Lani
08-21-2007, 05:07 PM
so far in mice, but in mice with her2+ breast cancer and even in mice who already have lung mets. mTor inhibitors are already in clinical trials in other cancers:
Rapamycin inhibits multiple stages of c-Neu/ErbB2–induced tumor progression in a transgenic mouse model of HER2-positive breast cancer
Jonathan D. Mosley1, John T. Poirier1, Darcie D. Seachrist1, Melissa D. Landis1 and Ruth A. Keri1,2
1 Department of Pharmacology and 2 Division of General Medical Sciences-Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio
Abstract
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]
Amplification of the HER2 (also called ErbB2 or c-Neu) proto-oncogene occurs in 25% to 30% of breast cancers and confers a poor prognosis due to refractoriness to conventional chemotherapies and high relapse rates (1, 2). HER2/ErbB2 is a member of the epidermal growth factor family of receptor tyrosine kinases (3). In conjunction with ErbB3, HER2/ErbB2 activates a number of signaling pathways including the phosphatidylinositol 3-kinase (PI3K) pathway (4). When PI3K is activated, it signals through the Akt/protein kinase B kinase, which subsequently activates the growth regulator mammalian target of rapamycin (mTOR; ref. 5). The mTOR kinase regulates cell proliferation and growth through translational control of an array of proteins (6)... In human breast cancer, Zhou et al. (11) have linked mTOR activation to HER2-positivity; high levels of phosphorylated Akt, phosphorylated mTOR, and phosphorylated 4EBP1 were all associated with HER2/ErbB2 expression as well as decreased disease-free survival. Rapamycin, an inhibitor of mTOR, decreases proliferation of a number of mammary epithelial cell lines, particularly those that overexpress HER2/ErbB2, have activated Akt, or have up-regulated p70S6K (12–14). In addition, forced expression of HER2/ErbB2 in MCF-7 cells promotes invasiveness and colony formation that can be blocked by rapamycin (11, 14). 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).
To date, the effects of rapamycin on multiple stages of ErbB2/Neu-induced tumor formation—ranging from early, hyperplastic changes through distal metastases—have not been assessed. In the present study, we used mouse mammary tumor virus (MMTV)-c-Neu mice (17) to determine if rapamycin has more global inhibitory effects on multiple stages of tumorigenic progression that extend beyond inhibition of proliferation of primary tumors. These mice express rat c-Neu/ErbB2 selectively in the mammary gland and have been used to study preneoplastic changes in the gland (18–20) and mechanisms of metastatic progression (21–23). Herein, we report that rapamycin induces regression of primary tumors that overexpress c-Neu/ErbB2 as well as hyperplastic epithelia. Rapamycin also attenuates proliferation of established lung metastases in these mice. Together, these data indicate that rapamycin can inhibit multiple stages of tumor progression, suggesting that inhibition of the mTOR pathway may be a useful chemopreventive strategy as well as an effective treatment for early-stage and late-stage HER2/ErbB2 positive breast cancers.
Rapamycin inhibits multiple stages of c-Neu/ErbB2–induced tumor progression in a transgenic mouse model of HER2-positive breast cancer
Jonathan D. Mosley1, John T. Poirier1, Darcie D. Seachrist1, Melissa D. Landis1 and Ruth A. Keri1,2
1 Department of Pharmacology and 2 Division of General Medical Sciences-Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio
Abstract
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]
Amplification of the HER2 (also called ErbB2 or c-Neu) proto-oncogene occurs in 25% to 30% of breast cancers and confers a poor prognosis due to refractoriness to conventional chemotherapies and high relapse rates (1, 2). HER2/ErbB2 is a member of the epidermal growth factor family of receptor tyrosine kinases (3). In conjunction with ErbB3, HER2/ErbB2 activates a number of signaling pathways including the phosphatidylinositol 3-kinase (PI3K) pathway (4). When PI3K is activated, it signals through the Akt/protein kinase B kinase, which subsequently activates the growth regulator mammalian target of rapamycin (mTOR; ref. 5). The mTOR kinase regulates cell proliferation and growth through translational control of an array of proteins (6)... In human breast cancer, Zhou et al. (11) have linked mTOR activation to HER2-positivity; high levels of phosphorylated Akt, phosphorylated mTOR, and phosphorylated 4EBP1 were all associated with HER2/ErbB2 expression as well as decreased disease-free survival. Rapamycin, an inhibitor of mTOR, decreases proliferation of a number of mammary epithelial cell lines, particularly those that overexpress HER2/ErbB2, have activated Akt, or have up-regulated p70S6K (12–14). In addition, forced expression of HER2/ErbB2 in MCF-7 cells promotes invasiveness and colony formation that can be blocked by rapamycin (11, 14). 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).
To date, the effects of rapamycin on multiple stages of ErbB2/Neu-induced tumor formation—ranging from early, hyperplastic changes through distal metastases—have not been assessed. In the present study, we used mouse mammary tumor virus (MMTV)-c-Neu mice (17) to determine if rapamycin has more global inhibitory effects on multiple stages of tumorigenic progression that extend beyond inhibition of proliferation of primary tumors. These mice express rat c-Neu/ErbB2 selectively in the mammary gland and have been used to study preneoplastic changes in the gland (18–20) and mechanisms of metastatic progression (21–23). Herein, we report that rapamycin induces regression of primary tumors that overexpress c-Neu/ErbB2 as well as hyperplastic epithelia. Rapamycin also attenuates proliferation of established lung metastases in these mice. Together, these data indicate that rapamycin can inhibit multiple stages of tumor progression, suggesting that inhibition of the mTOR pathway may be a useful chemopreventive strategy as well as an effective treatment for early-stage and late-stage HER2/ErbB2 positive breast cancers.