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 biologic outputs remain 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 self-renewal, triggered DNA replication stress, and induced formation of premalignant 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 biologic 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 proneoplastic threshold is an important anticancer defense in normal cells, with important implications for understanding pregnancy-associated breast cancer.

• Authors: Svetlana Avdulov, Jeremy Herrera, Karen Smith, Mark Peterson, Jose R Gomez-Garcia, Thomas C Beadnell, Kathryn L Schwertfeger, Alexey O Benyumov, J Carlos Manivel, Shunan Li, Anja-Katrin Bielinsky, Douglas Yee, Peter B Bitterman, Vitaly A Polunovsky
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 4 Pg. 687-97 (Feb 15 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 25524901 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Eukaryotic Initiation Factor-4E
• Myc protein, mouse
• Proto-Oncogene Proteins c-myc
• ras Proteins

Topics

• Animals
• Breast Neoplasms (genetics, pathology)
• Carcinogenesis (genetics)
• Cell Proliferation (genetics)
• DNA Replication (genetics)
• Eukaryotic Initiation Factor-4E (biosynthesis, genetics)
• Female
• Humans
• Mammary Glands, Animal (metabolism, pathology)
• Mammary Glands, Human (metabolism, pathology)
• Mice
• Neoplastic Stem Cells (metabolism, pathology)
• Pregnancy
• Protein Biosynthesis
• Proto-Oncogene Proteins c-myc (biosynthesis)
• ras Proteins (biosynthesis)