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Cell, Tumor, and Stem Cell Biology |
1 Molecular Oncology Research Institute and 2 Department of Pathology, Tufts-New England Medical Center, Boston, Massachusetts
Requests for reprints: Ioanna G. Maroulakou, Molecular Oncology Research Institute, Tufts-New England Medical Center, 750 Washington Street, Tufts-NEMC #5609, Boston, MA 02111. Phone: 617-636-6073; Fax: 617-636-6127; E-mail: imaroulakou{at}tufts-nemc.org.
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Abstract |
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Introduction |
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Akt is a serine-threonine protein kinase that is activated by a variety of stimuli via PI3K-dependent mechanisms (6–11). Being an effector of PI3K, Akt regulates a variety of cellular functions, including survival, proliferation, migration, and intermediary metabolism (7, 11–14). There are three Akt isoforms, which are very similar in sequence and which seem to be regulated similarly and to have overlapping functions. However, in animal studies, the ablation of individual Akt isoforms causes distinct phenotypes. Akt1–/– mice are small and exhibit perinatal lethality (15, 16), Akt2–/– mice develop insulin-resistant diabetes (17, 18), and Akt3–/– mice have small brains and exhibit mild neurologic defects (19, 20). Moreover, whereas Akt2–/–/Akt3–/– mice are viable and fertile, Akt1–/–/Akt2–/– mice die perinatally with severe musculoskeletal and adipose tissue defects (21) and Akt1–/–/Akt3–/– mice die at embryonic day 10.5 to embryonic day 11.5 with severe defects in the cardiovascular and nervous systems (22).
A recent study addressing the specificity of Akt isoforms showed that knocking down Akt1 activates extracellular signal-regulated kinase and promotes the induction of epithelial-mesenchymal transition (EMT) by insulin-like growth factor-I (IGF-I) or EGF in immortalized human mammary epithelial cells in culture. Knocking down Akt2 on the other hand reversed the prosurvival and proliferative effects of IGF-I, suppressed EMT induced by knocking down Akt1 in IGF-I receptor–overexpressing cells, and inhibited the migration of EGF-stimulated cells (23). These data suggested that Akt1 may selectively inhibit, whereas Akt2 may selectively enhance, the migration of immortalized mammary epithelial cells in culture. This conclusion is supported by the results of two additional recent studies. One of these studies showed that ectopic expression of constitutively active Akt1 reduces the expression of nuclear factor of activated T cells and cyclooxygenase-2 and inhibits the motility of breast cancer cells, whereas down-regulation of Akt1 by transfection of small interfering RNA has the opposite effect (24, 25). The other study showed that overexpression of the activated form of Akt1, which phosphorylates TSC2 (26), promotes TSC2 degradation, leading to the reduction of RhoGTPase activity and cell motility and invasiveness (27). The preceding studies were carried out in cultured cells. However, the effects of Akt1 in cell migration and invasiveness agreed with the results of earlier studies addressing the effects of a constitutively active Akt1 T308D/S473D (Akt1D/D) transgene on mammary oncogenesis by a mutant PyMT decoupled from the PI3K (28) or by activated Neu (29). The results of the former study showed that Akt1D/D compliments the mutant PyMT in tumor induction and tumor growth but not in cell invasiveness and metastasis (28). The results of the latter study showed that Akt1D/D synergizes with Neu also in tumor induction and tumor growth (29). However, the tumors developing in double transgenic mice were less invasive and less metastatic, suggesting that activated Akt1 inhibits tumor invasiveness and metastasis.
The present report addresses the specificity of Akt isoforms by focusing on the effects of their ablation on PyMT- and Neu-driven mammary oncogenesis in mice. The MMTV-Neu (5) and the MMTV-PyMT (4) transgenes were crossed into the Akt1–/–, Akt2–/–, and Akt3–/– genetic backgrounds, and the resulting transgenic/wild-type (wt) mice and transgenic/Akt1–/–, Akt2–/–, or Akt3–/– littermates were monitored for the development of mammary adenocarcinomas. The results showed that ablation of Akt1 inhibited cell proliferation and survival and delayed tumor induction by both transgenes. This effect was unique for the ablation of Akt1 because ablation of Akt2 accelerated whereas ablation of Akt3 had a small, not statistically significant inhibitory effect on Neu- and PyMT-induced oncogenesis.
