title: 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.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Avdulov
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Herrera
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Karen
authors.initials: K
authors.lastname: Smith
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Mark
authors.initials: M
authors.lastname: Peterson
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Gomez-Garcia
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Beadnell
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Schwertfeger
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Alexey O
authors.initials: AO
authors.lastname: Benyumov
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: J Carlos
authors.initials: JC
authors.lastname: Manivel
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Shunan
authors.initials: S
authors.lastname: Li
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Departament of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Anja-Katrin
authors.initials: AK
authors.lastname: Bielinsky
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Douglas
authors.initials: D
authors.lastname: Yee
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. polun001@umn.edu bitte001@umn.edu.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Bitterman
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. polun001@umn.edu bitte001@umn.edu.
authors.forename: Vitaly A
authors.initials: VA
authors.lastname: Polunovsky
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D039561:Eukaryotic Initiation Factor-4E / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D014176:Protein Biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D018631:ras Proteins / Q000096:biosynthesis
chemical_list: D039561:Eukaryotic Initiation Factor-4E; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D018631:ras Proteins