Antitumor Activity of Rapamycin in a Transgenic Mouse Model of ErbB2-Dependent Human Breast Cancer

Liu, Mei; Howes, Amy L.; Lesperance, Jacqueline; Stallcup, William B.; Hauser, Craig A.; Kadoya, Kuniko; Oshima, Robert G.; Abraham, Robert T.

doi:10.1158/0008-5472.can-04-4589

Cited by 92 publications

(90 citation statements)

References 46 publications

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“…Critical to the advancement of effective treatment modalities for this disease is the development and utilization of biologically relevant cancer models to assess the effect and mechanisms of action of molecularly targeted anticancer therapies. Studies presented herein extend previous research on the effects of rapamycin in the c-Neu/ErbB2 mammary tumor models by assessing the effect of rapamycin on hyperplasia of the mammary gland as well as metastatic tumor cells (15,16).…”

Section: Discussionmentioning

confidence: 57%

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Rapamycin inhibits multiple stages of c-Neu/ErbB2–induced tumor progression in a transgenic mouse model of HER2-positive breast cancer

Mosley

Poirier

Seachrist

et al. 2007

Molecular Cancer Therapeutics

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Amplification of the HER2 (ErbB2, c-Neu) proto-oncogene in breast cancer is associated with poor prognosis and high relapse rates. HER2/ErbB2, in conjunction with ErbB3, signals through the Akt/phosphatidylinositol 3-kinase pathway and leads to the activation of mammalian target of rapamycin (mTOR), a critical mRNA translation regulator that controls cell growth. Gene expression analysis of mammary tumors collected from mouse mammary tumor virus-c-Neu transgenic mice revealed that mRNA levels of several mTOR pathway members were either up-regulated (p85/phosphatidylinositol 3-kinase and p70S6 kinase) or down-regulated (eIF-4E-BP1) in a manner expected to enhance signaling through this pathway. Treatment of these mice with the mTOR inhibitor rapamycin caused growth arrest and regression of primary tumors with no evidence of weight loss or generalized toxicity. The treatment effects were due to decreased proliferation, associated with reduced cyclin D1 expression, and increased cell death in primary tumors. Whereas many of the dead epithelial cells had the histopathologic characteristics of ischemic necrosis, rapamycin treatment was not associated with changes in microvascular density or apoptosis. Rapamycin also inhibited cellular proliferation in lung metastases. In summary, data from this preclinical model of ErbB2/Neu-induced breast cancer show that inhibition of the mTOR pathway with rapamycin blocks multiple stages of ErbB2/Neu-induced tumorigenic progression. [Mol Cancer Ther 2007;6(8):2188 -97]

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Section: Discussionmentioning

confidence: 57%

“…In mice that develop mammary tumors in response to overexpression of the rat ErbB2 (c-Neu) gene, the rapamycin analogue RAD001 inhibits proliferation of tumor cells (15). In addition, growth of mouse mammary tumors induced by a constitutively active form of c-Neu (NeuYD) is also attenuated by rapamycin (16).…”

Section: Introductionmentioning

confidence: 99%

Rapamycin inhibits multiple stages of c-Neu/ErbB2–induced tumor progression in a transgenic mouse model of HER2-positive breast cancer

Mosley

Poirier

Seachrist

et al. 2007

Molecular Cancer Therapeutics

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“…Rapamycin and spermidine extend the lifespan of yeast, flies, and worms and have beneficial effects on the health of rodents (16,17). Rapamycin slows tumorigenesis and extends lifespan in mice (17,18), and spermidine leads to enhanced resistance to oxidative stress and decreased cell death (17,19). In the first experiment gerbils were infected with L3 larvae and divided into three groups (n = 3 per group).…”

