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MYC Synergizes with Activated BRAFV600E in Mouse Lung Tumor Development by Suppressing Senescence.

Tabor, Vedrana; Bocci, Matteo LU ; Alikhani, Nyosha; Kuiper, Raoul and Larsson, Lars-Gunnar (2014) In Cancer Research 74(16). p.4222-4229
Abstract
The activated RAS/RAF cascade plays a crucial role in lung cancer, but is also known to induce cellular senescence - a major barrier imposed to tumor cells early in tumorigenesis. MYC is a key factor in suppression of RAS/BRAFV600E-induced senescence in vitro. However, it is still unclear whether Myc has the same role during tumor development in vivo. Using a conditional, compound knock-in model of Cre-activated BRAFV600E and tamoxifen (TAM)-regulatable MycER, we show that TAM-induced activation of MYC accelerated the onset and increased the number and size of BRAFV600E-driven adenomas in a dose dependent manner, resulting in reduced survival. Further, MYC activation lead to reduced expression of the senescence markers p16INK4A, p21CIP1... (More)
The activated RAS/RAF cascade plays a crucial role in lung cancer, but is also known to induce cellular senescence - a major barrier imposed to tumor cells early in tumorigenesis. MYC is a key factor in suppression of RAS/BRAFV600E-induced senescence in vitro. However, it is still unclear whether Myc has the same role during tumor development in vivo. Using a conditional, compound knock-in model of Cre-activated BRAFV600E and tamoxifen (TAM)-regulatable MycER, we show that TAM-induced activation of MYC accelerated the onset and increased the number and size of BRAFV600E-driven adenomas in a dose dependent manner, resulting in reduced survival. Further, MYC activation lead to reduced expression of the senescence markers p16INK4A, p21CIP1 and H3K9me3-containing heterochromatin foci, and an increased percentage of Ki-67+ tumor cells. This suggests that MYC already early during tumor formation suppresses a BRAFV600E-induced senescence-like state. Initial activation of MYC followed by TAM withdrawal still resulted in an increased number of tumors and reduced survival. However, these tumors were of smaller size, showed increased expression of p16INK4A and p21CIP1 and reduced number of Ki-67+ cells, indicating that MYC inactivation restores BRAFV600E-induced senescence. Surprisingly, MYC activation did not promote adenoma to carcinoma progression. This suggests that senescence suppression by MYC is a discrete step in tumor development important for sustained tumor growth but preceding malignant transformation, and that additional oncogenic events are required for carcinoma development and metastasis. These findings contribute to our understanding of the neoplastic transformation process with implications for future treatment strategies. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Cancer Research
volume
74
issue
16
pages
4222 - 4229
publisher
American Association for Cancer Research Inc.
external identifiers
  • pmid:24934810
  • wos:000341186700003
  • scopus:84905968843
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-13-3234
language
English
LU publication?
yes
id
d30f06fd-df97-45eb-a490-c71a7044591f (old id 4528387)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24934810?dopt=Abstract
date added to LUP
2014-07-06 11:29:19
date last changed
2017-11-19 03:21:18
@article{d30f06fd-df97-45eb-a490-c71a7044591f,
  abstract     = {The activated RAS/RAF cascade plays a crucial role in lung cancer, but is also known to induce cellular senescence - a major barrier imposed to tumor cells early in tumorigenesis. MYC is a key factor in suppression of RAS/BRAFV600E-induced senescence in vitro. However, it is still unclear whether Myc has the same role during tumor development in vivo. Using a conditional, compound knock-in model of Cre-activated BRAFV600E and tamoxifen (TAM)-regulatable MycER, we show that TAM-induced activation of MYC accelerated the onset and increased the number and size of BRAFV600E-driven adenomas in a dose dependent manner, resulting in reduced survival. Further, MYC activation lead to reduced expression of the senescence markers p16INK4A, p21CIP1 and H3K9me3-containing heterochromatin foci, and an increased percentage of Ki-67+ tumor cells. This suggests that MYC already early during tumor formation suppresses a BRAFV600E-induced senescence-like state. Initial activation of MYC followed by TAM withdrawal still resulted in an increased number of tumors and reduced survival. However, these tumors were of smaller size, showed increased expression of p16INK4A and p21CIP1 and reduced number of Ki-67+ cells, indicating that MYC inactivation restores BRAFV600E-induced senescence. Surprisingly, MYC activation did not promote adenoma to carcinoma progression. This suggests that senescence suppression by MYC is a discrete step in tumor development important for sustained tumor growth but preceding malignant transformation, and that additional oncogenic events are required for carcinoma development and metastasis. These findings contribute to our understanding of the neoplastic transformation process with implications for future treatment strategies.},
  author       = {Tabor, Vedrana and Bocci, Matteo and Alikhani, Nyosha and Kuiper, Raoul and Larsson, Lars-Gunnar},
  issn         = {1538-7445},
  language     = {eng},
  number       = {16},
  pages        = {4222--4229},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {MYC Synergizes with Activated BRAFV600E in Mouse Lung Tumor Development by Suppressing Senescence.},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-13-3234},
  volume       = {74},
  year         = {2014},
}