Overall, the data presented in this report agree with the results of earlier studies suggesting that Akt1 may inhibit, whereas Akt2 may enhance, the local invasiveness of breast cancer cells. However, in the context of the complex environment of the whole animal, Akt1 promotes, whereas Akt2 inhibits, tumor induction and tumor growth, an outcome that could not have been predicted from the results of the earlier in vitro studies. The present study provides clues on the role of individual Akt isoforms in mammary oncogenesis and may therefore influence how Akt inhibitors will be used for the treatment of breast cancer.
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Materials and Methods |
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Whole mounts of the mammary gland and histology. The left inguinal and thoracic mammary glands were dissected, and whole mounts were prepared as described (30). Tissues were paraffin embedded, sectioned, and stained with H&E. A pathologist (S.P.N.) analyzed the histologic sections blindly. The code was broken only after all the data were compiled.
Immunohistochemistry and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling assays. To identify cells expressing Neu, or Ki-67, formalin-fixed mammary gland sections were immunostained with the anti-Neu rabbit polyclonal antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) or with the anti-Ki-67 rabbit monoclonal antibody SP1 (NeoMarkers, Fremont, CA). To address the expression of cyclin D1, formalin-fixed tissue sections were stained with an anti-cyclin D1 rabbit monoclonal antibody (NeoMarkers), and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL) staining was carried out on formalin-fixed, paraffin-embedded sections with the ApopTag kit (InterGen, Purchase, NY).
Reverse transcription-PCR and Western blotting. Reverse transcription-PCR (RT-PCR) was carried out using primers specific for the MMTV-Neu transgene as described previously (31). SDS/PAGE, Western blotting, and the probing of Western blots with anti-Akt and anti-ß-actin antibodies were carried out using standard procedures (see Supplementary Data for details).
Statistical analysis. Data have been analyzed by t test, 
2, or ANOVA factorial analysis using the StatView statistical software program (SAS, Abacus Concepts, Berkeley, CA). Results are expressed as mean ± SE.
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Results |
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Akt1 is up-regulated, whereas Akt2 is down-regulated, in tumors arising in MMTV-ErbB2/Neu and MMTV-PyMT transgenic mice. If ablation of Akt1 inhibits tumor development in Neu and PyMT transgenic mice, one would predict that mammary adenocarcinomas developing in Akt wt transgenic mice would express Akt1. To address this question, we probed Western blots of tumors arising in Neu and PyMT transgenic, Akt+/+, and Akt1–/–, Akt2–/–, and Akt3–/– mice with antibodies specific for the three Akt isoforms. The normal mammary gland of a 10-week-old virgin wt mouse was used as a control. The results showed that in PyMT- and Neu-induced tumors Akt1 and Akt3 were slightly up-regulated, whereas Akt2 was down-regulated. However, the down-regulation of Akt2 was more pronounced in tumors arising in Akt wt than in Akt1–/– or Akt3–/– mice, suggesting that Akt2 expression may be modulated to compensate for the loss of Akt1 or Akt3 (Fig. 1C; Supplementary Fig. S1). The results of this experiment are consistent with the hypothesis that Akt1, which promotes tumor induction (Fig. 1B), may also be required for tumor growth.
