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The effect Akt2 deletion on tumor development in Pten(+/-) mice.

ABSTRACT: The serine/threonine kinase Akt is frequently activated in human cancers and is considered an attractive therapeutic target. However, the relative contributions of the different Akt isoforms to tumorigenesis, and the effect of their deficiencies on cancer development are not well understood. We had previously shown that Akt1 deficiency is sufficient to markedly reduce the incidence of tumors in Pten(+/-) mice. Particularly, Akt1 deficiency inhibits endometrial carcinoma and prostate neoplasia in Pten(+/-) mice. Here, we analyzed the effect of Akt2 deficiency on the incidence of tumors in Pten(+/-) mice. Relative to Akt1, Akt2 deficiency had little-to-no effect on the incidence of prostate neoplasia, endometrial carcinoma, intestinal polyps and adrenal lesions in Pten(+/-) mice. However, Akt2 deficiency significantly decreased the incidence of thyroid tumors in Pten(+/-), which correlates with the relatively high level of Akt2 expression in the thyroid. Thus, unlike Akt1 deletion, Akt2 deletion is not sufficient to markedly inhibit tumorigenesis in Pten(+/-) mice in most tested tissues. The relatively small effect of Akt2 deletion on the inhibition of tumorigenesis in Pten(+/-) mice could be explained, in part, by an insufficient decrease in total Akt activity, due to the relatively lower Akt2 versus Akt1 expression, and relatively high blood insulin levels in Pten(+/-)Akt2(-/-) mice. The relatively high blood insulin levels in Pten(+/-)Akt2(-/-) mice may elevate the activity of Akt1, and possibly Akt3, thus, limiting the reduction of total Akt activity and preventing this activity from dropping to a threshold level required to inhibit tumorigenesis.

SUBMITTER: Xu PZ

PROVIDER: S-EPMC3272625 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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The effect Akt2 deletion on tumor development in Pten(+/-) mice.

Xu P-Z PZ Chen M-L ML Jeon S-M SM Peng X-d XD Hay N N

Oncogene 20110711 4

The serine/threonine kinase Akt is frequently activated in human cancers and is considered an attractive therapeutic target. However, the relative contributions of the different Akt isoforms to tumorigenesis, and the effect of their deficiencies on cancer development are not well understood. We had previously shown that Akt1 deficiency is sufficient to markedly reduce the incidence of tumors in Pten(+/-) mice. Particularly, Akt1 deficiency inhibits endometrial carcinoma and prostate neoplasia in ...[more]

PMID: 21743498

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Project description:BackgroundPten functionally acts as a tumor suppressor gene. Lately, tissue-specific ablation of Pten gene in mice has elucidated the role of Pten in different tumor progression models. However, a temporally controlled Pten loss in all adult tissues to examine susceptibility of various tissues to Pten-deficient tumorigenesis has not been addressed yet. Our goal was to explore the genesis of Pten-deficient malignancies in multiple tissue lineages of the adult mouse.Methods and findingsWe utilized an inducible Cre/loxP system to delete Pten exon 5 in the systemic organs of ROSA26 (R26)-CreER(T);Pten(fx/fx) mice. On reaching 45 weeks 4OHT-induced Pten loss, we found that the R26-CreER(T);Pten(fx/fx) mice developed a variety of malignancies. Overall tumor mean latency was 17 weeks in the Pten-deficient mice. Interestingly, mutant females developed malignancies more quickly at 10 approximately 11 weeks compared with a tumor latency of 21 weeks for mutant males. Lymphoma incidence (76.9% in females; 40.0% in males) was higher than the other malignancies found in the mutant mice. Mutant males developed prostate (20.0%), intestinal cancer (35.0%) and squamous cell carcinoma (10.0%), whereas the mutant females developed squamous cell carcinoma (15.4%) and endometrial cancer (46.1%) in addition to lymphomas. Furthermore, we tested the pharmacological inhibition of the PTEN downstream effectors using LY294002 on Pten-deficient prostate hyperplasia. Our data revealed that, indeed, the prostate hyperplasia resulting from the induced Pten loss was significantly suppressed by LY294002 (p = 0.007).ConclusionsThrough monitoring a variety of Pten-deficient tumor formation, our results revealed that the lymphoid lineages and the epithelium of the prostate, endometrium, intestine and epidermis are highly susceptible to tumorigenesis after the Pten gene is excised. Therefore, this R26-CreER(T); Pten(fx/fx) mouse model may provide an entry point for understanding the role of Pten in the tumorigenesis of different organs and extend the search for potential therapeutic approaches to prevent Pten-deficient malignancies.

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The effect Akt2 deletion on tumor development in Pten(+/-) mice.

Publications

The effect Akt2 deletion on tumor development in Pten(+/-) mice.

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