Rapamycin Inhibits Growth of Premalignant and Malignant Mammary Lesions in a Mouse Model of Ductal Carcinoma <i>In situ</i>

Namba, Ruria; Young, Lawrence J.T.; Abbey, Craig K.; Kim, Lisa; Damonte, Patrizia; Borowsky, Alexander D.; Qi, Jinyi; Tepper, Clifford G.; MacLeod, Carol L.; Cardiff, Robert D.; Gregg, Jeffrey P.

doi:10.1158/1078-0432.ccr-05-2170

Cited by 74 publications

(54 citation statements)

References 34 publications

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“…HIF-1␣ has been shown to be an excellent correlate of rapamycin response in a transgenic model of prostate neoplasia dependent on activated Akt, and in VHL-deficient renal cell carcinoma xenografts (20,39). Consistent with the findings here in spontaneously arising hamartomas in LKB1ϩ/Ϫ mice, recent studies using human glioblastoma xenografts and transplanted murine breast carcinomas also found rapamycinsensitivity of FDG-PET imaging of these tumors (50,51). Data from LKB1 and AMPK-deficient MEFs demonstrate that HIF-1␣ and HIF-1␣ targets are dramatically up-regulated in these cells under normoxic conditions, indicating that HIF-1␣ up-regulation is not a secondary consequence of other tumor mutations or hypoxia present within the hamartomas.…”

Section: Discussionsupporting

confidence: 79%

mTOR and HIF-1α-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome

Shackelford

Vasquez

Corbeil

et al. 2009

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

189

161

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Peutz-Jeghers syndrome (PJS) is a familial cancer disorder due to inherited loss of function mutations in the LKB1/ STK11 serine/ threonine kinase. PJS patients develop gastrointestinal hamartomas with 100% penetrance often in the second decade of life, and demonstrate an increased predisposition toward the development of a number of additional malignancies. Among mitogenic signaling pathways, the mammalian-target of rapamycin complex 1 (mTORC1) pathway is hyperactivated in tissues and tumors derived from LKB1-deficient mice. Consistent with a central role for mTORC1 in these tumors, rapamycin as a single agent results in a dramatic suppression of preexisting GI polyps in LKB1؉/؊ mice. However, the key targets of mTORC1 in LKB1-deficient tumors remain unknown. We demonstrate here that these polyps, and LKB1-and AMPK-deficient mouse embryonic fibroblasts, show dramatic up-regulation of the HIF-1␣ transcription factor and its downstream transcriptional targets in an rapamycin-suppressible manner. The HIF-1␣ targets hexokinase II and Glut1 are up-regulated in these polyps, and using FDG-PET, we demonstrate that LKB1؉/؊ mice show increased glucose utilization in focal regions of their GI tract corresponding to these gastrointestinal hamartomas. Importantly, we demonstrate that polyps from human PeutzJeghers patients similarly exhibit up-regulated mTORC1 signaling, HIF-1␣, and GLUT1 levels. Furthermore, like HIF-1␣ and its target genes, the FDG-PET signal in the GI tract of these mice is abolished by rapamycin treatment. These findings suggest a number of therapeutic modalities for the treatment and detection of hamartomas in PJS patients, and potential for the screening and treatment of the 30% of sporadic human lung cancers bearing LKB1 mutations.AMPK ͉ FDG-PET ͉ glycolysis ͉ hamartoma ͉ polyposis

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Section: Discussionsupporting

confidence: 79%

mTOR and HIF-1α-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome

Shackelford

Vasquez

Corbeil

et al. 2009

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

189

161

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“…[25][26][27][28][29] In particular, five MMTV-c-Neu mice bearing tumors were treated with 150 g rapamycin (a dose approximately 3 times higher than the dose used in our study) for 32 days and tumor regression was observed. 29 However, the effect of rapamycin on longevity of cancer-prone mice has not been previously investigated.…”

Section: Discussionmentioning

confidence: 90%

“…29 Second, consistent with indirect mechanism of action, rapamycin inhibited cancer growth in mice more profoundly than in cell culture. 27,31 And third, similar to CR, rapamycin extends lifespan in a heterogeneous group of mice, which die from various diseases not necessarily related to cancer.…”

Section: Discussionmentioning

confidence: 98%

Rapamycin Extends Maximal Lifespan in Cancer-Prone Mice

Anisimov

Zabezhinski

Popovich

et al. 2010

The American Journal of Pathology

219

166

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Aging is associated with obesity and cancer. Calorie restriction both slows down aging and delays cancer. Evidence has emerged that the nutrient-sensing mammalian target of rapamycin (mTOR) pathway is involved in cellular and organismal aging. Here we show that the mTOR inhibitor rapamycin prevents age-related weight gain, decreases rate of aging, increases lifespan, and suppresses carcinogenesis in transgenic HER-2/neu cancer-prone mice. Rapamycin dramatically delayed tumor onset as well as decreased the number of tumors per animal and tumor size. We suggest that, by slowing down organismal aging, rapamycin delays cancer.

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“…42). In these mice, an early transient increase in apoptosis was observed in tumor cells after 3 h of rapamycin treatment but not after 7 days.…”

Section: Discussionmentioning

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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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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Rapamycin Inhibits Growth of Premalignant and Malignant Mammary Lesions in a Mouse Model of Ductal Carcinoma In situ

Cited by 74 publications

References 34 publications

mTOR and HIF-1α-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome

mTOR and HIF-1α-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome

Rapamycin Extends Maximal Lifespan in Cancer-Prone Mice

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

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