EIF4E threshold levels differ in governing normal and neoplastic expansion of mammary stem and luminal progenitor cells

Svetlana V Avdulov, Jeremy Herrera, Karen Smith, Mark Peterson, Jose Gomez-Garcia, Thomas C. Beadnell, Kaylee Schwertfeger, Alexey Benyumov, J. Carlos Manivel, Shunan Li, Anja K Bielinsky, Douglas Yee, Peter B Bitterman, Vitaly A Polunovsky

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 eIF4Edependent 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 onco-gene-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.

Original languageEnglish (US)
Pages (from-to)687-697
Number of pages11
JournalCancer Research
Volume75
Issue number4
DOIs
StatePublished - Feb 15 2015

Fingerprint

Eukaryotic Initiation Factor-4E
Breast
Stem Cells
DNA Replication
Lactation
Pregnancy
Peptide Initiation Factors
Human Mammary Glands
Morphogenesis
Transgenic Mice
DNA Damage
Carcinogenesis
Epithelium
Cell Proliferation
Hormones
Breast Neoplasms
Population
Genes

Cite this

EIF4E threshold levels differ in governing normal and neoplastic expansion of mammary stem and luminal progenitor cells. / Avdulov, Svetlana V; Herrera, Jeremy; Smith, Karen; Peterson, Mark; Gomez-Garcia, Jose; Beadnell, Thomas C.; Schwertfeger, Kaylee; Benyumov, Alexey; Manivel, J. Carlos; Li, Shunan; Bielinsky, Anja K; Yee, Douglas; Bitterman, Peter B; Polunovsky, Vitaly A.

In: Cancer Research, Vol. 75, No. 4, 15.02.2015, p. 687-697.

Research output: Contribution to journalArticle

Avdulov, Svetlana V ; Herrera, Jeremy ; Smith, Karen ; Peterson, Mark ; Gomez-Garcia, Jose ; Beadnell, Thomas C. ; Schwertfeger, Kaylee ; Benyumov, Alexey ; Manivel, J. Carlos ; Li, Shunan ; Bielinsky, Anja K ; Yee, Douglas ; Bitterman, Peter B ; Polunovsky, Vitaly A. / EIF4E threshold levels differ in governing normal and neoplastic expansion of mammary stem and luminal progenitor cells. In: Cancer Research. 2015 ; Vol. 75, No. 4. pp. 687-697.
@article{e7c4897348724dfa9b8d91f2127397aa,
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 eIF4Edependent 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 onco-gene-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.",
author = "Avdulov, {Svetlana V} and Jeremy Herrera and Karen Smith and Mark Peterson and Jose Gomez-Garcia and Beadnell, {Thomas C.} and Kaylee Schwertfeger and Alexey Benyumov and Manivel, {J. Carlos} and Shunan Li and Bielinsky, {Anja K} and Douglas Yee and Bitterman, {Peter B} and Polunovsky, {Vitaly A}",
year = "2015",
month = "2",
day = "15",
doi = "10.1158/0008-5472.CAN-14-2571",
language = "English (US)",
volume = "75",
pages = "687--697",
journal = "Cancer Research",
issn = "0008-5472",
number = "4",

}

TY - JOUR

T1 - EIF4E threshold levels differ in governing normal and neoplastic expansion of mammary stem and luminal progenitor cells

AU - Avdulov, Svetlana V

AU - Herrera, Jeremy

AU - Smith, Karen

AU - Peterson, Mark

AU - Gomez-Garcia, Jose

AU - Beadnell, Thomas C.

AU - Schwertfeger, Kaylee

AU - Benyumov, Alexey

AU - Manivel, J. Carlos

AU - Li, Shunan

AU - Bielinsky, Anja K

AU - Yee, Douglas

AU - Bitterman, Peter B

AU - Polunovsky, Vitaly A

PY - 2015/2/15

Y1 - 2015/2/15

N2 - 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 eIF4Edependent 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 onco-gene-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.

AB - 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 eIF4Edependent 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 onco-gene-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.

UR - http://www.scopus.com/inward/record.url?scp=84923172084&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923172084&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-14-2571

DO - 10.1158/0008-5472.CAN-14-2571

M3 - Article

C2 - 25524901

AN - SCOPUS:84923172084

VL - 75

SP - 687

EP - 697

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 4

ER -