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Proc Natl Acad Sci U S A. 2007 May 1; 104(18): 7438–7443.
Published online 2007 Apr 25. doi:  10.1073/pnas.0605874104
PMCID: PMC1863437
Cell Biology

Akt1 governs breast cancer progression in vivo


The serine threonine kinase Akt1 has been implicated in the control of cellular metabolism, survival and growth. Here, disruption of the ubiquitously expressed member of the Akt family of genes, Akt1, in the mouse demonstrates a requirement for Akt1 in ErbB2-induced mammary tumorigenesis. Akt1 deficiency delayed tumor growth and reduced lung metastases, correlating with a reduction in phosphorylation of the Akt1 target, tuberous sclerosis 2 (TSC2) at Ser-939. Akt1-deficient mammary epithelial tumor cells (MEC) were reduced in size and proliferative capacity, with reduced cyclin D1 and p27KIP1 abundance. Akt1 deficiency abrogated the oncogene-induced changes in polarization of MEC in three-dimensional culture and reverted oncogene-induced relocalization of the phosphorylated ezrin–radixin–moesin proteins. Akt1 increased MEC migration across an endothelial cell barrier, enhancing the persistence of migratory directionality. An unbiased proteomic analysis demonstrated Akt1 mediated MEC migration through paracrine signaling via induction of expression and secretion of CXCL16 and MIP1γ. Akt1 governs MEC polarity, migratory directionality and breast cancer onset induced by ErbB2 in vivo.

Keywords: cyclin D1, ErbB2

The cell survival oncoprotein Akt1, also known as protein kinase B (PKB), is frequently hyperactivated in human cancers. Akt1 is recruited to the plasma membrane in the presence of phosphoinositide triphosphate (PI-3,4,5-P). Akt1 plays a central role in the ability of external signals to promote cell survival by preventing cytochrome c release from mitochondria (13) and maintaining mitochondrial membrane integrity by increasing hexokinase association with mitochondria (4). In mammalian cells, activating growth factors and oncogenes stimulate Akt1 kinase activity to promote antiapoptotic signaling (4). Three separate genes with high sequence identity encode the major isoforms of Akt/PKB (Akt1/PKBα, Akt2/PKBβ, Akt3/PKBγ). Substrate specificity of the Akt isoforms are similar, although Akt1 is the predominant isoform expressed in most tissues. Constitutive activation of Akt1 kinase occurs in human cancer through deletion and mutation of the tumor suppressor gene PTEN, the phosphatase that negatively regulates Akt1, through amplification of the Akt1 genes or through amplification of the catalytic subunit of PI3 kinase (57).

ErbB2/ErbB3 receptor activation, which occurs frequently in breast cancer, induces PI3K and Akt1 kinase activity (8, 9). The ErbB2 oncogene is amplified in up to 30% of human breast cancers and is associated with poor patient prognosis in response to chemotherapeutic agents. ErbB2 induces AKT1 activity, cellular growth, and therapeutic resistance (10). The activation of ErbB2 is an early event in human breast cancer, with ErbB2 over-expressed in up to 80% of primary ductal carcinoma in situ lesions (11). Matrigel cultures of MCF10A cells (12) and primary murine mammary epithelial cells (13) allow molecular analysis of genetic events regulating epithelial cell polarity and luminal formation and their role in oncogenic signaling.

Akt1 phosphorylates the tuberous sclerosis (TSC) gene 2 at a conserved Ser residue, disrupting the TSC1/TSC2 complex, thereby derepressing mTOR (target of rapamycin) and activating S6 kinase (14, 15). Tsc2 modulates actin dynamics, inducing a cortical F-actin distribution and regulating RhoA activity (16). A subset of key downstream transcriptional targets, including forkhead ligand1 (FKHR-L1), MDM2, BAD, Huntington, and arfaptin2, are phosphorylated by Akt (17). The pro-proliferative and prosurvival effects induced by Akt1 kinase are conducted through regulation of caspase 9, IκB kinase α, Bad, and induction of the GSK3β/cyclin D1 signaling pathways (reviewed in refs. 17 and 18). The role of Akt1 in migration and invasion has been examined primarily by using expression systems in cultured cells. Activated Akt1 promotes cellular invasiveness in human pancreatic cancer cells, fibrosarcoma cells, and fibroblasts (1921) but inhibits migration of MDAMB231 cells (22). These studies examined the function of Akt1 in vivo, using mice deleted of the Akt1 gene.


