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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 volume in MTB-IGFIR, MTB-IGFIR/Akt1-/- and MTB-IGFIR/Akt2-/- mice. Graphs showing tumor volumes in (A) MTB-IGFIR/Akt1−/− mice (red squares, red lines; n=6) compared to MTB-IGFIR mice (black circles, black lines; n=11) and (B) MTB-IGFIR/Akt2−/− mice (green diamonds, green lines; n=6) compared to MTB-IGFIR mice (black circles, black lines; n=11). Tumor volumes for each mouse were plotted as a scatter plot and the best fit, exponential line was drawn. The same group of MTB-IGFIR mice were used for both comparisons.
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Figure 3: Mammary tumor volume in MTB-IGFIR, MTB-IGFIR/Akt1-/- and MTB-IGFIR/Akt2-/- mice. Graphs showing tumor volumes in (A) MTB-IGFIR/Akt1−/− mice (red squares, red lines; n=6) compared to MTB-IGFIR mice (black circles, black lines; n=11) and (B) MTB-IGFIR/Akt2−/− mice (green diamonds, green lines; n=6) compared to MTB-IGFIR mice (black circles, black lines; n=11). Tumor volumes for each mouse were plotted as a scatter plot and the best fit, exponential line was drawn. The same group of MTB-IGFIR mice were used for both comparisons.

Mentions: Tumor growth rates were also evaluated using the formula for Specific Growth Rate (SGR) [33]. It was observed that mammary tumors in MTB-IGFIR/Akt1−/− mice had SGRs that were approximately half that of the MTB-IGFIR mice. This difference in growth rate was significant. The mammary tumors in MTB-IGFIR/Akt2−/− mice had growth rates that were approximately 36% slower than MTB-IGFIR mice and this difference was also statistically significant. Figure 3 shows a scatter plot with best fit exponential tumor growth curves to illustrate the differences in mammary tumor growth rates. As indicated in these plots there was some variability regarding growth rates of mammary tumors in MTB-IGFIR/Akt1−/− and MTB-IGFIR/Akt2−/− mice, however, the majority of the tumors grew at a slower rate than the mammary tumors of MTB-IGFIR mice.


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 volume in MTB-IGFIR, MTB-IGFIR/Akt1-/- and MTB-IGFIR/Akt2-/- mice. Graphs showing tumor volumes in (A) MTB-IGFIR/Akt1−/− mice (red squares, red lines; n=6) compared to MTB-IGFIR mice (black circles, black lines; n=11) and (B) MTB-IGFIR/Akt2−/− mice (green diamonds, green lines; n=6) compared to MTB-IGFIR mice (black circles, black lines; n=11). Tumor volumes for each mouse were plotted as a scatter plot and the best fit, exponential line was drawn. The same group of MTB-IGFIR mice were used for both comparisons.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Mammary tumor volume in MTB-IGFIR, MTB-IGFIR/Akt1-/- and MTB-IGFIR/Akt2-/- mice. Graphs showing tumor volumes in (A) MTB-IGFIR/Akt1−/− mice (red squares, red lines; n=6) compared to MTB-IGFIR mice (black circles, black lines; n=11) and (B) MTB-IGFIR/Akt2−/− mice (green diamonds, green lines; n=6) compared to MTB-IGFIR mice (black circles, black lines; n=11). Tumor volumes for each mouse were plotted as a scatter plot and the best fit, exponential line was drawn. The same group of MTB-IGFIR mice were used for both comparisons.
Mentions: Tumor growth rates were also evaluated using the formula for Specific Growth Rate (SGR) [33]. It was observed that mammary tumors in MTB-IGFIR/Akt1−/− mice had SGRs that were approximately half that of the MTB-IGFIR mice. This difference in growth rate was significant. The mammary tumors in MTB-IGFIR/Akt2−/− mice had growth rates that were approximately 36% slower than MTB-IGFIR mice and this difference was also statistically significant. Figure 3 shows a scatter plot with best fit exponential tumor growth curves to illustrate the differences in mammary tumor growth rates. As indicated in these plots there was some variability regarding growth rates of mammary tumors in MTB-IGFIR/Akt1−/− and MTB-IGFIR/Akt2−/− mice, however, the majority of the tumors grew at a slower rate than the mammary tumors of MTB-IGFIR mice.

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