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Loss of Akt1 or Akt2 delays mammary tumor onset and suppresses tumor growth rate in MTB-IGFIR transgenic mice
BACKGROUND: Akt is a serine/threonine kinase that mediates signaling downstream of tyrosine kinase receptors like the type I insulin-like growth factor receptor (IGF-IR). In fact, we have previously shown that mammary tumors induced by elevated expression of the IGF-IR are associated with hyperactiv...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750479/ https://www.ncbi.nlm.nih.gov/pubmed/23919516 http://dx.doi.org/10.1186/1471-2407-13-375 |
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author | Watson, Katrina L Moorehead, Roger A |
author_facet | Watson, Katrina L Moorehead, Roger A |
author_sort | Watson, Katrina L |
collection | PubMed |
description | BACKGROUND: Akt is a serine/threonine kinase that mediates signaling downstream of tyrosine kinase receptors like the type I insulin-like growth factor receptor (IGF-IR). In fact, we have previously shown that mammary tumors induced by elevated expression of the IGF-IR are associated with hyperactivation of Akt. However, there are three mammalian isoforms of Akt (Akt1, Akt2 and Akt3) and these isoforms regulate distinct physiologic properties within cells. In this manuscript, the impact of disrupting Akt1 or Akt2 in mammary tumors induced by IGF-IR overexpression were examined to determine whether specific Akt isoforms regulate different aspects of mammary tumorigenesis. METHODS: Akt1 and Akt2 levels were stably ablated in mammary tumors of MTB-IGFIR transgenic mice by crossing MTB-IGFIR transgenic mice with either Akt1(−/−) or Akt2(−/−) mice. Tumor onset, growth rate, and metastasis were determined. RESULTS: Ablation of Akt1 or Akt2 significantly delayed tumor onset and tumor growth rate but did not significantly alter lung metastasis. Despite the absence of Akt1 or Akt2, mammary tumors that developed in the MTB-IGFIR mice maintained detectable levels of phosphorylated Akt. Disruption of Akt1 or Akt2 did not affect cell morphology or the expression of luminal or basal cytokeratins in mammary tumors. CONCLUSIONS: Although loss of Akt1 or Akt2 significantly inhibited mammary tumor onset and growth rates the effects were less dramatic than anticipated. Despite the complete loss of Akt1 or Akt2, the level of total phosphorylated Akt remained largely unaffected in the mammary tumors suggesting that loss of one Akt isoform is compensated by enhanced activation of the remaining Akt isoforms. These findings indicate that therapeutic strategies targeting the activation of individual Akt isoforms will prove less effective than simultaneously inhibiting the activity of all three Akt isoforms for the treatment of breast cancer. |
format | Online Article Text |
id | pubmed-3750479 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-37504792013-08-24 Loss of Akt1 or Akt2 delays mammary tumor onset and suppresses tumor growth rate in MTB-IGFIR transgenic mice Watson, Katrina L Moorehead, Roger A BMC Cancer Research Article BACKGROUND: Akt is a serine/threonine kinase that mediates signaling downstream of tyrosine kinase receptors like the type I insulin-like growth factor receptor (IGF-IR). In fact, we have previously shown that mammary tumors induced by elevated expression of the IGF-IR are associated with hyperactivation of Akt. However, there are three mammalian isoforms of Akt (Akt1, Akt2 and Akt3) and these isoforms regulate distinct physiologic properties within cells. In this manuscript, the impact of disrupting Akt1 or Akt2 in mammary tumors induced by IGF-IR overexpression were examined to determine whether specific Akt isoforms regulate different aspects of mammary tumorigenesis. METHODS: Akt1 and Akt2 levels were stably ablated in mammary tumors of MTB-IGFIR transgenic mice by crossing MTB-IGFIR transgenic mice with either Akt1(−/−) or Akt2(−/−) mice. Tumor onset, growth rate, and metastasis were determined. RESULTS: Ablation of Akt1 or Akt2 significantly delayed tumor onset and tumor growth rate but did not significantly alter lung metastasis. Despite the absence of Akt1 or Akt2, mammary tumors that developed in the MTB-IGFIR mice maintained detectable levels of phosphorylated Akt. Disruption of Akt1 or Akt2 did not affect cell morphology or the expression of luminal or basal cytokeratins in mammary tumors. CONCLUSIONS: Although loss of Akt1 or Akt2 significantly inhibited mammary tumor onset and growth rates the effects were less dramatic than anticipated. Despite the complete loss of Akt1 or Akt2, the level of total phosphorylated Akt remained largely unaffected in the mammary tumors suggesting that loss of one Akt isoform is compensated by enhanced activation of the remaining Akt isoforms. These findings indicate that therapeutic strategies targeting the activation of individual Akt isoforms will prove less effective than simultaneously inhibiting the activity of all three Akt isoforms for the treatment of breast cancer. BioMed Central 2013-08-07 /pmc/articles/PMC3750479/ /pubmed/23919516 http://dx.doi.org/10.1186/1471-2407-13-375 Text en Copyright © 2013 Watson and Moorehead; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Watson, Katrina L Moorehead, Roger A Loss of Akt1 or Akt2 delays mammary tumor onset and suppresses tumor growth rate in MTB-IGFIR transgenic mice |
title | Loss of Akt1 or Akt2 delays mammary tumor onset and suppresses tumor growth rate in MTB-IGFIR transgenic mice |
title_full | Loss of Akt1 or Akt2 delays mammary tumor onset and suppresses tumor growth rate in MTB-IGFIR transgenic mice |
title_fullStr | Loss of Akt1 or Akt2 delays mammary tumor onset and suppresses tumor growth rate in MTB-IGFIR transgenic mice |
title_full_unstemmed | Loss of Akt1 or Akt2 delays mammary tumor onset and suppresses tumor growth rate in MTB-IGFIR transgenic mice |
title_short | Loss of Akt1 or Akt2 delays mammary tumor onset and suppresses tumor growth rate in MTB-IGFIR transgenic mice |
title_sort | loss of akt1 or akt2 delays mammary tumor onset and suppresses tumor growth rate in mtb-igfir transgenic mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750479/ https://www.ncbi.nlm.nih.gov/pubmed/23919516 http://dx.doi.org/10.1186/1471-2407-13-375 |
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