C/EBPδ promotes nuclear localization of p21CIP1 and cytotoxicity of tamoxifen in ER(+) breast tumor cells

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NCI	CANCER-17

Authors

• S. Kim
• H.R. Ali
• S. Sharan
• C. Caldas
• E. Sterneck

Abstract

C/EBPδ is expressed in normal breast epithelial cells and down-regulated in breast cancer tissue and cell lines (1,2). In the MMTV-Neu mouse mammary tumor model, loss of C/EBPδ leads to increased tumor incidence while reducing tumor metastasis (3). The C/EBPδ protein is expressed in 50% of invasive estrogen receptor α positive ER(+) breast carcinomas, which is associated with longer survival of ER(+) cancer patients. Therefore, we investigated the role of C/EBPδ in the response of breast tumor cells to the ER inhibitor tamoxifen (TAM). Depletion of C/EBPδ increased the survival of TAM treated MCF-7 cells, suggesting that C/EBPδ contributes to the cytotoxicity of TAM. Nuclear localization of the p21CIP1 is necessary for inhibition of cell growth/survival by TAM, and cytoplasmic p21CIP1 in tumors is associated with poor prognosis (4,5). C/EBPδ silencing led to cytoplasmic localization of p21CIP1 and increased the level of pERK kinases, which had was previously been shown to promote cytoplasmic localization of p21CIP1 (6). And a constitutively nuclear mutant form of p21CIP1 rescues the TAM-response of C/EBPδ-silenced MCF-7 cells. These results suggest that a target gene of C/EBPδ is necessary to inhibit ERK phophorylation and thereby promotes nuclear localization of p21CIP1 and TAM toxicity.

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