Akt activation disrupts mammary acinar architecture and enhances proliferation in an mTOR-dependent manner

Debnath, Jayanta; Walker, Stephanie; Brugge, Joan S.

doi:10.1083/jcb.200304159

Cited by 139 publications

(167 citation statements)

References 53 publications

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“…However, these mutant PI3K isoforms did not lead to a significant disruption in adherent cell junction formation as visualised by peripheral ZO-1 staining (Figure 4d). In MCF10A cells, over-expression of either HER2 or activated AKT leads to aberrant proliferation, luminal cell survival and disruption of acinar architecture [26,27]. In contrast, we found that in NMuMG cells, neither expression of AKT1 E17K, nor over-expression of HER2 had a significant effect either on 3D lumen formation or adherent cell junction formation ( Figure 4g-k).…”

Section: Mammary Epithelial Cell Transformation By P110α Akt1 Her2 mentioning

confidence: 78%

“…In these models, several types of primary and immortal mammary epithelial cells give rise to spherical colonies with a single hollow lumen. However, in separate studies, cells lacking PTEN [24], expressing oncogenic mutants of p110 [25] or AKT1 [26], or over-expressing HER2 [27], have each been found to display aberrant tissue architecture and fail to form a single hollow lumen. On the other hand, expression of mutant AKT1 E17K from the endogenous gene in engineered MCF10A cells did not cause morphological changes, in contrast to mutant PIK3CA expression [28].…”

Section: Introductionmentioning

confidence: 99%

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Disruption of epithelial architecture caused by loss of PTEN or by oncogenic mutant p110α/PIK3CA but not by HER2 or mutant AKT1

et al. 2012

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Genetic changes in HER2, PTEN, PIK3CA and AKT1 are all common in breast cancer and lead to the elevated phosphorylation of downstream targets of the PI3K/AKT signalling pathway. Changes in HER2, PTEN, PIK3CA and AKT have all been reported to lead to both enhanced proliferation and failures in hollow lumen formation in three dimensional epithelial culture models, but it is not clear whether these failures in lumen formation are caused by any failure in the spatial coordination of lumen formation (hollowing) or purely a failure in the apoptosis and clearance of luminal cells (cavitation). Here we use NMuMG mammary epithelial cells, which form a hollow lumen without significant apoptosis, to compare the transformation by these four genetic changes. We find that either mutant PIK3CA expression or PTEN loss, but not mutant AKT1 E17K, cause disrupted epithelial architecture, whereas HER2 over-expression drives strong proliferation without affecting lumen formation in these cells. We also show that PTEN requires both lipid and protein phosphatase activity, its extreme C-terminal PDZ binding sequence and probably Myosin 5A to control lumen formation through a mechanism that does not correlate with its ability to control AKT, but which is selectively lost through mutation in some tumours. These findings correlate AKT independent signalling activated by mutant PIK3CA or PTEN loss, but not strongly by HER2, with disrupted epithelial architecture and tumour formation.

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Section: Mammary Epithelial Cell Transformation By P110α Akt1 Her2 mentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Disruption of epithelial architecture caused by loss of PTEN or by oncogenic mutant p110α/PIK3CA but not by HER2 or mutant AKT1

et al. 2012

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“…The Spearman rank correlation analysis showed very 5 The IHC score of phosphorylated Akt, BAD and caspase-9 in breast tumors was stratified into low (negative-moderate) and high (strong) for the analysis. significant correlations between NOS2 and COX2 expression, and the phosphorylation of Akt, BAD, and caspase-9.…”

Section: Akt Pathway Activation In Relationship To Markers Of Inflammmentioning

confidence: 99%

“…1,2 The 3 closely related Akt isoforms induce cell proliferation and soft agar growth, and disrupt the acinar architecture of human mammary cells, but do not induce transformation by themselves. [3][4][5] Akt activation requires 2 critical phosphorylation steps at Thr308 and Ser473. The phosphorylation is induced by ligand-mediated activation of growth factor receptors and receptor tyrosine kinases.…”

