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Loss of Akt1 or Akt2 delays mammary tumor onset and suppresses tumor growth rate in MTB-IGFIR transgenic mice.

Watson KL, Moorehead RA - BMC Cancer (2013)

Bottom Line: Ablation of Akt1 or Akt2 significantly delayed tumor onset and tumor growth rate but did not significantly alter lung metastasis.Disruption of Akt1 or Akt2 did not affect cell morphology or the expression of luminal or basal cytokeratins in mammary tumors.Although loss of Akt1 or Akt2 significantly inhibited mammary tumor onset and growth rates the effects were less dramatic than anticipated.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON N1G2W1, Canada.

ABSTRACT

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.

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The levels of Akt1 and Akt2. Western blot for Akt1 and Akt2 in wild type (WT) mammary tissues from four different mice and mammary tumors from four different MTB-IGFIR transgenic mice. Akt3 was evaluated but could not be detected in any of the samples. The WT tissue was taken from adult mice that had not been exposed to doxycycline. β-actin served as a loading control.
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Figure 1: The levels of Akt1 and Akt2. Western blot for Akt1 and Akt2 in wild type (WT) mammary tissues from four different mice and mammary tumors from four different MTB-IGFIR transgenic mice. Akt3 was evaluated but could not be detected in any of the samples. The WT tissue was taken from adult mice that had not been exposed to doxycycline. β-actin served as a loading control.

Mentions: Previous characterization of the MTB-IGFIR transgenic mice showed that mammary tumors expressing high levels of IGF-IR also contained high levels of phosphorylated Akt [16]. However, it was not determined which of the Akt isoforms were important in the MTB-IGFIR mammary tumors. Therefore, as an initial experiment, the levels of the three Akt isoforms were evaluated in normal, wild type (WT) mammary tissue and in mammary tumors of MTB-IGFIR transgenic mice. Evaluation of Akt1, Akt2 and Akt3 revealed that Akt1 and Akt2 can be detected in both WT mammary tissue and mammary tumors (Figure 1) while Akt3 could not be detected in either WT mammary tissue or mammary tumors.


Loss of Akt1 or Akt2 delays mammary tumor onset and suppresses tumor growth rate in MTB-IGFIR transgenic mice.

Watson KL, Moorehead RA - BMC Cancer (2013)

The levels of Akt1 and Akt2. Western blot for Akt1 and Akt2 in wild type (WT) mammary tissues from four different mice and mammary tumors from four different MTB-IGFIR transgenic mice. Akt3 was evaluated but could not be detected in any of the samples. The WT tissue was taken from adult mice that had not been exposed to doxycycline. β-actin served as a loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750479&req=5

Figure 1: The levels of Akt1 and Akt2. Western blot for Akt1 and Akt2 in wild type (WT) mammary tissues from four different mice and mammary tumors from four different MTB-IGFIR transgenic mice. Akt3 was evaluated but could not be detected in any of the samples. The WT tissue was taken from adult mice that had not been exposed to doxycycline. β-actin served as a loading control.
Mentions: Previous characterization of the MTB-IGFIR transgenic mice showed that mammary tumors expressing high levels of IGF-IR also contained high levels of phosphorylated Akt [16]. However, it was not determined which of the Akt isoforms were important in the MTB-IGFIR mammary tumors. Therefore, as an initial experiment, the levels of the three Akt isoforms were evaluated in normal, wild type (WT) mammary tissue and in mammary tumors of MTB-IGFIR transgenic mice. Evaluation of Akt1, Akt2 and Akt3 revealed that Akt1 and Akt2 can be detected in both WT mammary tissue and mammary tumors (Figure 1) while Akt3 could not be detected in either WT mammary tissue or mammary tumors.

Bottom Line: Ablation of Akt1 or Akt2 significantly delayed tumor onset and tumor growth rate but did not significantly alter lung metastasis.Disruption of Akt1 or Akt2 did not affect cell morphology or the expression of luminal or basal cytokeratins in mammary tumors.Although loss of Akt1 or Akt2 significantly inhibited mammary tumor onset and growth rates the effects were less dramatic than anticipated.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON N1G2W1, Canada.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus