Natasha Atanaskova

Mayo Clinic - Rochester, Rochester, Minnesota, United States

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Publications (6)34.29 Total impact

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    ABSTRACT: The antiestrogen tamoxifen has been widely used for decades as selective estrogen receptor (ER) modulator for ERalpha-positive breast tumors. Tamoxifen significantly reduces tumor recurrence by binding to the activation function-2 (AF-2) domain of the ER. Acquired resistance to tamoxifen in breast cancer patients is a serious therapeutic problem. Antiestrogen-resistant breast cancer often shows increased expression of the epidermal growth factor receptor (EGFR) family members, EGFR and ErbB2. In this report we now show that overexpression of EGFR or activated AKT-2 in MCF-7 cells leads to phosphorylation of Ser167 in the AF-1 domain of ERalpha, enhanced ER-amplified in breast cancer 1 (ER:AIB1) interaction in the presence of tamoxifen, and resistance to tamoxifen. In contrast, transfection of activated MAPK kinase, an immediate upstream activator of MAPK (ERK 1 and 2) into MCF-7 cells leads to phosphorylation of Ser118 in the AF-1 domain of ERalpha, inhibition of ER-amplified in breast cancer 1 (ER:AIB1) interaction in the presence of Tam, and maintenance of sensitivity to tamoxifen. Inhibition of AKT by short inhibitory RNA blocked Ser167 phosphorylation in ER and restored tamoxifen sensitivity. However, maximum sensitivity to tamoxifen was observed when both AKT and MAPK were inhibited. Taken together, these data demonstrate that different phosphorylation sites in the AF-1 domain of ERalpha regulate the agonistic and antagonistic actions of tamoxifen in human breast cancer cells.
    Molecular Endocrinology 06/2006; 20(5):996-1008. · 4.75 Impact Factor
  • Kaladhar B Reddy, Sanaa M Nabha, Natasha Atanaskova
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    ABSTRACT: Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway is a frequent event in tumorigenesis. MAPKs have been implicated in cell migration, proteinase-induction, regulation of apoptosis, and angiogenesis, events that are essential for successful completion of metastasis. In this review, we discuss the potential role that MAPKs play in metastasis by regulating cell migration, proteinase-induction and apoptosis.
    Cancer and metastasis reviews 01/2004; 22(4):395-403. · 7.79 Impact Factor
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    ABSTRACT: Oncolytic virus therapy is a novel and expanding approach for treatment of cancer. However, its success is dependent on clarification of signaling mechanisms involved in determination of cell permissiveness to such viral agents. Such data can lead to the development of strategies for increasing efficiency and specificity of oncolytic viruses. We have shown that transformation with oncogenes in Ras signaling pathway plays an essential role in the determination of cell permissiveness to herpes virus and some of its oncolytic mutants. In this study we provide evidence that transcription factors down-stream of Ras can be used as a marker to predict permissiveness of human lymphoma cell lines to R3616, an oncolytic version of herpes simplex virus-1 with deletions in both copies of the viral g134.5 gene. Different lymphoma cell lines including Radji, Daudi. Jurkat, CA46, ST486, NC37, U937, Ramas and Molt4 were infected with R3616 at MOI∼0.5 and their permissiveness to this virus was evaluated by different methods such as western blotting for viral proteins and plaque titration for progeny virus.Raji cells appeared to be the most permissive cell line among the others at different multiplicities of infection. In the next step, the Ras signaling activity in each cell lines was detected using Ras-GTP pull-down assays and also Erk (extracellular signal regulated kinase) kinase assays for Ras downstream elements. The mount of phosphorylation form of Elk (a transcription factor down stream of Erk pathway) was also evaluated by western blotting. Interestingly, the Raji cells, exhibited the highest amount of permissiveness to R3616 as well as Ras signaling activity as was detected by increased phosphorylation of Erk and Elk. Induction of apoptosis in some of the other lymphoma cells upon infection with R3616 and its correlation with the amount of PI3K activity was also studied. The results of this study, therefore, provide evidence for signal-transduction based application of oncolytic herpes virus for attacking lymphoma.
    Molecular Therapy 01/2004; 9. · 7.04 Impact Factor
