Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P42345 (mTOR)
26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acquired resistance to endocrine therapy in breast cancer is associated with an increase in peptide growth factor signaling that results in cross-talk activation of the estrogen receptor (ER). Small molecule signal transduction inhibitors (STIs) can target components of these intracellular pathways, and may prove effective in anticancer therapy. However, early phase II clinical trials with various STIs as monotherapy in advanced breast cancer have shown only a modest level of efficacy for these intracellular inhibitors. Preclinical data suggest that combinations of tamoxifen with STIs may provide significantly greater growth inhibition than either therapy alone, and, furthermore, may delay the emergence of endocrine resistance. There are now several trials assessing the efficacy of combinations of small molecule tyrosine kinase inhibitors (TKIs), such as gefitinib and lapatinib, with either tamoxifen or aromatase inhibitors both in the second-line, endocrine-resistant and first-line, hormone-sensitive setting. Similar trials continue with both farnesyltransferase inhibitors (FTIs) and mTOR antagonists, where there are strong preclinical data to suggest additive or synergistic effects for either of these agents in combination with endocrine therapies. Biomarker studies in the presurgical setting are also being utilized as an alternative approach to investigate whether combined endocrine/STI therapy is an effective clinical strategy. This article reviews some of the preclinical evidence supporting this strategy, together with the current status of clinical trials in this area.
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PMID:Clinical trials of intracellular signal transductions inhibitors for breast cancer--a strategy to overcome endocrine resistance. 1611 91

Deprivation of estrogen causes breast tumors in women to adapt and develop enhanced sensitivity to this steroid. Accordingly, women relapsing after treatment with oophorectomy, which substantially lowers estradiol for a prolonged period, respond secondarily to aromatase inhibitors with tumor regression. We have utilized in vitro and in vivo model systems to examine the biologic processes whereby long-term estradiol deprivation (LTED) causes cells to adapt and develop hypersensitivity to estradiol. Several mechanisms are associated with this response, including up-regulation of estrogen receptor-alpha (ERalpha) and the MAP kinase, phosphoinositol 3 kinase (PI3-K) and mammalian target of rapamycin (mTOR) growth factor pathways. ERalpha is four- to tenfold up-regulated and co-opts a classical growth factor pathway using Shc, Grb-2 and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. The molecules involved in the non-genomic signaling process have been identified. Estradiol binds to cell membrane-associated ERalpha, which physically associates with the adaptor protein Shc, and induces its phosphorylation. In turn, Shc binds Grb-2 and Sos, which result in the rapid activation of MAP kinase. These non-genomic effects of estradiol produce biologic effects as evidenced by Elk-1 activation and by morphologic changes in cell membranes. Additional effects include activation of the PI3-K and mTOR pathways through estradiol-induced binding of ERalpha to the IGF-I and epidermal growth factor receptors. A major question is how ERalpha locates in the plasma membrane since it does not contain an inherent membrane localization signal. We have provided evidence that the IGF-I receptor serves as an anchor for ERalpha in the plasma membrane. Estradiol causes phosphorylation of the adaptor protein, Shc and the IGF-I receptor itself. Shc, after binding to ERalpha, serves as the 'bus' which carries ERalpha to Shc-binding sites on the activated IGF-I receptors. Use of small inhibitor (si) RNA methodology to knockdown Shc allows the conclusion that Shc is needed for ERalpha to localize in the plasma membrane. In order to abrogate growth factor-induced hypersensitivity, we have utilized a drug, farnesylthiosalicylic acid, which blocks the binding of GTP-Ras to its membrane acceptor protein, galectin 1, and reduces the activation of MAP kinase. We have also shown that this drug is a potent inhibitor of mTOR as an additional mechanism of inhibition of cell proliferation. The concept of 'adaptive hypersensitivity' and the mechanisms responsible for this phenomenon have important clinical implications. The efficacy of aromatase inhibitors in patients relapsing on tamoxifen could be explained by this mechanism and inhibitors of growth factor pathways should reverse the hypersensitivity phenomenon and result in prolongation of the efficacy of hormonal therapy for breast cancer.
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PMID:Long-term estradiol deprivation in breast cancer cells up-regulates growth factor signaling and enhances estrogen sensitivity. 1611

