|
|
char = S;code = 83
char = u;code = 117
char = p;code = 112
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = i;code = 105
char = o;code = 111
char = n;code = 110
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char = o;code = 111
char = f;code = 102
char = ;code = 32
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char = n;code = 110
char = c;code = 99
char = e;code = 101
char = r;code = 114
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char = y;code = 121
char = ;code = 32
char = c;code = 99
char = h;code = 104
char = e;code = 101
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char = i;code = 105
char = c;code = 99
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char = l;code = 108
char = ;code = 32
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char = d;code = 100
char = u;code = 117
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char = a;code = 97
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char = i;code = 105
char = o;code = 111
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = v;code = 118
char = u;code = 117
char = l;code = 108
char = n;code = 110
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char = r;code = 114
char = a;code = 97
char = b;code = 98
char = l;code = 108
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char = z;code = 122
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char = c;code = 99
char = e;code = 101
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = .;code = 46
result sql = Suppression of breast cancer by chemical modulation of vulnerable zinc fingers in estrogen receptor.
Suppression of breast cancer by chemical modulation of vulnerable zinc fingers in estrogen receptor.char = C;code = 67
char = u;code = 117
char = r;code = 114
char = r;code = 114
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = i;code = 105
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = ;code = 32
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
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = b;code = 98
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = t;code = 116
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = m;code = 109
char = i;code = 105
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = m;code = 109
char = i;code = 105
char = x;code = 120
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char = d;code = 100
char = ;code = 32
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = g;code = 103
char = e;code = 101
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char = i;code = 105
char = c;code = 99
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char = a;code = 97
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char = d;code = 100
char = ;code = 32
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char = s;code = 115
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = g;code = 103
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char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = i;code = 105
char = t;code = 116
char = y;code = 121
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = s;code = 115
char = e;code = 101
char = l;code = 108
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = ;code = 32
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
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = H;code = 72
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = ;code = 32
char = s;code = 115
char = h;code = 104
char = o;code = 111
char = w;code = 119
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = f;code = 102
char = u;code = 117
char = n;code = 110
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = z;code = 122
char = i;code = 105
char = n;code = 110
char = c;code = 99
char = ;code = 32
char = f;code = 102
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = e;code = 101
char = r;code = 114
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = ;code = 32
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
char = ;code = 32
char = D;code = 68
char = N;code = 78
char = A;code = 65
char = -;code = 45
char = b;code = 98
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = m;code = 109
char = a;code = 97
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = (;code = 40
char = D;code = 68
char = B;code = 66
char = D;code = 68
char = );code = 41
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = s;code = 115
char = c;code = 99
char = e;code = 101
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = b;code = 98
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = c;code = 99
char = h;code = 104
char = e;code = 101
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = h;code = 104
char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = l;code = 108
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = p;code = 112
char = h;code = 104
char = i;code = 105
char = l;code = 108
char = i;code = 105
char = c;code = 99
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char = d;code = 100
char = i;code = 105
char = s;code = 115
char = u;code = 117
char = l;code = 108
char = f;code = 102
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = n;code = 110
char = z;code = 122
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = n;code = 110
char = z;code = 122
char = i;code = 105
char = s;code = 115
char = o;code = 111
char = t;code = 116
char = h;code = 104
char = i;code = 105
char = a;code = 97
char = z;code = 122
char = o;code = 111
char = l;code = 108
char = o;code = 111
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = r;code = 114
char = i;code = 105
char = v;code = 118
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = w;code = 119
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char = i;code = 105
char = c;code = 99
char = h;code = 104
char = ;code = 32
char = s;code = 115
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char = l;code = 108
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = b;code = 98
char = l;code = 108
char = o;code = 111
char = c;code = 99
char = k;code = 107
char = ;code = 32
char = b;code = 98
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = ;code = 32
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
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = i;code = 105
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = p;code = 112
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = l;code = 108
char = e;code = 101
char = m;code = 109
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char = n;code = 110
char = t;code = 116
char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = b;code = 98
char = s;code = 115
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = e;code = 101
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char = t;code = 116
char = ;code = 32
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = n;code = 110
char = s;code = 115
char = c;code = 99
char = r;code = 114
char = i;code = 105
char = p;code = 112
char = t;code = 116
char = i;code = 105
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char = .;code = 46
char = ;code = 32
char = T;code = 84
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char = e;code = 101
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char = a;code = 97
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char = s;code = 115
char = o;code = 111
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char = s;code = 115
char = i;code = 105
char = g;code = 103
char = n;code = 110
