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result sql = Treatment with tamoxifen, or its metabolite 4-hydroxytamoxifen (4OHT), has cytostatic and cytotoxic effects on breast cancer cells in vivo and in culture. Although the effectiveness of 4OHT as an anti-breast cancer agent is due to its action as an estrogen receptor-alpha (ERalpha) antagonist, evidences show that 4OHT is also cytotoxic for ERalpha-negative breast cancer cells and can be effective therapy against tumors that lack estrogen receptors. These findings underscore 4OHT signaling complexities and belie the most basic understandings of 4OHT action and resistance. Here, we have investigated the effects of 4OHT on Ca2+ homeostasis and cell death in breast cancer cells in culture. Measurement of Ca2+ signaling in breast cancer cells showed that 4OHT treatment altered Ca2+ homeostasis and was cytotoxic for both an ERalpha+ and an ERalpha- cell line, MCF-7 and MDA-MB-231, respectively. Further investigation lead us to the novel discovery that 4OHT-induced increase of ATP-dependent Ca2+ release from the endoplasmic reticulum correlated with 4OHT-induced upregulation of protein phosphatase 1alpha (PP1alpha) and the inositol 1,4,5-trisphosphate receptor (IP3R). Blocking 4OHT-induced PP1alpha upregulation by siRNA strategy reduced the effects of 4OHT on both Ca2+ signaling and cytotoxicity. Results from these investigations strongly suggest a role for PP1alpha upregulation in a mechanism for 4OHT-induced changes to Ca2+ signaling that ultimately contribute to the cytotoxic effects of 4OHT.
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result sql = Regulation of intracellular calcium release and PP1alpha in a mechanism for 4-hydroxytamoxifen-induced cytotoxicity.
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char = x;code = 120
char = y;code = 121
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char = f;code = 102
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char = O;code = 79
char = H;code = 72
char = T;code = 84
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = h;code = 104
char = a;code = 97
char = s;code = 115
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char = c;code = 99
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char = o;code = 111
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char = t;code = 116
char = a;code = 97
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char = i;code = 105
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char = a;code = 97
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char = d;code = 100
char = ;code = 32
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char = t;code = 116
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = c;code = 99
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char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = s;code = 115
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char = o;code = 111
char = n;code = 110
char = ;code = 32
char = b;code = 98
char = r;code = 114
char = e;code = 101
char = a;code = 97
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char = t;code = 116
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char = c;code = 99
char = a;code = 97
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char = c;code = 99
char = e;code = 101
char = r;code = 114
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char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = s;code = 115
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char = i;code = 105
char = n;code = 110
char = ;code = 32
char = v;code = 118
char = i;code = 105
char = v;code = 118
char = o;code = 111
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char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = c;code = 99
char = u;code = 117
char = l;code = 108
char = t;code = 116
char = u;code = 117
char = r;code = 114
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char = .;code = 46
char = ;code = 32
char = A;code = 65
char = l;code = 108
char = t;code = 116
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char = o;code = 111
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char = g;code = 103
char = h;code = 104
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char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
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char = i;code = 105
char = v;code = 118
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char = s;code = 115
char = s;code = 115
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = 4;code = 52
char = O;code = 79
char = H;code = 72
char = T;code = 84
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = i;code = 105
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char = e;code = 101
char = a;code = 97
char = s;code = 115
char = t;code = 116
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char = c;code = 99
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = r;code = 114
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char = a;code = 97
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = t;code = 116
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char = i;code = 105
char = s;code = 115
char = ;code = 32
char = d;code = 100
char = u;code = 117
char = e;code = 101
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char = t;code = 116
char = o;code = 111
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char = i;code = 105
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
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char = o;code = 111
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char = a;code = 97
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char = ;code = 32
char = a;code = 97
char = n;code = 110
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char = e;code = 101
char = s;code = 115
char = t;code = 116
char = r;code = 114
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char = e;code = 101
char = n;code = 110
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char = r;code = 114
char = e;code = 101
char = c;code = 99
char = e;code = 101
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = r;code = 114
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char = a;code = 97
char = l;code = 108
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = ;code = 32
char = (;code = 40
char = E;code = 69
char = R;code = 82
char = a;code = 97
char = l;code = 108
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = );code = 41
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = a;code = 97
char = g;code = 103
char = o;code = 111
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char = i;code = 105
char = s;code = 115
char = t;code = 116
char = ,;code = 44
char = ;code = 32
char = e;code = 101
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char = d;code = 100
char = e;code = 101
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char = e;code = 101
char = s;code = 115
char = ;code = 32
char = s;code = 115
char = h;code = 104
char = o;code = 111
char = w;code = 119
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char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
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char = 4;code = 52
char = O;code = 79
char = H;code = 72
char = T;code = 84
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = o;code = 111
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char = c;code = 99
char = y;code = 121
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
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char = E;code = 69
char = R;code = 82
char = a;code = 97
char = l;code = 108
char = p;code = 112
char = h;code = 104
char = a;code = 97
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char = g;code = 103
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
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char = b;code = 98
char = r;code = 114
char = e;code = 101
char = a;code = 97
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char = t;code = 116
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char = c;code = 99
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char = c;code = 99
char = e;code = 101
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char = c;code = 99
char = e;code = 101
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char = l;code = 108
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char = a;code = 97
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char = ;code = 32
char = c;code = 99
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char = b;code = 98
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char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
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char = v;code = 118
char = e;code = 101
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char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = p;code = 112
char = y;code = 121
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char = a;code = 97
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char = a;code = 97
char = i;code = 105
char = n;code = 110
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char = t;code = 116
char = u;code = 117
char = m;code = 109
char = o;code = 111
char = r;code = 114
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char = t;code = 116
char = h;code = 104
char = a;code = 97
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char = l;code = 108
char = a;code = 97
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char = k;code = 107
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char = c;code = 99
char = e;code = 101
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char = t;code = 116
char = o;code = 111
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char = s;code = 115
char = .;code = 46
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char = T;code = 84
char = h;code = 104
char = e;code = 101
char = s;code = 115
char = e;code = 101
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char = 4;code = 52
char = O;code = 79
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char = T;code = 84
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char = s;code = 115
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char = o;code = 111
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char = 4;code = 52
char = O;code = 79
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char = T;code = 84
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char = a;code = 97
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char = t;code = 116
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char = .;code = 46
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char = e;code = 101
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char = e;code = 101
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char = f;code = 102
char = e;code = 101
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char = 4;code = 52
char = O;code = 79
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char = T;code = 84
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char = o;code = 111
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char = C;code = 67
char = a;code = 97
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char = a;code = 97
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char = i;code = 105
char = s;code = 115
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char = e;code = 101
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char = M;code = 77
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char = n;code = 110
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char = E;code = 69
char = R;code = 82
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char = p;code = 112
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char = a;code = 97
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char = p;code = 112
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char = a;code = 97
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char = a;code = 97
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char = D;code = 68
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char = M;code = 77
char = B;code = 66
char = -;code = 45
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char = 1;code = 49
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char = s;code = 115
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char = v;code = 118
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char = u;code = 117
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char = t;code = 116
char = h;code = 104
char = a;code = 97
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char = 4;code = 52
char = O;code = 79
char = H;code = 72
char = T;code = 84
char = -;code = 45
char = i;code = 105
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char = u;code = 117
char = c;code = 99
char = e;code = 101
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result sql = Treatment with tamoxifen, or its metabolite 4-hydroxytamoxifen (4OHT), has cytostatic and cytotoxic effects on breast cancer cells in vivo and in culture. Although the effectiveness of 4OHT as an anti-breast cancer agent is due to its action as an estrogen receptor-alpha (ERalpha) antagonist, evidences show that 4OHT is also cytotoxic for ERalpha-negative breast cancer cells and can be effective therapy against tumors that lack estrogen receptors. These findings underscore 4OHT signaling complexities and belie the most basic understandings of 4OHT action and resistance. Here, we have investigated the effects of 4OHT on Ca2+ homeostasis and cell death in breast cancer cells in culture. Measurement of Ca2+ signaling in breast cancer cells showed that 4OHT treatment altered Ca2+ homeostasis and was cytotoxic for both an ERalpha+ and an ERalpha- cell line, MCF-7 and MDA-MB-231, respectively. Further investigation lead us to the novel discovery that 4OHT-induced increase of ATP-dependent Ca2+ release from the endoplasmic reticulum correlated with 4OHT-induced upregulation of protein phosphatase 1alpha (PP1alpha) and the inositol 1,4,5-trisphosphate receptor (IP3R). Blocking 4OHT-induced PP1alpha upregulation by siRNA strategy reduced the effects of 4OHT on both Ca2+ signaling and cytotoxicity. Results from these investigations strongly suggest a role for PP1alpha upregulation in a mechanism for 4OHT-induced changes to Ca2+ signaling that ultimately contribute to the cytotoxic effects of 4OHT.
Publication: Mol. Cell. Biochem. 2007 Nov ;305(1-2)::45-54.
Publication Date: 2007 Nov
Study Author(s): Bollig, Aliccia;Xu, Liping;Thakur, Archana;Wu, Jiusheng;Kuo, Tuan H;Liao, Joshua D;
Institution: Karmanos Cancer Institute, Wayne State University, 110 E Warren, HWCRC room 731, Detroit, MI 48201, USA.
Shortcut link to this study:
Publication Date: 2007 Nov
Study Author(s): Bollig, Aliccia;Xu, Liping;Thakur, Archana;Wu, Jiusheng;Kuo, Tuan H;Liao, Joshua D;
Institution: Karmanos Cancer Institute, Wayne State University, 110 E Warren, HWCRC room 731, Detroit, MI 48201, USA.
Shortcut link to this study:
Treatment with tamoxifen, or its metabolite 4-hydroxytamoxifen (4OHT), has cytostatic and cytotoxic effects on breast cancer cells in vivo and in culture. Although the effectiveness of 4OHT as an anti-breast cancer agent is due to its action as an estrogen receptor-alpha (ERalpha) antagonist, evidences show that 4OHT is also cytotoxic for ERalpha-negative breast cancer cells and can be effective therapy against tumors that lack estrogen receptors. These findings underscore 4OHT signaling complexities and belie the most basic understandings of 4OHT action and resistance. Here, we have investigated the effects of 4OHT on Ca2+ homeostasis and cell death in breast cancer cells in culture. Measurement of Ca2+ signaling in breast cancer cells showed that 4OHT treatment altered Ca2+ homeostasis and was cytotoxic for both an ERalpha+ and an ERalpha- cell line, MCF-7 and MDA-MB-231, respectively. Further investigation lead us to the novel discovery that 4OHT-induced increase of ATP-dependent Ca2+ release from the endoplasmic reticulum correlated with 4OHT-induced upregulation of protein phosphatase 1alpha (PP1alpha) and the inositol 1,4,5-trisphosphate receptor (IP3R). Blocking 4OHT-induced PP1alpha upregulation by siRNA strategy reduced the effects of 4OHT on both Ca2+ signaling and cytotoxicity. Results from these investigations strongly suggest a role for PP1alpha upregulation in a mechanism for 4OHT-induced changes to Ca2+ signaling that ultimately contribute to the cytotoxic effects of 4OHT.
PMID: 17646931
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