To examine the role of Akt1 in ErbB2-induced mammary epithelial cell tumorigenesis, mice homozygously deleted of the Akt1 gene were crossed with mice expressing the ErbB2 oncogene targeted to the mammary epithelium (MMTV-ErbB2-8142). Mice expressing both alleles of Akt1 acquired mammary tumors with a mean tumor onset age (T50) of ≈210 days. Mice deleted of both Akt1 alleles rarely developed tumors (Fig. 1A). Deletion of a single Akt1 allele reduced the rate of tumorigenesis by ≈100 days. Hematogenous spread of tumor cells was detected in the lungs of MMTV-ErbB2 transgenic mice with tumors (Fig. 1 B and C). These mice showed multiple pulmonary tumor emboli. Migration of tumor cells through the basement membrane was observed, indicative of lung metastasis (Fig. 1B). The cytological features of the mammary adenocarcinoma was similar in the Akt1 wild type and Akt1 knockout animals [supporting information (SI) Fig. 6A]. Deletion of both Akt1 alleles reduced lung metastasis. In ErbB2/Akt−/− mice that developed mammary tumors, lung metastasis were not identified, even though tumors were of similar size to ErbB2/Akt+/+ mice (P < 0.05) (Fig. 1C). Tumor metastasis that developed in ErbB2/Akt+/+ mice continued to express the ErbB2 oncogene (Fig. 1D). Vascular density was increased in mice deleted of one or both Akt1 alleles (Fig. 1E). Total Akt abundance was unaltered; however, Akt1 was abolished in Akt1−/− tumors. Because Akt1 phosphorylation of TSC2 has been linked to increased cellular growth in Drosophila (15, 33), we examined the phosphorylation of TSC2 at the conserved Akt1 Ser-939 in the mammary tumors of the mice. In the mammary tumors that developed in Akt1−/− mice, Tsc2 and Rb phosphorylation was significantly reduced (Fig. 1 F–H).

Fig. 1.
Akt1-deficient mice are resistant to ErbB2-induced mammary tumorigenesis. (A) The percentage of mice free of ErbB2-induced mammary tumors is shown in Akt1+/+, Akt1+/−, and Akt1−/− transgenic mice. (B) Histopathology of tumor cells ...

To examine at a higher level of resolution the molecular mechanisms by which Akt1 contributed to ErbB2-induced tumor onset and growth, cell lines were derived from mammary epithelial tumors induced by ErbB2 in the context of either Akt1+/+ or Akt1−/− mice (Fig. 2A). Six lines were derived, with three lines from each genotype. The morphology of the mammary epithelial cells derived from these animals showed a reduced diameter in Akt1−/− cells (Fig. 2A). Western blot analysis confirmed deletion of the Akt1 gene in Akt1−/− mice and expression of the ErbB2 transgene (Fig. 2B). In cell suspension, the Akt1−/− cells showed >10% reduction of cellular diameter (Fig. 2C) (P = 0.002). Akt1 deficiency reduced the rate of basal cellular proliferation (assessed by using the MTT assay) by 50% (P < 0.05) (Fig. 2D). EGF and insulin increased proliferation of mammary epithelial tumor cells (MEC) by 15% compared with Akt1−/− MEC (Fig. 2D). Akt1−/− cell lines showed reduced abundance of p21CIP1, p27KIP1, and cyclin D1 (Fig. 2E), consistent with the findings that AKT1 induces cyclin D1 (24) and reduces p21CIP1 (9) in cultured cells.

Fig. 2.
Akt1 reduced cellular proliferation and cellular size of Akt1-deficient mammary tumor cells. (A) Cellular morphology of MEC lines of MMTV-ErbB2 transgenic mice of either Akt1+/+ or Akt1−/− genotype. (B–D) Western blot (B), cellular ...