Response to endocrine therapy in breast cancer correlates with estrogen receptor (ER) and progesterone receptor (PR) status. It was originally hypothesized that the ability of PR to predict response to endocrine therapy was due to the fact that PR is an estrogen-regulated gene and that its levels represented a marker of functional ER activity. However, it is now known that loss of PR can occur via multiple mechanisms, many of which do not include ER function, e.g., hypermethylation of the PR promoter and loss of heterozygosity of the PR gene. We have shown that growth factor signaling pathways can directly down-regulate PR levels via the phosphatidylinositol 3'-kinase (PI3K)/Akt/mTOR pathway, and that this can occur independent of ER. For example, overexpression of myr-Akt in MCF-7 cells causes complete loss of PR protein and mRNA but does not reduce ER levels or activity, thus generating ER+/PR- MCF-7 cells. Therefore, the absence of PR may not simply reflect a lack of ER activity but rather may reflect hyperactive cross-talk between ER and growth factor signaling pathways. Consistent with this hypothesis, several recent clinical studies have found that ER+/PR- breast cancers overexpress human epidermal growth factor receptor (HER) 1 and HER2 compared with ER+/PR+ breast cancers. Although HER receptors can lower ER levels, one study showed that loss of PR correlated with high HER2 levels in a multivariate analysis. Furthermore, loss of PTEN, a negative regulator of the PI3K/Akt signaling pathway, has been shown to be associated with specific loss of PR and no change in ER levels. Given the well-recognized resistance of ER+/PR- breast cancer to antiestrogens, more studies are needed to better understand the etiology of ER+/PR- breast cancer, particularly the analysis of other growth factor receptors and their downstream signaling intermediates with respect to PR status.
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PMID:Progesterone receptor loss correlates with human epidermal growth factor receptor 2 overexpression in estrogen receptor-positive breast cancer. 1646 18

Enhancing the benefit of endocrine therapy by overcoming de novo or acquired resistance remains an important goal in systemic breast cancer therapy. Progress continues to be made in elucidating the molecular pathways by which estrogen receptor-positive breast cancer cells escape from endocrine therapy. The increasing recognition of the roles of epidermal growth factor receptor (EGFR) and human EGFR2 in cross-talk activation of estrogen receptor signaling has led to studies aimed at identifying whether small-molecule tyrosine kinase inhibitors targeted against these receptors give additive or synergistic effects when combined with endocrine agents. Activation of the phosphatidylinositol-3-OH kinase/Akt pathway has also been associated with resistance to either tamoxifen or estrogen deprivation, and preclinical studies have shown that the mammalian target of rapamycin antagonist temsirolimus can restore endocrine sensitivity in breast cancer cells. Randomized phase II trials of aromatase inhibitors combined with EGFR/human EGFR2 tyrosine kinase inhibitors or mammalian target of rapamycin antagonists have been completed in both the neoadjuvant and advanced breast cancer settings. Larger phase III trials with both approaches are now in progress and have been powered to detect whether either strategy can significantly prolong time to disease progression compared with endocrine therapy alone. The correlation of molecular and clinical results from these ongoing studies will be important to establish appropriate biological variables for selecting those patients who may benefit most from this combined approach.
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PMID:Clinical efforts to combine endocrine agents with targeted therapies against epidermal growth factor receptor/human epidermal growth factor receptor 2 and mammalian target of rapamycin in breast cancer. 1646 25

Fibroblast growth factor (FGF) signaling can bypass the requirement for estrogen receptor (ER) activation in the growth of ER-positive (ER+) breast cancer cells. Fibroblast growth factor-1 stimulation leads to phosphorylation of the adaptor protein Suc1-associated neurotrophic factor-induced tyrosine-phosphorylated target (SNT-1) on C-terminal tyrosine residues, whereas it is constitutively bound through its N-terminal phosphotyrosine-binding domain (PTB) to FGF receptors (FGFRs). By expressing the PTB domain of SNT-1 (SNT-1 PTB) in an inducible manner in an ER+ breast carcinoma line, ML20, we asked whether we could uncouple FGFR activation from its downstream signaling components and abrogate FGF-1-induced antiestrogen-resistant growth. Induction of SNT-1 PTB resulted in a significant decrease of FGF-1-dependent tyrosine phosphorylation of endogenous SNT-1, strong inhibition of complex formation between SNT-1, Gab-1 and Sos-1, and reduced activation of Ras, mitogen-activated protein kinase (MAP kinase), and Akt. SNT-1 PTB also inhibited the phosphorylation of p70S6K on Thr421/Ser424 and Ser411, which may result from the abrogation of MAP kinase activity. Moreover, we also observed a decreased phosphorylation of the MAP kinase-independent site Thr389. This may reflect both inhibition of PI-3 kinase pathways and mammalian target of rapamycin (mTOR)-dependent signaling, as the phosphorylation of Thr389 site was sensitive to treatment with the PI3-K and mTOR inhibitors, LY294002 and rapamycin, respectively. Collectively these results suggest that SNT-1 plays a pivotal role in FGF-dependent activation of the Ras-MAP kinase, PI-3 kinase, and mTOR pathways in these cells. Fibroblast growth factor-1 dependent colony formation of ML20 cells in media containing the pure antiestrogen ICI 182,780 was also markedly inhibited upon induction of SNT-1 PTB, suggesting that blockade of FGFR-SNT-1 interactions might abrogate FGF-mediated antiestrogen resistance in breast cancers.
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PMID:Expression of the SNT-1/FRS2 phosphotyrosine binding domain inhibits activation of MAP kinase and PI3-kinase pathways and antiestrogen resistant growth induced by FGF-1 in human breast carcinoma cells. 1668 55

The effect of combinations of a mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, and an estrogen receptor-alpha (ERalpha) antagonist, ERA-923, on breast carcinoma in culture and in a xenograft model has been studied. Phase III trials are underway using temsirolimus for several cancers. ERA-923 was studied in a phase I trial for tamoxifen refractory metastatic breast cancer and was shown to have good safety profiles. Combination of noninhibitory doses of temsirolimus with suboptimal doses of ERA-923 synergistically inhibited the growth of MCF-7 cells. Synergy was found across a wide range of doses and could also be achieved by combining temsirolimus with other antiestrogens such as raloxifene and 4-hydroxytamoxifen. In vivo combination of temsirolimus and ERA-923 at certain doses and schedules completely inhibited tumor growth, while individual agents were only partially effective. Although the mechanism underlying the synergism remains to be understood, the results were associated with the ability of temsirolimus to block the transcriptional activity mediated by ERalpha as well as an increase in G1 arrest when it was combined with ERA-923. Results demonstrated for the first time that the combination of temsirolimus and a pure antiestrogen has excellent anticancer activity in preclinical models and, therefore, may have clinical use in treating hormone-dependent tumors.
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PMID:Combination therapy for treating breast cancer using antiestrogen, ERA-923, and the mammalian target of rapamycin inhibitor, temsirolimus. 1695 35

Signal transduction pathways play a crucial role in breast cancer development, progression, and response to different therapies. A major problem in breast cancer therapy is the heterogeneity among different tumor types and cell lines commonly used in preclinical studies. To characterize the signaling pathways of some of the commonly used breast cancer cell lines and dissect the relationship among a number of pathways and some key genetic and molecular events in breast cancer development, such as p53 mutation, ErbB2 expression, and estrogen receptor (ER)/progesterone receptor (PR) status, we performed pathway profiling of 14 breast cancer cell lines by measuring the expression and phosphorylation status of 40 different cell signaling proteins with 53 specific antibodies using a protein lysate array. Cluster analysis of the expression data showed that there was close clustering of phosphatidylinositol 3-kinase, Akt, mammalian target of rapamycin (mTOR), Src, and platelet-derived growth factor receptor beta (PDGFRbeta) in all of the cell lines. The most differentially expressed proteins between ER- and PR-positive and ER- and PR-negative breast cells were mTOR, Akt (pThr308), PDGFRbeta, PDGFRbeta (pTyr751), panSrc, Akt (pSer473), insulin-like growth factor-binding protein 5 (IGFBP5), Src (pTyr418), mTOR (pSer2448), and IGFBP2. Many apoptotic proteins, such as apoptosis-inducing factor, IGFBP3, bad, bax, and cleaved caspase 9, were overexpressed in mutant p53-carrying breast cancer cells. Hexokinase isoenzyme 1, ND2, and c-kit were the most differentially expressed proteins in high and low ErbB2-expressing breast cancer cells. This study demonstrated that ER/PR status, ErbB2 expression, and p53 status are major molecules that impact downstream signaling pathways.
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PMID:Dissection of signaling pathways in fourteen breast cancer cell lines using reverse-phase protein lysate microarray. 1712 30

