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)

The intrinsic subtype has demonstrated that breast cancers can be classified into biologically and clinically meaningful subgroups. Most breast tumors categorized as one of the intrinsic subtypes, i.e., basal-like, have an estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2-negative phenotype, so-called triple-negative (TN) phenotype; however, TN breast cancer is not a synonym for basal-like subtype. TN breast cancers account for 10-20% of all breast cancers, and are more biologically aggressive than breast cancers of other subgroups. Tailored therapies, such as endocrine therapy and anti-HER2 therapy, are not applicable to TN breast cancer. To develop novel strategies against TN breast cancer, it is essential to understand the specific pathways driving the aggressive behavior of TN breast cancer. Preclinical and clinical studies have suggested that DNA-damaging agents and poly ADP-ribose polymerase inhibitors are active in TN breast cancer harboring BRCA1 dysfunction; anti-epidermal growth factor receptor (EGFR) antibodies and EGFR tyrosine kinase inhibitors are active in TN breast cancer with EGFR gene amplification; dasatinib is active in TN breast cancer with activated Src tyrosine kinases; inhibitors of a mammalian target of rapamycin are active in TN breast cancer with loss of PTEN tumor suppressor; antiangiogenic therapies enhance antitumor activity of chemotherapeutic agents in hypervascular TN breast cancer; and irinotecan, trabectedin, ixabepilone, and ABI-007 are active in TN breast cancer. A number of clinical trials are ongoing to clarify the antitumor activity of these challenging treatment strategies. Further biological characterization of TN breast cancer is needed to develop more specific treatment strategies against TN breast cancer.
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PMID:Possible treatment strategies for triple-negative breast cancer on the basis of molecular characteristics. 1940 71

Breast cancer is a complex, molecular disease, in which a number of cellular pathways involving cell growth and proliferation, such as the MAPK, RB/E2F, P13K/AKT/mTOR, and TP53 pathways, are altered. These pathways represent molecular mechanisms that are composed and regulated by various genes. The genes that are altered in terms of cell growth and proliferation include the oncogenes HER2, c-MYC, and RAS, the ER genes, and the genes for cell cyclin D1 and E, and the tumor suppressor genes RB, TP53, and PTEN, and the breast cancer susceptibility genes BRCA1 and BRCA2. Although the nature of breast cancer is complex and has frustrated previous attempts at treatment or prevention, the elucidation of its molecular nature over the last several decades is now providing targets for effective therapies to treat the disease and hopefully one day to prevent it.
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PMID:The molecular genetics of breast cancer and targeted therapy. 1970 34

This Review outlines the understanding and management of triple-negative breast cancer (TNBC). TNBC shares morphological and genetic abnormalities with basal-like breast cancer (BLBC), a subgroup of breast cancer defined by gene-expression profiling. However, TNBC and BLBC tumors are heterogeneous and overlap is incomplete. Breast cancers found in BRCA1 mutation carriers are also frequently triple negative and basal like. TNBC and BLBC occur most frequently in young women, especially African Americans, and tend to exhibit aggressive, metastatic behavior. These tumors respond to conventional chemotherapy but relapse more frequently than hormone receptor-positive, luminal subtypes and have a worse prognosis. New systemic therapies are urgently needed as most patients with TNBC and/or BLBC relapse with distant metastases, and hormonal therapies and HER2-targeted agents are ineffective in this group of tumors. Poly (ADP-ribose) polymerase inhibitors, angiogenesis inhibitors, EGFR-targeted agents, and src kinase and mTOR inhibitors are among the therapeutic agents being actively investigated in clinical trials in patients with TNBC and/or BRCA1-associated tumors. Increased understanding of the genetic abnormalities involved in the pathogenesis of TNBC, BLBC and BRCA1-associated tumors is opening up new therapeutic possibilities for these hard-to-treat breast cancers.
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PMID:Triple-negative breast cancer: disease entity or title of convenience? 2087 96