mentioning

confidence: 99%

Inflammation and IGF‐I activate the Akt pathway in breast cancer

Prueitt

Boersma

Howe

et al. 2006

Intl Journal of Cancer

111

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Akt signaling may promote breast cancer progression and poor disease outcome. We hypothesized that serum insulin-like growth factor I (IGF-I) and a proinflammatory tumor environment induce phosphorylation of Akt and downstream targets of Akt in breast cancer. We studied the relationship between Akt pathway activation, IGF-I and markers of inflammation, e.g., nitric oxide synthase-2 (NOS2), cyclooxygenase-2 (COX2) and tumor phagocyte density, in 248 breast tumors. We also examined the association of Akt phosphorylation with breast cancer survival. We observed that phosphorylation of Akt, BAD and caspase-9 correlated strongly with the expression of the 2 proinflammatory enzymes, NOS2 and COX2, in breast tumors (p < 0.001; Spearman rank correlation). Both NOS2 and COX2 expression were independently associated with Akt phosphorylation in the multivariate analysis. Serum IGF-I concentrations and the IGF-I/IGFBP3 ratio correlated with Akt phosphorylation at Thr308 and Ser473 in breast tumors (p 0.05; Spearman rank correlation). The association with Akt phosphorylation at Thr308 remained statistically significant in the multivariate analysis. Akt pathway activation was not associated with overall survival in the unstratified analysis, but we observed a statistical interaction between Akt phosphorylation and tumor phagocyte density on breast cancer survival (p interaction < 0.05). We further corroborated our findings in cell culture models by demonstrating that ANA-1 macrophages, nitric oxide and prostaglandin E 2 induce Akt phosphorylation in human breast cancer cells. In summary, a proinflammatory environment was found to activate the Akt pathway in breast cancer, and may modify the association between the Akt phosphorylation status and breast cancer survival. ' 2006 Wiley-Liss, Inc.Key words: breast cancer; Akt; inflammation; insulin-like growth factor; survival The Akt family of serine/threonine protein kinases are putative oncogenes that enhance the survival of various cell types. 1,2 The 3 closely related Akt isoforms induce cell proliferation and soft agar growth, and disrupt the acinar architecture of human mammary cells, but do not induce transformation by themselves. 3-5 Akt activation requires 2 critical phosphorylation steps at Thr308 and Ser473. The phosphorylation is induced by ligand-mediated activation of growth factor receptors and receptor tyrosine kinases. Insulin-like growth factor I (IGF-I), insulin and the epidermal growth factor are ligands that activate Akt through the receptormediated pathway. 1,6 The phosphorylation of membrane-bound Akt establishes the full Akt kinase activity and induces Akt translocation into the cytosol and nucleus. 7-10 Activated Akt phosphorylates a number of downstream targets such as BAD, caspase-9, p21, p27, GSK3b, Mdm2, mTOR, IKKa and others. 1,11,12 The phosphorylation of BAD and caspase-9 blocks the apoptotic activity of the 2 proteins and raises the threshold for apoptosis. [13][14][15] Thus, tumors that show a high phosphorylation of BAD and caspase-9 may have a ...

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“…One explanation may relate to the suppression of both p53 and p21. AKT is known to promote the cytoplasmic localization of p21 and promote nuclear translocation of Mdm2, a negative regulator of p53, thereby causing a reduction in p53 transactivation and levels (Debnath et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

AKT induces senescence in primary esophageal epithelial cells but is permissive for differentiation as revealed in organotypic culture

et al. 2006

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Epidermal growth factor receptor (EGFR) overexpression and activation is critical in the initiation and progression of cancers, especially those of epithelial origin. EGFR activation is associated with the induction of divergent signal transduction pathways and a gamut of cellular processes; however, the cell-type and tissue-type specificity conferred by certain pathways remains to be elucidated. In the context of the esophageal epithelium, a prototype stratified squamous epithelium, EGFR overexpression is relevant in the earliest events of carcinogenesis as modeled in a three-dimensional organotypic culture system. We demonstrate that the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, and not the MEK/MAPK (mitogen-activated protein kinase) pathway, is preferentially activated in EGFR-mediated esophageal epithelial hyperplasia, a premalignant lesion. The hyperplasia was abolished with direct inhibition of PI3K and of AKT but not with inhibition of the MAPK pathway. With the introduction of an inducible AKT vector in both primary and immortalized esophageal epithelial cells, we find that AKT overexpression and activation is permissive for complete epithelial formation in organotypic culture, but imposes a growth constraint in cells grown in monolayer. In organotypic culture, AKT mediates changes related to cell shape and size with an expansion of the differentiated compartment.

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Akt activation disrupts mammary acinar architecture and enhances proliferation in an mTOR-dependent manner

Cited by 139 publications

References 53 publications

Disruption of epithelial architecture caused by loss of PTEN or by oncogenic mutant p110α/PIK3CA but not by HER2 or mutant AKT1

Disruption of epithelial architecture caused by loss of PTEN or by oncogenic mutant p110α/PIK3CA but not by HER2 or mutant AKT1

Inflammation and IGF‐I activate the Akt pathway in breast cancer

AKT induces senescence in primary esophageal epithelial cells but is permissive for differentiation as revealed in organotypic culture

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