Because mammary adenocarcinomas are epithelial neoplasms, the high levels of Akt1 and the low levels of Akt2 in tumors arising in Neu/wt and PyMT/wt mice could be the result of preferential expression of Akt1 in epithelial cells and Akt2 in the stroma. To address this issue, we examined the relative expression of Akt1, Akt2, and Akt3 in mammary tissue and in isolated mammary epithelia from wt mice. The results confirmed that all three Akt isoforms are expressed in the mammary gland. In the isolated epithelia, Akt1 and Akt3 were expressed at levels that were similar to the levels of these proteins in the intact mammary gland, suggesting that Akt1 and Akt3 are expressed in both the epithelia and the stroma. However, the expression of Akt2 in the epithelium was very low, suggesting that Akt2 is expressed primarily in the stroma (Fig. 1D). These findings suggest that Akt1 may be up-regulated in the tumors because cells expressing high levels of Akt may have a selective advantage during oncogenesis. The low levels of Akt2 on the other hand may reflect the cellular pattern of expression of this isoform.
Histopathology and invasive and metastatic potential of mammary adenocarcinomas developing in wt, Akt1–/–, Akt2–/–, and Akt3–/– mice. The data in Fig. 2 and Table 1 suggest that ablation of different Akt isoforms causes different selective pressures that may ultimately affect the histopathology of the developing tumors. However, overall, the tumors developing in mice with different Akt backgrounds exhibit significant overlaps in histopathology (Fig. 2A and B; Table 1; see figure legend for details). All tumor-bearing animals were analyzed for metastatic foci in the lung. Pulmonary metastases of PyMT-driven adenocarcinomas were almost universally parenchymal, whereas metastatic foci of Neu-driven adenocarcinomas were primarily intravascular (Fig. 2A, A2 and Fig. 2B, B2; Table 1). A histopathologic feature that should be highlighted here is the invasiveness of Neu-induced tumors, which is apparently slightly enhanced in tumors developing in Akt1–/– mice.
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The ablation of Akt1 does not inhibit the expression of MMTV promoter-driven transgenes. Transgenes driven by the MMTV promoter are induced in the mammary gland stochastically during puberty. Mutations that interfere with the induction of transgenes that encode oncogenic proteins would be expected to inhibit the oncogenic potential of these transgenes. To determine whether the ablation of Akt1 interferes with the induction of MMTV LTR–driven transgenes, we used immunohistochemistry and semiquantitative RT-PCR to examine the expression of Neu in three 10- to 12-week-old Neu/wt mice and in three Neu/Akt1–/– mice. Immunohistochemical slides were analyzed for the number of positive cells in four randomly selected fields from each mouse. A representative sample of the immunohistochemical data (Fig. 3C) shows that the ablation of Akt1 does not affect the induction of the transgene. The cumulative number of Neu-positive cells in the four randomly selected fields (Fig. 3D, left) and RT-PCR-based analyses (Fig. 3D, right) comparing Neu/Akt1wt and Neu/Akt1–/– mammary gland tissues for the expression of the MMTV-Neu transgene confirmed this conclusion.
The data in Fig. 3 show that mutations in any of the three Akt isoforms do not affect mammary gland development or the expression of MMTV LTR–driven transgenes. We therefore conclude that the profound effects of mutation of individual Akt isoforms on tumor induction by Neu or PyMT are due to changes in the transduction of Neu- or PyMT-induced oncogenic signals.
The ablation of Akt1 is associated with a decrease in the number and size of hyperplastic and transformed foci in the mammary gland of MMTV-PyMT transgenic mice. The tumor incidence in Neu/Akt1–/– mice is very low with only 3 mice out of a group of 18 developing detectable tumors after 65 weeks of observation. Because of this, and because the effects of Akt1 ablation on tumor incidence and latency in Neu- and PyMT-driven tumors are similar, almost all subsequent experiments addressing the mechanism by which Akt1 ablation interferes with tumor induction were carried out on the PyMT transgenic model. The ablation of Akt1 may interfere with tumor induction by suppressing the rate of appearance of transformed foci, by inhibiting their rate of growth, or both. To distinguish between these possibilities, we compared whole mounts of the mammary gland of 8- and 12-week-old PyMT/wt and PyMT/Akt1–/– mice and 30-week-old PyMT/Akt1–/– mice (three mice per group). This analysis revealed that, at early time points, PyMT/Akt1–/– mice harbor fewer and smaller hyperplastic foci than PyMT/wt mice. At subsequent time points, the number of foci in the Akt1–/– mice was increased, but their size continued to be smaller (Fig. 4A ). The small size of hyperplastic foci in PyMT/Akt1–/– mice suggested that the ablation of Akt1 might interfere with the transduction of transgene-generated signals that control growth. Their small number in the early stages of oncogenesis may also be a reflection of their slow growth. Foci that grow slowly may indeed be difficult to detect early because it may take them longer to grow to a detectable size. However, the small number of hyperplastic foci in PyMT/Akt1–/– mice may also be interpreted to suggest that ablation of Akt1 inhibits genetic and/or epigenetic events involved in tumor initiation.