Triple-negative [estrogen receptor (ER)-/progesterone receptor (PR)-/HER2-] breast cancers account for ~15% of overall breast cancers. Triple-negative breast cancers demonstrate a panel of specific molecular alterations including a high rate of p53 mutations, frequent loss of function of BRCA1, phosphatase and tensin homolog (PTEN) loss and a specific panel of tyrosine kinase activation [fibroblast growth factor receptor 2 (FGFR2)]. This molecular entity is considered as sensitive to chemotherapy in the adjuvant setting. When metastatic, the disease is usually aggressive and drug resistant, leading to cancer death within 18 months for the majority of patients. There is no evidence from randomized trials that triple-negative breast cancers have a different sensitivity to specific chemotherapy compared with other molecular classes. Similar findings have been reported for bevacizumab. Several recent research efforts have focused on this entity in the last few years. DNA alkylating agents have shown promising activity in the neoadjuvant setting, but no evidence from a phase III trial currently supports its use. Several targeted therapies are also being successfully developed. Poly(ADP ribose) polymerase 1 (PARP1) inhibitors induce tumor response as a single agent in BRCA1-mutated breast cancer, and could sensitize cisplatin in the whole triple negative population. Several other targeted agents are being developed in this setting, including epidermal growth factor receptor (EGFR), FGFR2, mammalian target of rapamycin (mTOR) and NOTCH inhibitors.
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PMID:Treatment of triple-negative metastatic breast cancer: toward individualized targeted treatments or chemosensitization? 2094 32

mTOR (mammalian target of rapamycin) signaling plays a key role in the development of many tumor types. Therefore, mTOR is an attractive target for cancer therapeutics. Although mTOR inhibitors are thought to have radiosensitization activity, the molecular bases remain largely unknown. Here we show that treating MCF7 breast cancer cells with rapamycin (an mTOR inhibitor) results in significant suppression of homologous recombination (HR) and nonhomologous end joining (NHEJ), two major mechanisms required for repairing ionizing radiation-induced DNA DSBs. We observed that rapamycin impaired recruitment of BRCA1 and Rad51 to DNA repair foci, both essential for HR. Moreover, consistent with the suppressive role of rapamycin on both HR and NHEJ, persistent radiation-induced DSBs were detected in cells pretreated with rapamycin. Furthermore, the frequency of chromosome and chromatid breaks was increased in cells treated with rapamycin before and after irradiation. Thus our results show that radiosensitization by mTOR inhibitors occurs via disruption of the major two DNA DSB repair pathways.
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PMID:The mTOR inhibitor rapamycin suppresses DNA double-strand break repair. 2126 15

Tumor resistance remains a major clinical challenge. Numerous pathways are under investigation to determine how best to target therapies to specific mutations in tumor biology and circumvent resistance. Agents in development include inhibitors of the poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) pathway, such as iniparib, olaparib, and veliparib; the PI3K/Akt/mTOR pathway inhibitor everolimus; and the Src family tyrosine kinase inhibitor dasatinib. Research is ongoing to determine whether patients with specific biochemical attributes, such as the presence of a BRCA1 or BRCA2 mutation, will have a better response to targeted therapy and whether targeted agents act synergistically with chemotherapeutic agents.
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PMID:Novel agents and future directions for refractory breast cancer. 2160 Mar 81

Metformin may reduce the incidence of breast cancer and enhance response to neoadjuvant chemotherapy in diabetic women. This trial examined the effects of metformin on Ki67 and gene expression in primary breast cancer. Non-diabetic women with operable invasive breast cancer received pre-operative metformin. A pilot cohort of eight patients had core biopsy of the cancer at presentation, a week later (without treatment; internal control), then following metformin 500-mg o.d. for 1 week increased to 1-g b.d. for a further week continued to surgery. A further 47 patients had core biopsy at diagnosis were randomized to metformin (the same dose regimen) or no drug, and 2 weeks later had core biopsy at surgery. Ki67 immunohistochemistry, transcriptome analysis on formalin-fixed paraffin-embedded cores and serum insulin determination were performed blinded to treatment. Seven patients (7/32, 21.9%) receiving metformin withdrew because of gastrointestinal upset. The mean percentage of cells staining for Ki67 fell significantly following metformin treatment in both the pilot cohort (P = 0.041, paired t-test) and in the metformin arm (P = 0.027, Wilcoxon rank test) but was unchanged in the internal control or metformin control arms. Messenger RNA expression was significantly downregulated by metformin for PDE3B (phosphodiesterase 3B, cGMP-inhibited; a critical regulator of cAMP levels that affect activation of AMP-activated protein kinase, AMPK), confirmed by immunohistochemistry, SSR3, TP53 and CCDC14. By ingenuity pathway analysis, the tumour necrosis factor receptor 1 (TNFR1) signaling pathway was most affected by metformin: TGFB and MEKK were upregulated and cdc42 downregulated; mTOR and AMPK pathways were also affected. Gene set analysis additionally revealed that p53, BRCA1 and cell cycle pathways also had reduced expression following metformin. Mean serum insulin remained stable in patients receiving metformin but rose in control patients. This trial presents biomarker evidence for anti-proliferative effects of metformin in women with breast cancer and provides support for therapeutic trials of metformin.
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PMID:Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. 2165 90

