells. Analysis of two independent breast tumor tissue microarrays revealed that the CEBPD protein is preferentially expressed in ER+ BC, and that CEBPD expression was associated with longer patient survival. Mechanistic studies using the MCF-7 cell line showed that ER supports CEBPD expression at the level of the protein without affecting its mRNA expression. Loss of CEBPD attenuates cell proliferation, motility and invasiveness. Furthermore, CEBPD promotes estrogen-dependence and cytoxicity of tamoxifen. mRNA-Seq analysis of CEBPD-silenced MCF-7 cells revealed that CEBPD inhibits expression of the Slug (SNAI2) transcription factor, which can promote epithelial-mesenchymal transition (EMT). Silencing of Slug reverted the increased motility of CEBPD-silenced MCF-7 cells. Furthermore, CEBPD promotes expression and nuclear localization of the p21 tumor suppressor protein by promoting p53 protein expression. Tamoxifen-sensitivity of CEBPD-silenced MCF-7 cells could be partially restored by a constitutively nuclear p21 protein. Taken together, our results indicate that CEBPD expression in ER+ BC contributes to a more benign tumor phenotype.

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