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Mammary epithelia of MMTV-PyMT/wt mice exhibit more robust proliferation than mammary epithelia of MMTV-PyMT/Akt1–/– mice. The preceding experiments suggested that Akt1 ablation may interfere with proliferation and/or may promote apoptosis of cells in hyperplastic foci induced by the PyMT transgene. To determine whether Akt1 ablation inhibits cell proliferation, early neoplastic foci and hyperplastic lesions of mammary gland tissue sections of three 8-week-old and three 12-week-old PyMT/wt mice were stained for the Ki-67 proliferation marker and they were compared with similarly stained lesions of three 8-week-old and three 27-week-old PyMT/Akt1–/– mice. The comparison revealed that the ablation of Akt1 indeed inhibits cell proliferation (Fig. 5A ).
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The preceding data addressed the role of Akt1 and Akt2 in the expression of the proliferation marker Ki-67 and/or the expression of cyclin D1 in the early stages of oncogenesis in PyMT transgenic mice. To determine the role of Akt1 in the expression of these markers in established tumors, we stained advanced mammary adenocarcinomas derived from three 12-week-old PyMT/wt and three 27-week-old PyMT/Akt1–/– mice for either Ki-67 or cyclin D1. The results showed that the expression of both markers may be slightly higher in advanced tumors developing in wt as opposed to Akt1 knockout mice. However, the observed differences were not statistically significant at this stage (Fig. 5C). Therefore, tumor cells of advanced PyMT/Akt1–/– tumors adapt to the loss of Akt1 and proliferate at rates that are comparable with the proliferation rates of tumor cells of advanced PyMT/wt tumors.
Akt1 ablation promotes apoptosis of mammary epithelia in MMTV-PyMT transgenic mice. To address the role of Akt1 in cell survival in hyperplastic and early neoplastic foci developing in PyMT transgenic mice, mammary glands of three 8-week-old and three 12-week-old PyMT/wt mice and three 8-week-old and three 27-week-old PyMT/Akt1–/– mice were analyzed for apoptosis using the TUNEL assay. This analysis detected a larger than 2-fold increase in the number of apoptotic cells in hyperplastic and early neoplastic lesions in Akt1–/– mice (Fig. 6A, left and B ). Similar observations were made when we analyzed advanced tumors from the same category of mice (Fig. 6A, right and B). The analysis of the advanced tumors also revealed foci of apoptotic cell clusters, which were limited to the tumors developing in Akt1 knockout mice (Fig. 6C).
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Discussion |
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There was overlap in histopathology between Neu-induced and PyMT-induced tumors arising in wt and Akt1–/–, Akt2–/–, and Akt3–/– mice. However, tumors arising in mice of different Akt-deficient genetic backgrounds tended to exhibit trends toward different histopathologic patterns. The histopathologic trends observed in transgenic mice lacking different Akt isoforms suggest that the ablation of different isoforms may generate isoform-specific selective pressures that promote the development of biologically distinct neoplasms. However, the biological boundaries between the neoplasms arising in Akt1–/–, Akt2–/–, and Akt3–/– mice were not clearly defined.
The development of the mammary gland during puberty in all Akt knockout mice was indistinguishable from the development of the mammary gland in wt mice. Moreover, the expression of the transgene was not affected by the ablation of Akt1, Akt2, or Akt3. These data combined, suggest that the observed differences in Neu- or PyMT-induced tumorigenesis in Akt1–/–, Akt2–/–, and Akt3–/– mice are due to differences in the transduction of Neu and PyMT oncogenic signals among the three Akt isoforms.