Genomic information is being used to develop robust prognostic and predictive biomarkers that will provide companion diagnostics for emerging molecular targeted therapies. The genetics and associated molecular pathways in ovarian cancer are increasingly being used for the development of novel targeted drugs with a much greater therapeutic specificity than standard chemotherapy. This review will provide an update on recent research on the therapeutic opportunities presented by mutational alterations to the epidermal growth factor receptor (EGFR) and phosphatidylinositide-3-kinase (PI3K/AKT/mTOR) pathways. In addition, the role of the deficient BRCA1/2-mediated homologous recombination (HR) ("BRCAness") pathway is presented. Understanding the molecular biology of these pathways in the context of contemporary drug development means that somatic mutations and epigenetic losses of BRCA1/2 and PTEN in ovarian cancer are being used to predict sensitivity to new poly(ADP-ribose) polymerase (PARP) inhibitors that exhibit synthetic lethality with BRCA1/2 dysfunction and other repair pathways. Future predictive "biomarker pipelines" are being developed so that ovarian cancer patients will be able to avoid having treatments with drugs that will have no effect, whereas other patients with cancer may be eligible for therapies with a much higher probability of treatment response.
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PMID:Targeting genetic and epigenetic alterations in the treatment of serous ovarian cancer. 2213 82

Loss or decrease of wild type BRCA1 function, by either mutation or reduced expression, has a role in hereditary and sporadic human breast and ovarian cancers. We report here that the PI3K/AKT pathway is constitutively active in BRCA1-defective human breast cancer cells. Levels of phospho-AKT are sustained even after serum starvation in breast cancer cells carrying deleterious BRCA1 mutations. Knockdown of BRCA1 in MCF7 cells increases the amount of phospho-AKT and sensitizes cells to small molecule protein kinase inhibitors (PKIs) targeting the PI3K/AKT pathway. Restoration of wild type BRCA1 inhibits the activated PI3K/AKT pathway and de-sensitizes cells to PKIs targeting this pathway in BRCA1 mutant breast cancer cells, regardless of PTEN mutations. In addition, clinical PI3K/mTOR inhibitors, PI-103, and BEZ235, showed anti-proliferative effects on BRCA1 mutant breast cancer cell lines and synergism in combination with chemotherapeutic drugs, cisplatin, doxorubicin, topotecan, and gemcitabine. BEZ235 synergizes with the anti-proliferative effects of gemcitabine by enhancing caspase-3/7 activity. Our results suggest that the PI3K/AKT pathway can be an important signaling pathway for the survival of BRCA1-defective breast cancer cells and pharmacological inhibition of this pathway is a plausible treatment for a subset of breast cancers.
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PMID:Inhibition of constitutively activated phosphoinositide 3-kinase/AKT pathway enhances antitumor activity of chemotherapeutic agents in breast cancer susceptibility gene 1-defective breast cancer cells. 2248 90

Standard chemotherapy regimens can prove effective for patients with early triple-negative breast cancer (TNBC); however, patients with advanced disease typically respond poorly and rapidly progress, and the outcome is poor. New targeted therapies are therefore an urgent unmet medical need for this patient population. Translational and clinical studies into new TNBC treatments have been facilitated by the increased understanding of the aberrant signal transduction pathways regulating growth and survival and the development of chemoresistance in TNBC. Some of the established targeted agents that have been approved in other indications may prove beneficial to patients with TNBC; however, in the absence of approved targeted agents for the treatment of TNBC, most new agents remain experimental. Increased understanding of molecular profiles of TNBC subtypes is likely to improve therapeutic strategies with targeted agents. Novel strategies have reached clinical evaluation in patients with TNBC, including targeting angiogenesis vascular endothelial growth factor and proliferation signalling (receptor tyrosine kinases and mammalian target of rapamycin). Aggressive TNBCs have been found to associate closely with BRCA1 mutation or dysregulation. The recent development of new investigational agents targeting DNA repair, either directly with poly(adenosine disphosphate-ribose) polymerase inhibitors or indirectly through DNA-binding or DNA-damage potentiation, is a major focus of current clinical studies. These and other targeted therapies represent a new approach to TNBC therapy.
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PMID:Emerging targeted therapies in triple-negative breast cancer. 2301 5


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