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char = f;code = 102
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = l;code = 108
char = y;code = 121
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char = i;code = 105
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char = m;code = 109
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char = s;code = 115
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char = i;code = 105
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char = n;code = 110
char = u;code = 117
char = d;code = 100
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char = m;code = 109
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char = M;code = 77
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char = s;code = 115
char = i;code = 105
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char = .;code = 46
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char = F;code = 70
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char = c;code = 99
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char = r;code = 114
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char = f;code = 102
char = e;code = 101
char = r;code = 114
char = e;code = 101
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char = a;code = 97
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char = l;code = 108
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char = i;code = 105
char = s;code = 115
char = r;code = 114
char = u;code = 117
char = p;code = 112
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char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = v;code = 118
char = u;code = 117
char = l;code = 108
char = n;code = 110
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = b;code = 98
char = l;code = 108
char = e;code = 101
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char = C;code = 67
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char = e;code = 101
char = r;code = 114
char = m;code = 109
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char = n;code = 110
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = z;code = 122
char = i;code = 105
char = n;code = 110
char = c;code = 99
char = ;code = 32
char = f;code = 102
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = e;code = 101
char = r;code = 114
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char = ;code = 32
char = t;code = 116
char = h;code = 104
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = p;code = 112
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = ;code = 32
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 = m;code = 109
char = e;code = 101
char = d;code = 100
char = i;code = 105
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = t;code = 116
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = r;code = 114
char = c;code = 99
char = i;code = 105
char = n;code = 110
char = o;code = 111
char = m;code = 109
char = a;code = 97
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = g;code = 103
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = i;code = 105
char = o;code = 111
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char = ;code = 32
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char = r;code = 114
char = ;code = 32
char = r;code = 114
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char = s;code = 115
char = u;code = 117
char = l;code = 108
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = v;code = 118
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = c;code = 99
char = i;code = 105
char = p;code = 112
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = a;code = 97
char = ;code = 32
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char = e;code = 101
char = w;code = 119
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
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char = g;code = 103
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = h;code = 104
char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = ;code = 32
char = b;code = 98
char = r;code = 114
char = e;code = 101
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char = s;code = 115
char = t;code = 116
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char = v;code = 118
char = e;code = 101
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char = o;code = 111
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char = ;code = 32
char = D;code = 68
char = N;code = 78
char = A;code = 65
char = ;code = 32
char = b;code = 98
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char = n;code = 110
char = d;code = 100
char = i;code = 105
char = n;code = 110
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char = ;code = 32
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
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char = l;code = 108
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char = s;code = 115
char = s;code = 115
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char = n;code = 110
char = t;code = 116
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char = g;code = 103
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = s;code = 115
char = m;code = 109
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = b;code = 98
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = .;code = 46
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
result sql = Current antiestrogen therapy for breast cancer is limited by the mixed estrogenic and antiestrogenic activity of selective estrogen receptor modulators. Here we show that the function of zinc fingers in the estrogen receptor DNA-binding domain (DBD) is susceptible to chemical inhibition by electrophilic disulfide benzamide and benzisothiazolone derivatives, which selectively block binding of the estrogen receptor to its responsive element and subsequent transcription. These compounds also significantly inhibit estrogen-stimulated cell proliferation, markedly reduce tumor mass in nude mice bearing human MCF-7 breast cancer xenografts, and interfere with cell-cycle and apoptosis regulatory gene expression. Functional assays and computational analysis support a molecular mechanism whereby electrophilic agents preferentially disrupt the vulnerable C-terminal zinc finger, thus suppressing estrogen receptor-mediated breast carcinoma progression. Our results provide the proof of principle for a new strategy to inhibit breast cancer at the level of DNA binding, rather than the classical antagonism of estrogen binding.
char = u;code = 117
char = p;code = 112
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = b;code = 98
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = t;code = 116
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = c;code = 99
char = h;code = 104
char = e;code = 101
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = v;code = 118
char = u;code = 117
char = l;code = 108
char = n;code = 110
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = b;code = 98
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = z;code = 122
char = i;code = 105
char = n;code = 110
char = c;code = 99
char = ;code = 32
char = f;code = 102
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = e;code = 101
char = r;code = 114
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = ;code = 32
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
char = .;code = 46
result sql = Suppression of breast cancer by chemical modulation of vulnerable zinc fingers in estrogen receptor.