The Akt1−/− MEC were transduced with retroviral expression vectors encoding either constitutively active AKT1 (mAKT) or the wild type Akt1 (cAKT) linked through an internal ribosomal entry site to a GFP fusion protein. The expression levels of mAKT and cAKT were similar by Western blot analysis (Fig. 2F). Expression of AKT1, identified by GFP expression, reverted the morphological change of Akt1 deficiency (Fig. 2F and SI Fig. 7). Ki67 staining was reduced from 30.5% to 3.8%, and BrdU uptake was reduced from 26.7% to 6.9% in Akt1−/− MEC (Fig. 2 G and H). Cellular adhesion of Akt1−/− cells was reduced compared with Akt1+/+ cells at each time point (Fig. 3A). Akt1 deficiency reduced cellular migration by 3.5-fold (Fig. 3B). A quantitation of cellular migration showed reduced wound closure in Akt1−/− cells at 24 h (Fig. 3C).

Fig. 3.
Akt1 deficiency reduces cellular migration and migratory directionality. (A) ErbB2 MEC were assessed for cellular adhesion at 2 and 6 h by OD550. (B and C) ErbB2 MEC transwell migration assays (B) and the cellular migration determined by wounding assay ...

To determine the role of endogenous Akt1 in MEC adhesion, polarity, and morphology, analysis of key cytoskeletal components was conducted (Fig. 4A). Stress fibers were assessed by rhodamine phalloidin staining of F-actin. Akt1 wild-type cells showed a larger diameter and increased cortical F-actin. In Akt1-deficient MEC, stress fiber morphology was diffuse throughout the cell (Fig. 4A). Paxillin is a 68-kDa docking protein that associates with components of the focal adhesion complex and is required for focal adhesion disassembly at the base of extending lamellipodia (34). Perturbation of paxillin function inhibits focal adhesion turnover, resulting in loss of polarity and directional migration, and mutational analysis of Y118 implicates this residue in regulating actin dynamics (35, 36). In Akt1+/+ MEC, paxillin was distributed in both the nuclear and cytoplasmic compartments and colocalized with tyrosine-phosphorylated paxillin (Y118) in a cortical and centripetal distribution (Fig. 4B). In Akt1−/− MECs tyrosine-phosphorylated paxillin was observed at focal contacts throughout both the body and the periphery of the cell (Fig. 4B).

Fig. 4.
Akt1 regulates mammary acini formation and cellular polarity in 3D matrigel. (A) Mammary epithelial cells derived from ErbB2 tumors of transgenic mice were fixed and stained for F-actin (phalloidin) and DAPI. (B) Distribution of paxillin and centripetal ...

To examine further the role of Akt1 on cellular morphogenesis, three-dimensional (3D) MEC cultures were conducted (37). Epithelial cells are known to have distinguishing histological features, including polarized morphology and specialized cell-cell contacts. The ErbB2/Akt1+/+ and ErbB2/Akt1−/− cells were grown in Matrigel (37). The ezrin–radixin–moesin (ERM) complex links adhesion molecules to filamentous actin participating in cytoskeletal remodeling during cellular migration. ErbB2 transformation disrupted the distribution of hDLg (human disk large) and phosphorylated ERM normally found in nontransformed MECs (Fig. 4C). Deletion of Akt1 abrogated the ErbB2-mediated changes in polarity of the MEC (Fig. 4C and SI Fig. 9). Thus, in Akt−/− MEC, antibodies to hDLg showed a lateral and basal distribution. Antibody staining to phosphorylated ERM was distributed subjacent to the plasma membrane within acini. These studies indicate a key role for Akt1 in oncogene-induced polarity changes of MEC in 3D culture (Fig. 4D).

