eIF4E Threshold Levels Differ in Governing Normal and Neoplastic Expansion of Mammary Stem and Luminal Progenitor Cells

Abstract

Translation initiation factor eIF4E mediates normal cell proliferation, yet induces tumorigenesis when overexpressed. The mechanisms by which eIF4E directs such distinct biological outputs remains unknown. We found that mouse mammary morphogenesis during pregnancy and lactation is accompanied by increased cap-binding capability of eIF4E and activation of the eIF4E-dependent translational apparatus, but only subtle oscillations in eIF4E abundance. Using a transgenic mouse model engineered so that lactogenic hormones stimulate a sustained increase in eIF4E abundance in stem/progenitor cells of lactogenic mammary epithelium during successive pregnancy/lactation cycles, eIF4E overexpression increased cell self-renewal, triggered DNA replication stress, and induced formation of pre-malignant and malignant lesions. Using complementary in vivo and ex vivo approaches, we found that increasing eIF4E levels rescued cells harboring oncogenic c-Myc or H-RasV12 from DNA replication stress and oncogene-induced replication catastrophe. Our findings indicate that distinct threshold levels of eIF4E govern its biological output in lactating mammary glands, and that eIF4E overexpression in the context of stem/progenitor cell population expansion can initiate malignant transformation by enabling cells to evade DNA damage checkpoints activated by oncogenic stimuli. Maintaining eIF4E levels below its pro-neoplastic threshold is an important anticancer defense in normal cells, with important implications for understanding pregnancy-associated breast cancer.

Galeterone and VNPT55 disrupt Mnk‐eIF4E to inhibit prostate cancer cell migration and invasion

“…3D). Although gal/ VNPT55 do not completely inhibit phosphorylation of eIF4E, the decrease evidently is significantly below the threshold which results in inhibition of translation of oncogenic mRNA, in agreement with a recently published study [31]. Protein expression analysis of Mnk1/ 2 in CWR22Rv1 cells demonstrates a dose-dependent effect ( Fig.…”

New frontiers in translational control of the cancer genome

“…Indeed, eIF4E dose was recently identified as a crucial determinant of the translation of oxidative stress response genes essential for cellular transformation and in vivo lung tumorigenesis, such as ferritin heavy polypeptide 1 ( FTH1 ) and the rate-limiting enzyme for glutathione synthesis glutamate–cysteine ligase catalytic subunit ( GCLC ) 10 . Similarly, increased eIF4E dose was shown to rescue human mammary epithelial cells from oncogene-induced replication stress through the activation of a pro-survival DNA damage response 192 . In line with these studies, eIF4E phosphorylation has also been implicated in resistance to oxidative stress, starvation and DNA-damaging agents in cancer cells 193 .…”

Equol, an Isoflavone Metabolite, Regulates Cancer Cell Viability and Protein Synthesis Initiation via c-Myc and eIF4G

“…Mammosphere assays have been used to identify stem celllike properties of self-renewal and tumorigenesis in aggressive cancer cell populations (42,43,61). Enhanced c-Myc expression and the associated increase in translation initiation have been implicated with mammary stem cell amplification and tumorigenic potential (62)(63)(64); especially in human growth factor receptor 2 (HER2)-amplified breast cancers, such as the MDA-MB-435 HER2ϩϩ cell line used in this study (65). Therefore, collectively, our data suggest that equol-mediated amplification of c-Myc and eIF4G may direct increased cancer stem cell-like and tumorigenic properties.…”