Immortalization of normal human mammary epithelial cells in two steps by direct targeting of senescence barriers does not require gross genomic alterations
Abstract
Telomerase reactivation and immortalization are critical for human carcinoma progression. However, little is known about the mechanisms controlling this crucial step, due in part to the paucity of experimentally tractable model systems that can examine human epithelial cell immortalization as it might occur in vivo. We achieved efficient non-clonal immortalization of normal human mammary epithelial cells (HMEC) by directly targeting the 2 main senescence barriers encountered by cultured HMEC. The stress-associated stasis barrier was bypassed using shRNA to p16INK4; replicative senescence due to critically shortened telomeres was bypassed in post-stasis HMEC by c-MYC transduction. Thus, 2 pathologically relevant oncogenic agents are sufficient to immortally transform normal HMEC. The resultant non-clonal immortalized lines exhibited normal karyotypes. Most human carcinomas contain genomically unstable cells, with widespread instability first observed in vivo in pre-malignant stages; in vitro, instability is seen as finite cells with critically shortened telomeres approach replicative senescence. Our results support our hypotheses that: (1) telomere-dysfunction induced genomic instability in pre-malignant finite cells may generate the errors required for telomerase reactivation and immortalization, as well as many additional “passenger” errors carried forward into resulting carcinomas; (2) genomic instability during cancer progression is needed to generate errors that overcome tumor suppressive barriers,more »
- Authors:
-
- Lawrence Berkeley National Laboratory, Berkeley, California, (United States), Life Sciences Division
- Arizona Cancer Center; The University of Arizona; Tucson, AZ USA
- Department of Pathology; The University of Arizona College of Medicine; Tucson, AZ USA
- Department of Pathology; The University of Arizona College of Medicine; Tucson, AZ USA;
- Case Comprehensive Cancer Center; Case Western Reserve University; Cleveland, OH USA
- 7 University of California San Francisco; San Francisco, CA USA
- Lawrence Berkeley National Laboratory, Berkeley, California, (United States), Life Sciences Division; 2 Arizona Cancer Center; The University of Arizona; Tucson, AZ USA
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1220569
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Cell Cycle (Georgetown, Tex)
- Additional Journal Information:
- Journal Name: Cell Cycle (Georgetown, Tex); Journal Volume: 13; Journal Issue: 21; Journal ID: ISSN 1538-4101
- Publisher:
- Taylor and Francis
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; carcinogenesis; c-Myc; genomic instability; human mammary epithelial cells; immortalization; p16INK4a; senescence; telomerase
Citation Formats
Garbe, James C., Vrba, Lukas, Sputova, Klara, Fuchs, Laura, Novak, Petr, Brothman, Arthur R., Jackson, Mark, Chin, Koei, LaBarge, Mark A., Watts, George, Futscher, Bernard W., and Stampfer, Martha R. Immortalization of normal human mammary epithelial cells in two steps by direct targeting of senescence barriers does not require gross genomic alterations. United States: N. p., 2014.
Web. doi:10.4161/15384101.2014.954456.
Garbe, James C., Vrba, Lukas, Sputova, Klara, Fuchs, Laura, Novak, Petr, Brothman, Arthur R., Jackson, Mark, Chin, Koei, LaBarge, Mark A., Watts, George, Futscher, Bernard W., & Stampfer, Martha R. Immortalization of normal human mammary epithelial cells in two steps by direct targeting of senescence barriers does not require gross genomic alterations. United States. https://doi.org/10.4161/15384101.2014.954456
Garbe, James C., Vrba, Lukas, Sputova, Klara, Fuchs, Laura, Novak, Petr, Brothman, Arthur R., Jackson, Mark, Chin, Koei, LaBarge, Mark A., Watts, George, Futscher, Bernard W., and Stampfer, Martha R. Wed .
"Immortalization of normal human mammary epithelial cells in two steps by direct targeting of senescence barriers does not require gross genomic alterations". United States. https://doi.org/10.4161/15384101.2014.954456. https://www.osti.gov/servlets/purl/1220569.