Akt1 deficiency reduced the distance, velocity and persistence of migratory directionality (PMD) (Fig. 5 A–D). To determine whether the migratory function of Akt1 involved intra- or extracellular (paracine) signaling, the supernatant of Akt1+/+ MEC was added to ErbB2/Akt1−/− MEC (Fig. 5A). The media of ErbB2/Akt1+/+ MEC rescued the defect in migration of ErbB2/Akt1−/− cells (Fig. 5 A and B). The media from ErbB2/Akt1−/− MEC did not reduce migration of ErbB2/Akt1+/+ cells. The media of the ErbB2/Akt1+/+ MEC rescued the defect in cellular velocity of ErbB2/Akt1−/− MEC (Fig. 5C). Similarly, reintroduction of AKT1 into Akt1−/− MEC rescued the migratory defect (Fig. 5E).

Fig. 5.
Akt1 governs secretion of promigratory factors from MEC. (A and B) ErbB2-MEC were analyzed for directional migration (D/T) in the presence of either native supernatant or coculture with medium from Akt1+/+ MEC (B). (B–D) Analysis of ErbB2-MEC ...

To identify candidate proteins induced by Akt1 that may contribute to migratory directionality, a murine cytokine antibody array was deployed. The majority of cytokines and growth factors were similar between Akt1+/+ and Akt1−/− MECs (SI Fig. 8). Significant 2-fold differences were observed, in the abundance of a subset of proteins (CXCL-16, MIP1γ, IGFBP-3, VEGFA1, SDF1A/CXCL12) (Fig. 5F and SI Table 1). Alteration in protein abundance was confirmed by RIA of the supernatant. These studies demonstrated a >90% decrease in CXCL-16 and MIP1γ and an eight-fold increase in IGFBP-3 (Fig. 5F) in Akt1−/− MEC. Quantitative RT-PCR of the mRNA from Akt1+/+ vs. Akt1−/− MEC showed the relative abundance of the receptors for MIP1γ and SDF-1 (CCRI, CXCR4) were also commensurately reduced (Fig. 5F). Addition of CXCL-16 immunoneutralizing antibody reduced ErbB2/Akt+/+ MEC migration by >60% (Fig. 5G). Addition of a physiological concentration of CXCL-16 enhanced transmigration of ErbB2/Akt1−/− MEC by 1.5-fold. MIP1γ was increased in ErbB2/Akt1+/+ cells. Addition of MIP1γ immunoneutralizing antibody reduced migration of ErbB2/Akt1+/+ MEC by 42% (P < 0.001). Addition of MIP1γ to ErbB2/Akt1−/− cells enhanced migration by 250% (P < 0.001). As anticipated, addition of MIP1γ antibody to ErbB2/Akt1+/+ cells reduced Boyden chamber migration. SDF-1 inhibited migration of ErbB2/Akt1+/+ MEC but had no effect on migration of ErbB2/Akt1−/− cells. Collectively, these studies are consistent with a role for reduced CXCL-16 and MIP1γ abundance in the reduced migration phenotype of Akt1−/− MECs.


These studies demonstrated a key role for Akt1 in ErbB2-induced tumor progression in vivo. ErbB2/Akt1−/− MEC showed reduced cellular proliferation in response to insulin and reduced colony formation. These alterations in cellular growth characteristics correlated with reduced expression of the key cell-cycle regulator cyclin D1 and p21CIP1, which was consistent with prior findings in which Akt1 enhanced p21CIP1 stability (58) and induced cyclin D1 expression through an IKKα/β-catenin signaling pathway (24). Cyclin D1 is required for ErbB2-induced growth of MEC, and the reduction in cyclin D1 abundance likely contributes to the reduced proliferative response of ErbB2/Akt1−/− MEC observed here. Increased ErbB2 abundance and phosphorylation of Akt1 are each associated with poor prognosis in human breast cancer (59).

