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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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Mammary tumor proliferation in MTB-IGFIR, MTB-IGFIR/Akt1-/- and MTB-IGFIR/Akt2-/- mice. The mitotic index of mammary tumors from MTB-IGFIR mice (black bar; n=11), MTB-IGFIR/Akt1−/− mice (grey bar; n=6) and MTB-IGFIR/Akt2−/− mice (white bar; n=6) was determined using Ki67 immunohistochemistry. The bars represent the mean and standard error of the percentage of tumor cells positive for Ki67 staining.
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Figure 4: Mammary tumor proliferation in MTB-IGFIR, MTB-IGFIR/Akt1-/- and MTB-IGFIR/Akt2-/- mice. The mitotic index of mammary tumors from MTB-IGFIR mice (black bar; n=11), MTB-IGFIR/Akt1−/− mice (grey bar; n=6) and MTB-IGFIR/Akt2−/− mice (white bar; n=6) was determined using Ki67 immunohistochemistry. The bars represent the mean and standard error of the percentage of tumor cells positive for Ki67 staining.

Mentions: To determine whether tumor proliferation was affected in either the MTB-IGFIR/Akt1−/− or MTB-IGFIR/Akt2−/− mice Ki67 immunohistochemistry was performed. It was observed that tumor cell proliferation in the MTB-IGFIR/Akt1−/− tumors was reduced approximately 55% compared to MTB-IGFIR tumors while proliferation rates in the MTB-IGFIR/Akt2−/− tumors were reduced approximately 20% (Figure 4). The data was however quite variable and thus neither result were statistically significant.


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)

Mammary tumor proliferation in MTB-IGFIR, MTB-IGFIR/Akt1-/- and MTB-IGFIR/Akt2-/- mice. The mitotic index of mammary tumors from MTB-IGFIR mice (black bar; n=11), MTB-IGFIR/Akt1−/− mice (grey bar; n=6) and MTB-IGFIR/Akt2−/− mice (white bar; n=6) was determined using Ki67 immunohistochemistry. The bars represent the mean and standard error of the percentage of tumor cells positive for Ki67 staining.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Mammary tumor proliferation in MTB-IGFIR, MTB-IGFIR/Akt1-/- and MTB-IGFIR/Akt2-/- mice. The mitotic index of mammary tumors from MTB-IGFIR mice (black bar; n=11), MTB-IGFIR/Akt1−/− mice (grey bar; n=6) and MTB-IGFIR/Akt2−/− mice (white bar; n=6) was determined using Ki67 immunohistochemistry. The bars represent the mean and standard error of the percentage of tumor cells positive for Ki67 staining.
Mentions: To determine whether tumor proliferation was affected in either the MTB-IGFIR/Akt1−/− or MTB-IGFIR/Akt2−/− mice Ki67 immunohistochemistry was performed. It was observed that tumor cell proliferation in the MTB-IGFIR/Akt1−/− tumors was reduced approximately 55% compared to MTB-IGFIR tumors while proliferation rates in the MTB-IGFIR/Akt2−/− tumors were reduced approximately 20% (Figure 4). The data was however quite variable and thus neither result were statistically significant.

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