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    ABSTRACT: The estrogen receptor alpha (ERalpha) signaling plays an essential role in breast cancer progression and endocrine therapy. Mitogen-activated protein kinase (MAPK/Erk1/2) has been implicated in ligand-independent activation of ER, resulting in the cross-talk between growth factor and ER mediated signaling. In this study, we examined the effect of the cross-talk on estradiol (E(2))-mediated signaling, tumor growth and its effect on anti-estrogen therapy. Our findings demonstrate that expression of constitutively activated mitogen activated kinase kinase (MEK1), an immediate upstream activator of MAPK in estrogen receptor positive MCF-7 breast cancer cells (MEK/MCF-7), showed an increase in ERalpha-driven transcriptional activation. In MEK/MCF-7 cells maximal transactivation levels were achieved in response to treatment with much lower E(2) concentrations (10(-10) M E(2)) when compared to MCF-7 control cells (10(-8) M E(2)). Furthermore, we have seen an increased association between ERalpha and its nuclear coactivators AIB1 or TIF-2, in MEK/MCF-7 cells relative to those seen in MCF-7 control cells. In addition, in vivo studies show that MEK/MCF-7 cell tumors are approximately threefold larger than those of MCF-7 cell, in the presence of E(2). Immunohistochemical staining demonstrates that progesterone receptor (PR) and pS2, two E(2)-regulated gene products, are significantly increased in MEK/MCF-7 cell tumors compared to those of MCF-7 control tumors, suggesting that activation of ERalpha by MAPK enhances the expression of E(2)-regulated genes and accelerates tumor growth. Remarkably, the antiestrogens tamoxifen and ICI 182,780, were shown both in vitro and in vivo studies to efficiently antagonize the stimulatory effects of E(2) on ER regulated transactivation and tumor growth in MEK/MCF-7 as well as MCF-7 cell lines. Taken together, these data suggest that MAPK/ER cross-talk enhances ERalpha-mediated signaling and accelerates E(2)-dependent tumor growth without diminishing sensitivity to the inhibitory effects of anti-estrogens.
    Oncogene 07/2002; 21(25):4000-8. · 7.36 Impact Factor
  • Natasha Atanaskova
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    ABSTRACT: The estrogen receptor alpha (ERα) signaling plays an essential role in breast cancer progression and endocrine therapy. Mitogen-activated protein kinase (MAPK/Erk1/2) has been implicated in ligand-independent activation of ER, resulting in the cross-talk between growth factor and ER mediated signaling. In this study, we examined the effect of the cross-talk on estradiol (E 2)-mediated signaling, tumor growth and its effect on anti-estrogen therapy. Our findings demonstrate that expression of constitutively activated mitogen activated kinase kinase (MEK1), an immediate upstream activator of MAPK in estrogen receptor positive MCF-7 breast cancer cells (MEK/MCF-7), showed an increase in ER-driven transcriptional activation. In MEK/MCF-7 cells maximal transactivation levels were achieved in response to treatment with much lower E2 concentrations (10−10M E 2) when compared to MCF-7 control cells (10−8M E2). Furthermore, we have seen an increased association between ER and its nuclear coactivators AIB1 or TIF-2, in MEK/MCF-7 cells relative to those seen in MCF-7 control cells. In addition, in vivo studies show that MEK/MCF-7 cell tumors are ∼3-fold larger than those of MCF-7 cell, in the presence of E2. Immunohistochemical staining demonstrates that progesterone receptor (PR) and pS2, two E2-regulated gene products, are significantly increased in MEK/MCF-7 cell tumors compared to those of MCF-7 control tumors, suggesting that activation of ER by MAPK enhances the expression of E2-regulated genes and accelerates tumor growth. Remarkably, the antiestrogens tamoxifen and ICI 182,780, were shown both in vitro and in vivo studies to efficiently antagonize the stimulatory effects of E2 on ER regulated transactivation and tumor growth in MEK/MCF-7 as well as MCF-7 cell lines. Taken together, these data suggest that MAPK/ER cross-talk enhances ER-mediated signaling and accelerates E2-dependent tumor growth without diminishing sensitivity to the inhibitory effects of antiestrogens. ^
    01/2002;
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    ABSTRACT: We have shown that ER-negative and invasive human breast cancer cell lines MDA-MB-468 and MDA-MB-231 have constitutively higher mitogen activated protein kinase (ERK1&2/MAPK) when compared to the ER-positive and non-invasive MCF-7 human breast cancer cells. In MCF-7 cells, TGFalpha stimulation induced only transient MAPK activation, leading to a transient increase in cell migration. However, MDA 231 and MDA 468 cells, TGFalpha stimulation induced sustained MAPK activation, which correlated with enhanced cell motility and in vitro invasion. Serum stimulation activates ERK/MAPK activity persistently in both ER-positive and ER-negative breast cancer cells, leading to enhanced and sustained cell migration. Inhibition of MAPK activation by anti-sense MEK expression in MDA-MB-468 cells significantly inhibits cell migration and in vitro invasion. In contrast, MCF-7 cells expressing constitutively activated MEK show a significant increase in MAPK activity and cell migration, but this failed to enhance in vitro invasion. The kinetic profiles of MAPK activation and inhibition show a relationship between the duration and magnitude of MAPK activation and cell migration in both ER-positive and ER-negative human breast cancer cells. These studies show that cell motility is modulated by the magnitude and the duration of MAPK activation; but increased activation of MAPK may not be sufficient to allow in vitro invasion in non-invasive MCF-7 breast cancer cells.
    Oncogene 08/2001; 20(31):4209-18. · 7.36 Impact Factor

Publication Stats

342 Citations
34.29 Total Impact Points

Institutions

  • 2004
    • Mayo Clinic - Rochester
      Rochester, Minnesota, United States
  • 2002–2004
    • Wayne State University
      • Department of Pathology
      Detroit, MI, United States