These studies identify a role for Akt1 in regulating mammary tumor metastasis. The Akt1-deficient cells showed a less spread phenotype with reduced migration that was restored by Akt1 reintroduction or by secreted factors from Akt1+/+ MEC. Cell spreading correlates in a biphasic manner with cell motility, and inadequate adhesion, hyperactive adhesion, and failed adhesion complex remodeling are also associated with reduced mobility (43). Similarly, either insufficient or hyperactive Akt1 impairs migration of mammary epithelial cells (10, 44). The reduction in migratory directionality of Akt1−/− MEC is consistent with studies in Dictyostelium as Akt1 and Pak-null mutant of Dictyostelium fail to orient toward the chemoattractant (36, 45). Phosphorylation of TSC2, the 200-kDa tuberin protein at the Akt1 consensus site (Ser 939) (15, 46), was increased in the ErbB2/Akt1+/+ mammary tumors. The ErbB2/Akt1+/+ MEC displayed increased cortical F-actin, and increased peripheral focal contacts reminiscent of cells in which the relative abundance of free Tsc2 is increased and RhoA activity enhanced (16). Consistent with a role for enhanced RhoA, cofilin phosphorylation was enhanced in ErbB2/Akt1+/+ tumors (data not shown). Collectively, these studies are consistent with a role for Akt1-mediated phosphorylation of Tsc2 to enhance cell migration. In contrast with cultured cells in which the abundance of Tsc2 is reduced by activating mutations of Akt1 (47), Tsc2 abundance was not reduced by activation of Akt1 in vivo, which may contribute to the prometastatic phenotype of Akt1 in vivo.

Akt1-induced secreted factors rescued the defect in cellular migration of Akt1-deficient cells. Dominant-negative inhibitors of Akt1 reduce chemokinesis of endothelial cells (48). Reduced secretion of promigratory factors (MIP1γ, CXCL-16) or increased production of migration inhibitory factors may contribute to the reduced migration of Akt−/− MEC. CXCL-16 abundance was reduced in ErbB2/Akt−/− MEC. CXCL-16 is a membrane-anchored chemokine, cloned as a CXC chemokine ligand for the HIV-coreceptor Bonzo (49), and functions as both chemokine and adhesion molecule (50). Matrix metalloproteinases, including ADAM10 and ADAM17 (51), produce soluble CXCL-16 by shedding at the juxtamembrane region in endothelial cells, smooth muscle cells, and macrophages (52, 53). CXCL-16 expression is altered in atherogenesis, rheumatoid arthritis, and encephalomyelitis (54) and is induced in colon cancer (51, 55) and tumor-associated macrophages (56). CXCL-16 expression in aortic smooth muscle cells is induced by Akt1 (57), and CXCL-16 activates downstream signaling by Akt (57).

Akt1 induced MEC size, consistent with studies of myocytes in Akt1/Akt2-knockout mice (38) and of PTEN and Akt in Drosophila melanogaster (3942). Here, Akt1 regulated the loss of basal polarity and luminal sculpting that occurs in response to oncogenic stimuli. Oncogenic signals, including ErbB2, induced luminal space-filling by blocking apoptosis in MCF10A cells grown in Matrigel (60). ErbB2 plays a dominant role in regulating luminal filling, activating both the PI3-kinase/Akt1 and the MAP kinase pathway (37). In MCF10A cells, ERK rather than PI3-kinase/Akt governs ErbB2-induced luminal filling during luminal morphogenesis (60). Our in vivo studies demonstrate that a reduction in Akt1 abundance reduces the rate of onset of death from ErbB2-induced mammary tumorigenesis. Akt1 contributes to oncogene-induced tumor growth by providing a key function in oncogene-induced disorganization of mammary epithelial cells in 3D culture. Physiological levels of Akt1 promote and reduced levels of Akt1 reduce ErbB2-mediated mammary tumor metastases in vivo.

Materials and Methods

Transgenic Mice, Chemicals, and Reagents.

Experimental procedures with transgenic mice were approved by the ethics committee of Thomas Jefferson University. Akt1−/− mice (23) were backcrossed into the friend virus B-type strain and then crossed with MMTV-ErbB2 in the friend virus B-type strain. Murine mammary epithelial cell culture were isolated from mammary gland tumors and maintained as described (13) and analyzed after 25 passages with at least three lines of each genotype. Fluorescence activated cell sorting for Ki67 and BrdU positive cells (24) and the transduction of cells by the retroviral expression vector encoding either wild type Akt1 (cAKT) or the constitutively active Akt1 (mAKT1) in the vector pBABE-IRES-GFP was described in ref. 25.