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char = r;code = 114
char = r;code = 114
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = i;code = 105
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = a;code = 97
char = p;code = 112
char = y;code = 121
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = b;code = 98
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char = e;code = 101
char = a;code = 97
char = s;code = 115
char = t;code = 116
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = l;code = 108
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char = d;code = 100
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
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char = m;code = 109
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char = x;code = 120
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char = d;code = 100
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char = e;code = 101
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char = o;code = 111
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char = e;code = 101
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char = e;code = 101
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char = n;code = 110
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char = f;code = 102
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = e;code = 101
char = r;code = 114
char = s;code = 115
char = ;code = 32
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char = n;code = 110
char = ;code = 32
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char = h;code = 104
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = s;code = 115
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char = c;code = 99
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char = t;code = 116
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char = D;code = 68
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char = (;code = 40
char = D;code = 68
char = B;code = 66
char = D;code = 68
char = );code = 41
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = s;code = 115
char = c;code = 99
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char = p;code = 112
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char = i;code = 105
char = b;code = 98
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char = e;code = 101
char = ;code = 32
char = t;code = 116
char = o;code = 111
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char = c;code = 99
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char = c;code = 99
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char = l;code = 108
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char = i;code = 105
char = n;code = 110
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char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
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char = o;code = 111
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char = ;code = 32
char = b;code = 98
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char = ;code = 32
char = e;code = 101
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char = e;code = 101
char = c;code = 99
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char = i;code = 105
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char = e;code = 101
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char = z;code = 122
char = a;code = 97
char = m;code = 109
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char = d;code = 100
char = e;code = 101
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char = ;code = 32
char = b;code = 98
char = e;code = 101
char = n;code = 110
char = z;code = 122
char = i;code = 105
char = s;code = 115
char = o;code = 111
char = t;code = 116
char = h;code = 104
char = i;code = 105
char = a;code = 97
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char = o;code = 111
char = l;code = 108
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result sql = Current antiestrogen therapy for breast cancer is limited by the mixed estrogenic and antiestrogenic activity of selective estrogen receptor modulators. Here we show that the function of zinc fingers in the estrogen receptor DNA-binding domain (DBD) is susceptible to chemical inhibition by electrophilic disulfide benzamide and benzisothiazolone derivatives, which selectively block binding of the estrogen receptor to its responsive element and subsequent transcription. These compounds also significantly inhibit estrogen-stimulated cell proliferation, markedly reduce tumor mass in nude mice bearing human MCF-7 breast cancer xenografts, and interfere with cell-cycle and apoptosis regulatory gene expression. Functional assays and computational analysis support a molecular mechanism whereby electrophilic agents preferentially disrupt the vulnerable C-terminal zinc finger, thus suppressing estrogen receptor-mediated breast carcinoma progression. Our results provide the proof of principle for a new strategy to inhibit breast cancer at the level of DNA binding, rather than the classical antagonism of estrogen binding.
Publication: Nat. Med. 2004 Jan ;10(1)::40-7.
Publication Date: 2004 Jan
Study Author(s): Wang, Li Hua;Yang, Xiao Yi;Zhang, Xiaohu;Mihalic, Kelly;Fan, Ying-Xin;Xiao, Weihua;Howard, O M Zack;Appella, Ettore;Maynard, Andrew T;Farrar, William L;
Institution: Basic Research Program, SAIC-Frederick, National Cancer Institute-Frederick, National Institutes of Health, PO Box B, Frederick, Maryland 21702, USA. [email protected]
Shortcut link to this study:
Publication Date: 2004 Jan
Study Author(s): Wang, Li Hua;Yang, Xiao Yi;Zhang, Xiaohu;Mihalic, Kelly;Fan, Ying-Xin;Xiao, Weihua;Howard, O M Zack;Appella, Ettore;Maynard, Andrew T;Farrar, William L;
Institution: Basic Research Program, SAIC-Frederick, National Cancer Institute-Frederick, National Institutes of Health, PO Box B, Frederick, Maryland 21702, USA. [email protected]
Shortcut link to this study:
Current antiestrogen therapy for breast cancer is limited by the mixed estrogenic and antiestrogenic activity of selective estrogen receptor modulators. Here we show that the function of zinc fingers in the estrogen receptor DNA-binding domain (DBD) is susceptible to chemical inhibition by electrophilic disulfide benzamide and benzisothiazolone derivatives, which selectively block binding of the estrogen receptor to its responsive element and subsequent transcription. These compounds also significantly inhibit estrogen-stimulated cell proliferation, markedly reduce tumor mass in nude mice bearing human MCF-7 breast cancer xenografts, and interfere with cell-cycle and apoptosis regulatory gene expression. Functional assays and computational analysis support a molecular mechanism whereby electrophilic agents preferentially disrupt the vulnerable C-terminal zinc finger, thus suppressing estrogen receptor-mediated breast carcinoma progression. Our results provide the proof of principle for a new strategy to inhibit breast cancer at the level of DNA binding, rather than the classical antagonism of estrogen binding.
PMID: 14702633
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