Akt1 ablation delays the induction of detectable mammary tumors in both the Neu and the PyMT transgenic mice. This may be interpreted to suggest that the ablation of Akt1 inhibits tumor initiation. Another interpretation, which does not exclude the preceding one, is that it inhibits tumor growth and that the delayed detection may be due to the slow growth of preneoplastic and early neoplastic foci. The observation that the ablation of Akt1 correlates with a decrease in the size of hyperplastic and transformed foci in the mammary gland of PyMT transgenic mice provided support for the latter hypothesis. Experiments addressing the differences in the rate of growth of tumors developing in wt and Akt1 knockout mice confirmed this hypothesis and suggested that the ablation of Akt1 may also inhibit the growth of established tumors. The growth inhibition of established tumors caused by the ablation of Akt1 suggests that inhibition of Akt1 may not only have a protective effect in tumor initiation but that it may also have a therapeutic effect in growing tumors.
Evidence presented in this report showed that the dramatic delay in tumorigenesis induced by the ablation of Akt1 is due to the inhibition of cell proliferation and to the promotion of apoptosis caused by the loss of Akt1-transduced signals. In addition to the scattered apoptotic cells, tumors arising in Akt1 knockout mice were shown to also contain focal areas of enhanced apoptosis, which may develop because of hypoxia in sections of the developing tumor. The more frequent appearance of these apoptotic areas in tumors arising in Akt1 knockout mice could be the result of either impaired angiogenesis or enhanced apoptosis in hypoxic areas of the Akt1–/– tumors.
The effects of ablation of individual Akt isoforms in oncogenesis by Neu and PyMT could be either cell autonomous or stroma dependent. Although we have not yet addressed this question directly, our data show that Akt2 is primarily expressed in the stroma of the mammary gland. This suggests that the ablation of Akt2 may accelerate tumor induction and may enhance tumor growth by changing the expression of stroma-derived molecules that regulate the growth of the mammary epithelium. This hypothesis will be addressed directly in future studies.
The ablation of individual Akt isoforms modulates differentially the local invasiveness and metastatic potential of Neu- and PyMT-induced mammary tumors. Thus, Neu-induced tumors seem to exhibit different degrees of invasiveness depending on the Akt genotype of the mouse. Interestingly, the tumors arising in Akt1 knockout mice exhibit the highest degree of invasiveness (P < 0.0350). This agrees with the results of earlier studies on the role of individual Akt isoforms in cell migration in culture (23–25, 27) as well as with the results of earlier studies addressing the ability of constitutively active Akt1 (Akt1D/D) to compliment a mutant PyMT transgene that is uncoupled from PI3K (28) and to synergize with an activated Neu transgene (29). PyMT-induced tumors differ from Neu-induced tumors in that they are all locally invasive independent of the Akt genotype of the mouse. The frequency of distant metastases, however, is significantly lower in tumors arising in Akt1 and Akt2 knockout mice. The uncoupling of the two processes in mice of different genetic backgrounds suggests that the two may be functionally distinct.
The earlier studies on the role of different Akt isoforms on cell migration in culture had been interpreted to suggest that inhibition of Akt1 may be undesirable because it may increase the invasiveness and metastatic potential of tumor cells. Our data agree with the observation that ablation of Akt1 may increase the invasiveness of tumor cells. However, they show that the increased invasiveness does not always correlate with an increase in metastatic potential. Given that the Akt1–/– tumor cells survive poorly and proliferate slowly in the primary site, the decreased metastatic potential of these tumors may be due to the fact that Akt1–/– tumor cells may not survive or they may grow slowly following their transport into a metastatic site. Consequently, inhibition of Akt1 may protect animals harboring Neu- and PyMT-induced mammary adenocarcinomas despite the fact that Akt1 activity inhibits tumor invasiveness, whereas Akt2 activity may have the opposite effect.
