A gene transcription signature of the Akt/mTOR pathway in clinical breast tumors

Creighton, Chad J.

doi:10.1038/sj.onc.1210245

Cited by 74 publications

(69 citation statements)

References 24 publications

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“…In our study of human tumors, AKT1 mRNA expression correlated with both ER status and PIPP expression and was significantly decreased in triple negative breast cancers. Several other studies, however, have reported no correlation between AKT1 mRNA or protein expression and ER status (Creighton, 2007;Grell et al, 2012;Stå l et al, 2003), although pAKT1 levels were reported as higher in ER + than ER À tumors (Gershtein et al, 2007). In addition, increased AKT1 kinase activity has been reported in 45% of primary breast cancers (Sun et al, 2001).…”

Section: Discussionmentioning

confidence: 94%

The Inositol Polyphosphate 5-Phosphatase PIPP Regulates AKT1-Dependent Breast Cancer Growth and Metastasis

et al. 2015

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Metastasis is the major cause of breast cancer mortality. Phosphoinositide 3-kinase (PI3K) generated PtdIns(3,4,5)P3 activates AKT, which promotes breast cancer cell proliferation and regulates migration. To date, none of the inositol polyphosphate 5-phosphatases that inhibit PI3K/AKT signaling have been reported as tumor suppressors in breast cancer. Here, we show depletion of the inositol polyphosphate 5-phosphatase PIPP (INPP5J) increases breast cancer cell transformation, but reduces cell migration and invasion. Pipp ablation accelerates oncogene-driven breast cancer tumor growth in vivo, but paradoxically reduces metastasis by regulating AKT1-dependent tumor cell migration. PIPP mRNA expression is reduced in human ER-negative breast cancers associated with reduced long-term outcome. Collectively, our findings identify PIPP as a suppressor of oncogenic PI3K/AKT signaling in breast cancer.

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Section: Discussionmentioning

confidence: 94%

The Inositol Polyphosphate 5-Phosphatase PIPP Regulates AKT1-Dependent Breast Cancer Growth and Metastasis

et al. 2015

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“…In particular, it will be interesting to compare the differentially expressed genes identified in this study to those in the phase-II study of everolimus in combination with letrozole [16], once these gene profiles are published. Creighton [48] identified everolimus-sensitive and -insensitive genes induced by Akt in transgenic mice that positively correlated with Akt in human breast tumours, although the everolimus sensitive genes were associated with ER-negative status. A single gene from this signature, Mitochondrial ribosomal protein S7 (MRPS7) was significantly differentially expressed in matched responding tumours in this study.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling of response to mTOR inhibitor everolimus in pre-operatively treated post-menopausal women with oestrogen receptor-positive breast cancer

Sabine

Sims

Macaskill

et al. 2010

Breast Cancer Res Treat

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There is growing evidence that uncontrolled activation of the PI3K/Akt/mTOR pathway contributes to the development and progression of breast cancer. Inhibition of this pathway has antitumour effects in preclinical studies and efficacy in combination with other agents in breast cancer patients. The aim of this study is to characterise the effects of pre-operative everolimus treatment in primary breast cancer patients and to identify potential molecular predictors of response. Twenty-seven patients with oestrogen receptor (ER)-positive breast cancer completed 11-14 days of neoadjuvant treatment with 5-mg everolimus. Core biopsies were taken before and after treatment and analysed using Illumina HumanRef-8 v2 Expression BeadChips. Changes in proliferation (Ki67) and phospho-AKT were measured on diagnostic core biopsies/resection samples embedded in paraffin by immunohistochemistry to determine response to treatment. Patients that responded to everolimus treatment with significant reductions in proliferation (fall in % Ki67 positive cells) also had significant decreases in the expression of genes involved in cell cycle (P = 8.70E-09) and p53 signalling (P = 0.01) pathways. Highly proliferating tumours that have a poor prognosis exhibited dramatic reductions in the expression of cell cycle genes following everolimus treatment. The genes that most clearly separated responding from nonresponding pre-treatment tumours were those involved with protein modification and dephosphorylation, including DYNLRB2, ERBB4, PTPN13, ULK2 and DUSP16. The majority of ER-positive breast tumours treated with everolimus showed a significant reduction in genes involved with proliferation, these may serve as markers of response and predict which patients will derive most benefit from mTOR inhibition.

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“…6A). However, it is unlikely that increased PI3K/AKT signaling contributes to resistance, since AKT and S6 were also phosphorylated in GDC-0449-sensitive control tumors and an obvious PI3K gene-expression signature (25)(26)(27) was lacking in the microarray profiles of the resistant models when compared with sensitive controls (data not shown). Importantly, the PI3K inhibitor GDC-0941 (28) greatly reduced tumor growth in both control and resistant models, indicating that HPI-resistant tumors maintain their dependence on PI3K signaling ( Fig.…”

Section: Molecular Characterization Of 2 Additional Mb Allograft Modementioning

confidence: 99%

Small Molecule Inhibition of GDC-0449 Refractory Smoothened Mutants and Downstream Mechanisms of Drug Resistance

Dijkgraaf¹,

Alicke²,

Weinmann³

et al. 2011

Cancer Research

336

320

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Inappropriate Hedgehog (Hh) signaling has been directly linked to medulloblastoma (MB), a common malignant brain tumor in children. GDC-0449 is an Hh pathway inhibitor (HPI) currently under clinical investigation as an anticancer agent. Treatment of a MB patient with GDC-0449 initially regressed tumors, but this individual ultimately relapsed with a D473H resistance mutation in Smoothened (SMO), the molecular target of GDC-0449. To explore the role of the mutated aspartic acid residue in SMO function, we substituted D473 with every amino acid and found that all functional mutants were resistant to GDC-0449, with positively charged residues conferring potential oncogenic properties. Alanine scan mutagenesis of SMO further identified E518 as a novel prospective mutation site for GDC-0449 resistance. To overcome this form of acquired resistance, we screened a panel of chemically diverse HPIs and identified several antagonists with potent in vitro activity against these GDC-0449-resistant SMO mutants. The bis-amide compound 5 was of particular interest, as it was able to inhibit tumor growth mediated by drug resistant SMO in a murine allograft model of MB. However, focal amplifications of the Hh pathway transcription factor Gli2 and the Hh target gene cyclin D1 (Ccnd1) were observed in two additional resistant models, indicating that resistance may also occur downstream of SMO. Importantly, these HPI resistant MB allografts retained their sensitivity to PI3K inhibition, presenting additional opportunities for the treatment of such tumors. Cancer Res; 71(2); 435-44. Ó2010 AACR.

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A gene transcription signature of the Akt/mTOR pathway in clinical breast tumors

Cited by 74 publications

References 24 publications

The Inositol Polyphosphate 5-Phosphatase PIPP Regulates AKT1-Dependent Breast Cancer Growth and Metastasis

The Inositol Polyphosphate 5-Phosphatase PIPP Regulates AKT1-Dependent Breast Cancer Growth and Metastasis

Gene expression profiling of response to mTOR inhibitor everolimus in pre-operatively treated post-menopausal women with oestrogen receptor-positive breast cancer

Small Molecule Inhibition of GDC-0449 Refractory Smoothened Mutants and Downstream Mechanisms of Drug Resistance

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