The aim of this study was to evaluate the possible correlation between preoperative FDG-PET results in human breast cancer and the prognostic markers Ki-67, c- erb B2, p53, oestrogen/progesterone receptor status, axillary lymph node status, tumour size and tumour grading. Seventy-five female patients with breast cancer were included in this prospective study. Patient selection was independent of tumour size and the suspected clinical stage of disease. A high-resolution full-ring scanner (Siemens ECAT HR+) was used for PET imaging. The FDG uptake of breast tumours was calculated as the tumour to background ratio (TBR). In resected cancer tissue specimens, the proliferative fraction was evaluated by Ki-67 immunostaining. Additionally, immunostaining of the prognostic markers c-erb B2, p53, and progesterone and oestrogen receptors was performed. Haematoxylin and eosin-stained sections were used for tumour grading. Correlations between FDG uptake and prognostic markers were assumed to be significant at P<0.05 using the Mann-Whitney U test. In ductal breast cancer, mean TBR was 17.3 (median 7.7, range 1.6-122.7), while in lobular cancer it was 6.5 (median 3.7, range 1.4-22.7). Mean proliferative fraction (% Ki-67 positive tumour cells) was 15%+/-13.8% (median 10%, range 0%-60%). Twenty-three carcinomas showed <5% Ki-67 positive tumour cells. Statistical analysis indicated a positive correlation between FDG uptake and proliferative index in ductal breast cancer ( P<0.0001, r=0.63). By contrast, there was no correlation between FDG uptake and c- erb B2 ( P=0.79), p53 ( P=0.92), tumour grading ( P=0.09), oestrogen receptor status ( P=0.41), progesterone receptor status ( P=0.34), axillary lymph node status ( P=0.90) and tumour size ( P=0.3). It is concluded that FDG uptake is significantly higher in ductal breast cancer than in lobular cancer ( P<0.05). FDG uptake correlates with proliferative activity assessed by Ki-67 immunostaining ( P<0.05). A significant correlation with the other prognostic markers, however, could not be demonstrated.
Deregulation of the mTOR pathway is closely associated with tumorigenesis. Accordingly mTOR inhibitors such as rapamycin and mTOR-selective kinase inhibitors have been tested as cancer therapeutic agents. Inhibition of mTOR results in sensitization to DNA damaging agents, however the molecular mechanism is not well understood. We found that an mTOR-selective kinase inhibitor, AZD8055, significantly enhanced sensitivity of a pediatric rhabdomyosarcoma xenograft toradiotherapy and sensitized rhabdomyosarcoma cells to interstrand crosslinker (ICL) melphalan. Sensitization correlated with drug-induced downregulation of a key component of the Fanconi anemia (FA) pathway, FANCD2 through mTOR regulation of FANCD2 gene transcripts via mTORC1-S6K1. Importantly, we show that FANCD2 is required for the proper activation of ATM-Chk2 checkpoint in response to ICL and that mTOR signaling promotes ICL-induced ATM-Chk2 checkpoint activation by sustaining FANCD2. In FANCD2 deficient lymphoblasts, FANCD2 is essential to suppress endogenous and induced DNA damage, and FANCD2-deficient cells demonstrated impaired ATM-Chk2 and ATR-Chk1 activation, which was rescued by re-introduction of wild type FANCD2. Pharmacological inhibition of PI3K-mTOR-AKT pathway in Rh30 rhabdomyosarcoma cells attenuated ICL-induced activation of ATM, accompanied with the decrease of FANCD2. These data suggest that the mTOR pathway may promote the repair of DNA double strand breaks by sustaining FANCD2 and provide a novel mechanism of how the FA pathway modulates DNA damage response and repair.
RNA interference is the process that double-stranded RNA induces the homology-dependent degradation of cognate mRNA mediated by 21^23 nucleotide short interfering RNA (siRNA). Here, we describe a simple virus vector for e⁄cient delivery of siRNA into mammalian cells utilizing the well-de¢ned H1-RNA promoter and conventional adenovirus. In this pilot study, p53 was targeted by this vector. Our results demonstrate e⁄cient and speci¢c knock-down of p53 in breast cancer MCF-7 and lung carcinoma A549 cells and indicate a prospective application of this siRNA expressing recombinant adenovirus system in functional genomics, cancer gene therapy and virus inhibition. ß
The conserved TOR (target of rapamycin) kinase is part of a TORC1 complex that regulates cellular responses to environmental stress, such as amino acid starvation and hypoxia. Dysregulation of Akt-TOR signaling has also been linked to the genesis of cancer, and thus, this pathway presents potential targets for cancer chemotherapeutics. Here we report that rapamycin-sensitive TORC1 signaling is required for the S-phase progression and viability of yeast cells in response to genotoxic stress. In the presence of the DNA-damaging agent methyl methanesulfonate (MMS), TOR-dependent cell survival required a functional S-phase checkpoint. Rapamycin inhibition of TORC1 signaling suppressed the Rad53 checkpoint-mediated induction of ribonucleotide reductase subunits Rnr1 and Rnr3, thereby abrogating MMS-induced mutagenesis and enhancing cell lethality. Moreover, cells deleted for RNR3 were hypersensitive to rapamycin plus MMS, providing the first demonstration that Rnr3 contributes to the survival of cells exposed to DNA damage. Our findings support a model whereby TORC1 acts as a survival pathway in response to genotoxic stress by maintaining the deoxynucleoside triphosphate pools necessary for error-prone translesion DNA polymerases. Thus, TOR-dependent cell survival in response to DNA-damaging agents coincides with increased mutation rates, which may contribute to the acquisition of chemotherapeutic drug resistance.TOR (target of rapamycin) is a phosphatidylinositol 3-kinase-related kinase family member that regulates cellular responses to wide-ranging environmental stresses, including nutrient starvation, growth factor deprivation, and hypoxia (8,20,45). These diverse environmental cues are transmitted by multiprotein TOR complexes through a variety of downstream pathways to regulate cap-dependent mRNA translation, transcriptional stress responses, cell cycle progression from G 1 to S phase, and cell survival. Rapamycin (RAP) is a macrocyclic lactone antibiotic that, in complex with FKBP12 (the Saccharomyces cerevisiae homolog is Fpr1), specifically targets TOR. Since dysregulation of Akt-TOR signaling has been associated with tumorigenesis (7,8), this pathway provides potential targets for cancer chemotherapy, as evidenced by the development of RAP analogs in clinical trials. Yet despite intense investigation of RAP action and the phenotypic consequences of TOR inhibition, the mechanistic basis for the antitumor activity of RAP in preclinical and clinical studies remains unclear.The TOR kinase was initially identified in the yeast S. cerevisiae, in a genetic screen for mutants conferring resistance to RAP. S. cerevisiae carries two closely related Tor1 and Tor2 kinases, while other eukaryotic genomes encode a single kinase, typified by mammalian mTOR (45). As in mammalian cells, TOR signaling in yeast regulates cell growth through the function of distinct multiprotein complexes (29,39,45,46). In yeast, Tor1 or Tor2 participates in the formation of a RAPsensitive TOR complex 1 (TORC1) that consists of Kog1, Lst8, and ...
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