Despite the similarities of some of the data generated by the earlier in vitro studies and the studies presented here, the full range of our data led us to opposite conclusions about the likely therapeutic potential of inhibition of different Akt isoforms. The difference in data interpretation between the present in vivo study and the earlier in vitro studies is due, at least in part, to the nature of the present study, which extends the biological variables that could be affected by the ablation of Akt1, Akt2, and Akt3. Another possibility is that the regulation of different Akt isoforms and the ultimate consequences of Akt signals in tumors growing in animals depend on the integration of complex autocrine and paracrine stimuli that may be missing in the in vitro systems. These systems indeed lack the full range of interactions between the stroma and the epithelial cells, they are devoid of the immune system, and they lack hormonal and other factors that function at a distance from the site they are produced.
The hypothesis that Akt2 activity may promote whereas Akt1 activity may inhibit Neu- and PyMT-driven tumorigenesis, which was suggested by the earlier studies, seemed to be supported by clinicopathologic data showing that Akt2 is frequently overexpressed in human breast cancer (32). However, although Akt2 may be overexpressed more frequently than Akt1, mutations enhancing the cellular levels of D3 phosphorylated phosphoinositides, which are common in human breast cancer, activate not only Akt2 but also Akt1 and Akt3. More important, a recent large study on 402 estrogen receptor-
–positive breast carcinomas revealed that overexpression of Akt2 is associated with a lower rather than a higher rate of relapse in the course of tamoxifen treatment (33). The latter observation agrees with the data presented in this report because it suggests that Akt2 activity may have a protective effect in breast cancer. Further confirmation of the in vivo animal data presented in this report, in human breast cancer, will have significant translational implications because it will dramatically affect how Akt inhibitors may be used for the treatment of breast cancer.
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Acknowledgments |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
We thank Dr. M. Birnbaum for his kind gift of Akt2–/– mice, Dr. Thomas Ludwig for his kind gift of Akt3–/– mice, Drs. Nelson Brown and Philip Hinds for providing us with well-characterized primary epithelial cell cultures, Dr. R. Bronson for helpful suggestions about the histopathologic analysis of the tumors, Kris Bolen for technical assistance, and Drs. Philip Hinds and Charlotte Kuperwasser (Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, MA) for reviewing the manuscript.
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Footnotes |
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3 C. Mao et al. Unequal contribution of Akt isoforms in the DN to DP thymocyte transition, submitted for publication. 
Received 10/13/06. Revised 11/14/06. Accepted 11/16/06.
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in attainment of normal brain size. Mol Cell Biol 2005;25:1869–78. (PKB/Akt3) in postnatal brain development but not in glucose homeostasis. Development 2005;132:2943–54. (PKB) and Akt3/PKB on thymus, skin, and cardiovascular and nervous system development in mice. Mol Cell Biol 2005;25:10407–18.) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion. Cancer Res 2004;64:3171–8.This article has been cited by other articles:
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  D. Iliopoulos, C. Polytarchou, M. Hatziapostolou, F. Kottakis, I. G. Maroulakou, K. Struhl, and P. N. Tsichlis MicroRNAs Differentially Regulated by Akt Isoforms Control EMT and Stem Cell Renewal in Cancer Cells Sci. Signal., October 13, 2009; 2(92): ra62 - ra62. [Abstract] [Full Text] [PDF]
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R. L. Dillon, R. Marcotte, B. T. Hennessy, J. R. Woodgett, G. B. Mills, and W. J. Muller Akt1 and Akt2 Play Distinct Roles in the Initiation and Metastatic Phases of Mammary Tumor Progression Cancer Res., June 15, 2009; 69(12): 5057 - 5064. [Abstract] [Full Text] [PDF]
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J. D. Mosley, J. T. Poirier, D. D. Seachrist, M. D. Landis, and R. A. Keri Rapamycin inhibits multiple stages of c-Neu/ErbB2 induced tumor progression in a transgenic mouse model of HER2-positive breast cancer Mol. Cancer Ther., August 1, 2007; 6(8): 2188 - 2197. [Abstract] [Full Text] [PDF]
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