Eukaryotic initiation factor 4E-binding protein as an oncogene in breast cancer

Abstract

Background Eukaryotic Initiation Factor 4E-Binding Protein ( EIF4EBP1 , 4EBP1) is overexpressed in many human cancers including breast cancer, yet the role of 4EBP1 in breast cancer remains understudied. Despite the known role of 4EBP1 as a negative regulator of cap-dependent protein translation, 4EBP1 is predicted to be an essential driving oncogene in many cancer cell lines in vitro, and can act as a driver of cancer cell proliferation. EIF4EBP1 is located within the 8p11-p12 genomic locus, which is frequently amplified in breast cancer and is known to predict poor prognosis and resistance to endocrine therapy. Methods Here we evaluated the effect of 4EBP1 targeting using shRNA knock-down of expression of 4EBP1, as well as response to the mTORC targeted drug everolimus in cell lines representing different breast cancer subtypes, including breast cancer cells with the 8p11-p12 amplicon, to better define a context and mechanism for oncogenic 4EBP1. Results Using a genome-scale shRNA screen on the SUM panel of breast cancer cell lines, we found 4EBP1 to be a strong hit in the 8p11 amplified SUM-44 cells, which have amplification and overexpression of 4EBP1. We then found that knock-down of 4EBP1 resulted in dramatic reductions in cell proliferation in 8p11 amplified breast cancer cells as well as in other luminal breast cancer cell lines, but had little or no effect on the proliferation of immortalized but non-tumorigenic human mammary epithelial cells. Kaplan-Meier analysis of EIF4EBP1 expression in breast cancer patients demonstrated that overexpression of this gene was associated with reduced relapse free patient survival across all breast tumor subtypes. Conclusions These results are consistent with an oncogenic role of 4EBP1 in luminal breast cancer and suggests a role for this protein in cell proliferation distinct from its more well-known role as a regulator of cap-dependent translation. Electronic supplementary material The online version of this article (10.1186/s12885-019-5667-4) contains supplementary material, which is available to authorized users.

Deep computational analysis of human cancer and non-cancer tissues details dysregulation of eIF4F components and their interactions in human cancers

“…Genetic alterations such as point mutations and copy number variations (CNVs) are typical of cancers and often serve as important diagnostic tools (Loeb, 2011;Shlien and Malkin, 2009). Overexpression of EIF4E, EIF4EBP1, and EIF4G1 has each been attributed to the amplification of gene copies in many cancer types including breast, head and neck, and prostate cancers (Jaiswal et al, 2018;Rutkovsky et al, 2019;Sorrells et al, 1998;Sorrells et al, 1999). Recurrent amplification suggests positive selection of a gene for consequential overexpression of its gene product in tumors.…”

Development and implementation of the SUM breast cancer cell line functional genomics knowledge base

“…(Myst3) and EIF4EBP1 as important driver genes from this amplicon in these cells 10,44,48 . In addition, SUM-44 cells overexpress BCL2, which was a strong hit in the screen, and the cells are exquisitely sensitive to Navitoclax and Venetoclax.…”

Identification of an Autophagy-Related Prognostic Signature for Clear Cell Renal Cell Carcinoma

“…Silencing BAG1 in breast cancer cells increases resistance to tamoxifen and reduces apoptosis by activating the PI3K/Akt/mTOR signaling pathway (34), and the overexpression of ATG16L2 is related to poor prognosis in epithelial cancer (35). The overexpression of EIF4EBP1 is related to shorter recurrencefree survival in breast cancer patients (36). CX3CL1 is highly expressed in esophageal cancer and can promote its metastasis (37).…”