Section: Atg8a Localization On the Bacterial Vacuole And In The Cell mentioning

confidence: 99%

Autophagy regulates Wolbachia populations across diverse symbiotic associations

Voronin

Cook

Steven

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

113

117

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Wolbachia are widespread and abundant intracellular symbionts of arthropods and filarial nematodes. Their symbiotic relationships encompass obligate mutualism, commensalism, parasitism, and pathogenicity. A consequence of these diverse associations is that Wolbachia encounter a wide range of host cells and intracellular immune defense mechanisms of invertebrates, which they must evade to maintain their populations and spread to new hosts. Here we show that autophagy, a conserved intracellular defense mechanism and regulator of cell homeostasis, is a major immune recognition and regulatory process that determines the size of Wolbachia populations. The regulation of Wolbachia populations by autophagy occurs across all distinct symbiotic relationships and can be manipulated either chemically or genetically to modulate the Wolbachia population load. The recognition and activation of host autophagy is particularly apparent in rapidly replicating strains of Wolbachia found in somatic tissues of Drosophila and filarial nematodes. In filarial nematodes, which host a mutualistic association with Wolbachia, the use of antibiotics such as doxycycline to eliminate Wolbachia has emerged as a promising approach to their treatment and control. Here we show that the activation of host nematode autophagy reduces bacterial loads to the same magnitude as antibiotic therapy; thus we identify a bactericidal mode of action targeting Wolbachia that can be exploited for the development of chemotherapeutic agents against onchocerciasis, lymphatic filariasis, and heartworm.Brugia malayi | innate immunity | chemotherapy | helminth | endosymbiont W olbachia is a widespread and abundant endosymbiotic bacterium of arthropods and filarial nematodes that resides in vacuoles of host germline and somatic cells. Wolbachia show a diverse variety of symbiotic associations with their host, ranging from obligate mutualism in filarial nematodes to commensal, parasitic, or pathogenic associations in insects and other arthropod hosts (1-5).In filarial nematodes Wolbachia is obligatory for normal larval growth and development, embryogenesis, and survival of adult worms (1). Although the molecular basis of this mutualistic relationship remains unknown, a comparison of host and bacterial genomes suggests that intact biosynthetic pathways for haem, nucleotides, riboflavin, and FAD may be among the contributions of the bacteria to the biology of the nematode host (6-8). The biological processes most sensitive to Wolbachia loss include larval growth and development and embryogenesis in adult females. These processes have a high metabolic demand because of the rapid growth, development, and organogenesis of the nematode and are associated with the rapid expansion of Wolbachia populations following larval infection of mammalian hosts and in reproductively active adult females (9). Loss of Wolbachia results in extensive apoptosis of germline and somatic cells of embryos, microfilariae, and fourth-stage (L4) larvae, presumably because of the lack of provision of ...

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“…Blockade of mTOR signaling lead to down-regulation of ErbB3 at the mRNA and protein levels. ErbB3 alone is not ligand activated, but in complex with ErbB2 this tyrosine kinase initiates PI3K activation and subsequent Akt phosphorylation (29). Inhibition of ErbB3 by rapamycin is a recent observation, and it seems likely that mTOR modulates expression of other receptor signaling molecules.…”

Section: Discussionmentioning

confidence: 99%

“…Recent results suggest that mTOR regulates Akt through a feedback mechanism, whereby inhibition of mTOR leads to a subsequent decrease in Akt phosphorylation (15,29). These reports show that inhibition of mTOR activity can lead to down-regulation of phosphorylation of endogenous Akt.…”

Section: Inhibition Of Mtor Activity Inhibits Akt Phosphorylationmentioning

confidence: 93%

Mammalian Target of Rapamycin Promotes Vincristine Resistance through Multiple Mechanisms Independent of Maintained Glycolytic Rate

VanderWeele

Rudin

2005

Molecular Cancer Research

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Deregulation of the phosphoinositide 3-kinase-Akt pathway is a major contributor to oncogenesis and resistance to cancer therapy. Recent work has shown mammalian target of rapamycin (mTOR) to be a major target downstream of Akt that contributes to both transformation and therapeutic resistance. Although inhibitors of Akt are not yet clinically available, rapamycin, a mTOR-specific inhibitor, has long been used as an immunosuppressant, and several rapamycin analogues are now in clinical trials in oncology. Recent data indicate that a mTOR complex phosphorylates Akt, and this complex is insensitive to rapamycin. We show that dominant-negative mTOR diminishes phosphorylation of endogenous Akt and exogenous myristoylated Akt (mAkt), that prolonged exposure to rapamycin also inhibits Akt activation, and that this inhibition is dependent on new protein synthesis. These data suggest that mTOR facilitates Akt activation through mechanisms other than direct phosphorylation. A constitutively active mTOR mutant that fails to enhance Akt phosphorylation nevertheless promotes resistance to multiple antimicrotubule agents, indicating that mTOR also mediates survival independent of Akt. Although Akt-and mTOR-mediated survival has been linked to regulation of cellular metabolism, we also show that survival and metabolic control are separable. The hexokinase inhibitor 5-thioglucose markedly inhibits glycolytic rate but does not diminish vincristine resistance mediated by mAkt or mTOR, and it has only a minor effect on mTOR-or mAkt-mediated resistance to growth factor withdrawal, suggesting that Akt-mTOR-mediated resistance is largely independent of maintenance of glycolytic rate. We conclude that mTOR activity can promote resistance through multiple mechanisms independent of maintained glycolytic rate. (Mol Cancer Res 2005; 3(11):635 -44)

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Antitumor Activity of Rapamycin in a Transgenic Mouse Model of ErbB2-Dependent Human Breast Cancer

Cited by 92 publications

References 46 publications

Rapamycin inhibits multiple stages of c-Neu/ErbB2–induced tumor progression in a transgenic mouse model of HER2-positive breast cancer

Rapamycin inhibits multiple stages of c-Neu/ErbB2–induced tumor progression in a transgenic mouse model of HER2-positive breast cancer

Autophagy regulates Wolbachia populations across diverse symbiotic associations

Mammalian Target of Rapamycin Promotes Vincristine Resistance through Multiple Mechanisms Independent of Maintained Glycolytic Rate

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