Assay of Adhesion and F-Actin Staining.

Adhesion assays (25) and phalloidin staining were conducted as described in refs. 25 and 26. Cell diameter was assessed by using a Multisizer Z3 instrument from Beckman–Coulter (Miami, FL).

Western Blot Analysis.

Western blot analysis was conducted by using antibodies raised against cyclin D1 (DCS-6), p21CIP1 (C-19), p27KIP1 (M-197), cyclin A (C-19), TSC2, tuberin (C20), phosphoTSC2 (Santa Cruz Biotechnology, Santa Cruz, CA) (27, 28), Akt1 (2H10), and phospho/TSC2 (939) from Cell Signaling (Danvers, MA), ErbB2 (PC04) Oncogene Sciences (Cambridge, MA), and phosphoRb (Ser-780) from Sigma (St. Louis, MO).

3D Culture of Mammary Epithelial Cells, Cell Motility, and Migration Assays.

3D culture was performed as described in ref. 29. For the PMD assay, confluent MEC were used for the in vitro scratch wound healing assay, and the wounds were analyzed by using video image (25, 30).

The immunoneutralizing antibodies were directed to CXCL-16 (MAB53) (R & D Systems, Minneapolis, MN) (500 ng/ml), SDF1 (R & D Systems) (20 μg/m), MIP1γ (R & D Systems) (5 μg/ml), and VEGF (United States Biological, Swampscott, MA) (4 ng/ml). Ligands used were as follows: 500 ng/ml CXCL-16 (United States Biological), 100 nM SDF1α, 0.2 ng/ml VEGF (United States Biological), 0.1 μg/ml concentration of IGFBP-3 (R & D Systems), and 10 ng/ml MIPγ (United States Biological).

Real-Time PCR, Microvessel Analysis, and ELISA.

Real-time PCR (31) and the pattern and density of microvessel immunostaining for von Willebrand was described in ref. 32. For ELISA, cells were seeded at 80% of confluence, and the growth medium was changed 24 h later to basal medium, containing 0.12% BSA after washing with PBS. Forty-eight hours later, the conditioned media supernatant were collected and centrifuged at 650 × g for 5 min and filtered through a 0.45-μm membrane filter. Secreted CXCL16, MIP1γ, IGFBP3, and CXCL12 were measured in the conditioned media, using Quantitkine ELISA kits for MIP1γ, IGFBP3 (R & D Systems), and CXCL-16, CXCL-12 (Raybiotech, Narcross, GA) in triplicate.

Statistical Analysis.

Comparisons among groups were analyzed by two-sided t test. A difference of P < 0.05 was considered to be statistically significant. All analyses were done with SPSS software, Version 11.5. Data are expressed as mean ± SEM. In survival analysis of time to tumor offset, we used the standard log–rank test. In the analysis of vascular density, cell diameter, wound healing, and PMD assay, comparisons among groups were analyzed by two-sided t test. A difference of P < 0.05 was considered to be statistically significant.

Supplementary Material

Supporting Information:


We thank Ms. Dawn Scardino and Bernice Sykes for manuscript preparation. This work was supported by National Institutes of Health Grants R01CA70896, R01CA75503, R01CA107382 (to R.G.P); Kimmel Cancer Center Grants 1P30CA56036-08 (to R.G.P.) and 5R01DK48910 (to S.C.M.); American Cancer Society International Research Grants K01 CA85502 and R01 CCA093495 (to J.O.); National Institutes of Health Grant R01CA090764 (to N.H.); and American Cancer Society Illinois Division Grant 06-40 (to W.S.C.). This project is funded in part by the Dr. Ralph and Marian C. Falk Medical Research Trust and a Pennsylvania Department of Health grant (to R.G.P.).


MECmammary epithelial tumor cells
PMDpersistence of migratory directionality
TSCtuberous sclerosis.


The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0605874104/DC1.


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