@article{osti_1220569,
title = {Immortalization of normal human mammary epithelial cells in two steps by direct targeting of senescence barriers does not require gross genomic alterations},
author = {Garbe, James C. and Vrba, Lukas and Sputova, Klara and Fuchs, Laura and Novak, Petr and Brothman, Arthur R. and Jackson, Mark and Chin, Koei and LaBarge, Mark A. and Watts, George and Futscher, Bernard W. and Stampfer, Martha R.},
abstractNote = {Telomerase reactivation and immortalization are critical for human carcinoma progression. However, little is known about the mechanisms controlling this crucial step, due in part to the paucity of experimentally tractable model systems that can examine human epithelial cell immortalization as it might occur in vivo. We achieved efficient non-clonal immortalization of normal human mammary epithelial cells (HMEC) by directly targeting the 2 main senescence barriers encountered by cultured HMEC. The stress-associated stasis barrier was bypassed using shRNA to p16INK4; replicative senescence due to critically shortened telomeres was bypassed in post-stasis HMEC by c-MYC transduction. Thus, 2 pathologically relevant oncogenic agents are sufficient to immortally transform normal HMEC. The resultant non-clonal immortalized lines exhibited normal karyotypes. Most human carcinomas contain genomically unstable cells, with widespread instability first observed in vivo in pre-malignant stages; in vitro, instability is seen as finite cells with critically shortened telomeres approach replicative senescence. Our results support our hypotheses that: (1) telomere-dysfunction induced genomic instability in pre-malignant finite cells may generate the errors required for telomerase reactivation and immortalization, as well as many additional “passenger” errors carried forward into resulting carcinomas; (2) genomic instability during cancer progression is needed to generate errors that overcome tumor suppressive barriers, but not required per se; bypassing the senescence barriers by direct targeting eliminated a need for genomic errors to generate immortalization. Achieving efficient HMEC immortalization, in the absence of “passenger” genomic errors, should facilitate examination of telomerase regulation during human carcinoma progression, and exploration of agents that could prevent immortalization.},
doi = {10.4161/15384101.2014.954456},
journal = {Cell Cycle (Georgetown, Tex)},
number = 21,
volume = 13,
place = {United States},
year = {Wed Oct 29 00:00:00 EDT 2014},
month = {Wed Oct 29 00:00:00 EDT 2014}
}
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- Proceedings of the National Academy of Sciences, Vol. 114, Issue 47
Inhibition of nucleotide synthesis promotes replicative senescence of human mammary epithelial cells
journal, May 2019
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- Journal of Biological Chemistry, Vol. 294, Issue 27
A lincRNA connected to cell mortality and epigenetically-silenced in most common human cancers
journal, October 2015
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Experimental identification of cancer driver alterations in the era of pan‐cancer genomics
journal, October 2019
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The senescent methylome and its relationship with cancer, ageing and germline genetic variation in humans
journal, September 2015
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- Genome Biology, Vol. 16, Issue 1
Different culture media modulate growth, heterogeneity, and senescence in human mammary epithelial cell cultures
journal, October 2018
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Correction: Establishment of immortalized primary cell from the critically endangered Bonin flying fox (Pteropus pselaphon)
journal, May 2020
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The New Immortalized Uroepithelial Cell Line HBLAK Contains Defined Genetic Aberrations Typical of Early Stage Urothelial Tumors
journal, October 2016
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Comparison of methods for the isolation of human breast epithelial and myoepithelial cells
journal, May 2015
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Breast Tissue Biology Expands the Possibilities for Prevention of Age-Related Breast Cancers
journal, August 2019
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The Quest for Targets Executing MYC-Dependent Cell Transformation
journal, June 2016
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Generation of Immortalised But Unstable Cells after hTERT Introduction in Telomere-Compromised and p53-Deficient vHMECs
journal, July 2018
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Genomic Changes in Normal Breast Tissue in Women at Normal Risk or at High Risk for Breast Cancer
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Evidence for immortality and autonomy in animal cancer models is often not provided, which causes confusion on key issues of cancer biology
journal, January 2020
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- Journal of Cancer, Vol. 11, Issue 10