Amplified in breast cancer 1 (AIB1), an estrogen receptor (ER) coactivator, is frequently amplified or overexpressed in human breast cancer. We previously developed a transgenic mouse model in which AIB1 can act as an oncogene, giving rise to a premalignant hyperplastic mammary phenotype as well as to a high incidence of mammary tumors that are primarily ER(+). In this model, the AIB1 transgene is responsible for continued activation of the insulin-like growth factor-I receptor, suggesting a role for the activation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway in the premalignant phenotype and tumor development. Here we show that treatment of AIB1 transgenic mice with the mTOR inhibitor RAD001 reverts the premalignant phenotype. Furthermore, treatment of cell lines derived from AIB1-dependent mammary tumors with RAD001 in culture leads to a G(1) cell cycle arrest. Lastly, tumor growth after injection of ER(+) AIB1 tumor cell lines into wild-type animals is inhibited by RAD001 treatment. In this ER(+) model, inhibition of tumor growth by RAD001 was significantly better than inhibition by the antiestrogen 4-hydroxytamoxifen alone, whereas a combination of both RAD001 and 4-hydroxytamoxifen was most effective. Based on these results, we propose that the combination of mTOR inhibition and ER-targeted endocrine therapy may improve the outcome of the subset of ER(+) breast cancers overexpressing AIB1. These studies provide preclinical support for the clinical development of RAD001 and suggest that AIB1 may be a predictive factor of RAD001 response.
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PMID:Targeting the AIB1 oncogene through mammalian target of rapamycin inhibition in the mammary gland. 1714 84

The Akt pathway is commonly deregulated in many cancers. Clinical trials are currently underway to test the effectiveness of breast cancer treatment by inhibition of various Akt pathway intermediates. A set of genes induced by Akt in a transgenic mouse model, a subset of which were sensitive to mammalian target of rapamycin (mTOR) inhibitor RAD001, was examined in five public gene expression profile data sets of clinical breast tumor specimens (representing >1000 different samples in all). In each of the clinical data sets, the Akt mouse model genes as a group were significantly overexpressed in human tumors having high levels of AKT1 mRNA. The subset of genes both upregulated by Akt and dependent on mTOR activity were associated with estrogen receptor-negative status, higher grade, increasing tumor size and poor prognosis in multiple patient cohorts; these associations were either not present or not as strong for the Akt-induced, mTOR-independent genes or for AKT1 expression alone. The genes shown here to be relevant to Akt-mTOR both experimentally and pathologically have the potential for use in a molecular diagnostic to determine which patients should receive mTOR antagonist treatment.
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PMID:A gene transcription signature of the Akt/mTOR pathway in clinical breast tumors. 1721 1

Improving endocrine responsiveness and preventing the development of resistance is the goal of many current strategies that are looking to combine aromatase inhibitors with novel drugs that target various pathways in estrogen receptor (ER) positive breast cancer. Pre-clinical models of acquired resistance to aromatase inhibitors have suggested an increase in several signaling pathways including peptide growth factor signaling (EGFR, HER2) and activation of the mTOR signaling pathway. These may result in associated 'cross-talk' activation of ER-dependent gene transcription, such that dual blockade of ER together with other signaling pathways has become a logical approach to improve endocrine responsivness. Clinical strategies with aromatase inhibitors are looking to prevent activation of these pathways either through combination with the selective ER downregulator fulvestrant, or with various signal transduction inhibitors (STIs) including monoclonal antibodies (trastuzumab), small molecule tyrosine kinase inhibitors (TKIs) against EGFR or HER2 (lapatinib, gefitinib) and mTOR antagonists (temsirolimus). Early clinical data have emerged this year for some of these approaches with mixed results. This article reviews the rationale for these strategies, and discusses the lessons that need to be learnt if we are to successfully integrate these new drugs with aromatase inhibitors in the clinic.
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PMID:Clinical strategies for rationale combinations of aromatase inhibitors with novel therapies for breast cancer. 1762 64


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