Immortalization of normal human mammary epithelial cells in two steps by direct targeting of senescence barriers does not require gross genomic alterations

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60077344%3A_____%2F14%3A00482266" target="_blank" >RIV/60077344:_____/14:00482266 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.4161/15384101.2014.954456" target="_blank" >http://dx.doi.org/10.4161/15384101.2014.954456</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.4161/15384101.2014.954456" target="_blank" >10.4161/15384101.2014.954456</a>

Result language

angličtina

Original language name

Immortalization of normal human mammary epithelial cells in two steps by direct targeting of senescence barriers does not require gross genomic alterations

Original language description

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 p16(INK4), 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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10601 - Cell biology

Project

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Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2014

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Cell Cycle

ISSN

1538-4101

e-ISSN

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Volume of the periodical

13

Issue of the periodical within the volume

21

Country of publishing house

US - UNITED STATES

Number of pages

13

Pages from-to

3423-3435

UT code for WoS article

000348313100015

EID of the result in the Scopus database

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