CN102346193A - Akr1b10基因蛋白作为乳腺癌诊断标志物和药物靶标 - Google Patents

Akr1b10基因蛋白作为乳腺癌诊断标志物和药物靶标 Download PDF

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CN102346193A
CN102346193A CN2011102070768A CN201110207076A CN102346193A CN 102346193 A CN102346193 A CN 102346193A CN 2011102070768 A CN2011102070768 A CN 2011102070768A CN 201110207076 A CN201110207076 A CN 201110207076A CN 102346193 A CN102346193 A CN 102346193A
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akr1b10
breast cancer
gene protein
her2
expression
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张西臣
李泽中
李建华
何鑫
张伟红
邢沈阳
倪劲松
宫鹏涛
张楠
李�赫
张国才
杨举
李淑红
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Jilin University
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Jilin University
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Abstract

本发明提供一种AKR1B10基因蛋白作为乳腺癌诊断标志物和药物靶标的用途，公开了AKR1B10基因蛋白在乳腺导管原位癌的表达与HER2表达成正相关，与ER表达成负相关，AKR1B10基因蛋白可作为HER2高表达乳腺癌的标志物和药物靶标，用于乳腺癌的病理诊断和治疗靶标。

Description

AKR1B10基因蛋白作为乳腺癌诊断标志物和药物靶标
技术领域
本发明涉及新的乳腺导管原位癌的病理诊断标志物和药物靶标，尤其是提供了AKR1B10基因蛋白作为乳腺癌诊断标志物的用途，可在临床上用于乳腺导管原位癌的病理诊断和评估预后，也可作为乳腺癌治疗的潜在的靶标，属于医学生物技术领域。
背景技术
乳腺癌是威胁女性生命的恶性肿瘤之一，在乳腺原位癌阶段手术切除后的复发率明显低于乳腺癌发展到浸润癌的阶段，所以在原位癌时期诊断并治疗将大大减少患者的病死率。多数浸润癌由导管原位癌发展而来，研究导管原位癌向浸润癌转化过程的标志物，有效评估导管原位癌向浸润癌转化的风险对提高乳腺癌的治愈率至关重要。
HER2阳性乳腺癌患者通常治疗方法为手术后根据病理检查结果，选择使用HER2靶向治疗药物赫塞丁和化学疗法，前者在早期和和晚期（转移性乳腺癌）的治疗中显示了良好的效果，但价格昂贵。化学疗法在治疗HER2阳性乳腺癌中仍广泛应用，如使用紫杉醇或蒽环类药物，但面临产生耐药性和化疗失败的风险。
ER、PR和HER2等病理诊断标志物，用于乳腺癌的病理学分类和指导临床治疗，另外Ki-67、p53、p63、E-钙粘蛋白等也用作乳腺癌诊断标志物，但这些独立诊断标志物并不能直接指导治疗或指示化疗药物敏感性。HER2基因扩增或高表达乳腺癌总体预后差、生存率低，这类乳腺癌通常使用HER2靶向药物和化学疗法，而寻找与HER2表达相关并能指示化疗效果的标志物则尤为重要。
本发明涉及的AKR1B10基因蛋白 （aldo-keto reductase family 1 B10，醛糖还原酶家族1成员B10）以NADPH为辅酶，将醛类还原为醇，在体内特异性作用底物有视黄醛，通过调节视黄酸的代谢发挥调控作用。本发明的任务就是提供该基因蛋白在作为乳腺癌诊断标志物和药物靶标中的用途。在此处键入技术领域描述段落。
发明内容
 本发明提供了一种AKR1B10基因蛋白在诊断乳腺癌标志物中的用途，作为初期诊断的指标，评估导管原位癌向浸润癌转化风险及预后生存率，特别作为HER2阳性乳腺癌的诊断标志物。
本发明进一步提供了AKR1B10基因蛋白在治疗乳腺癌中作为靶向药物的用途。
本发明涉及的“AKR1B10基因蛋白”是已知的醛糖还原酶家族1成员B10，其蛋白产物AKR1B10以NADPH为辅酶，将醛类还原为醇。
以下实验表明AKR1B10基因蛋白在作为乳腺导管原位癌病理诊断标志物和在治疗乳腺导管原位癌靶标药物中的用途：
实验例1
选取长春某医院人乳腺原位癌病例28例，对同一病人的病理切片分别进行AKR1B10蛋白、ER、HER2免疫组化染色，选取其中较典型病例，如图1所示，发现AKR1B10基因蛋白表达与癌基因ER、HER2可能有相关性。使用Tuscen TSView照相系统采集照片，采用Motic  Images Advanced3.2图像分析软件，测得导管内癌部位灰度值，每张切片的5个点取平均值，灰度值越大阳性表达越少，灰度值越小阳性表达越多，灰度值数据如表1。测得的数值进行Spearman相关性分析比较三者关系，结果见表2，AKR1B10蛋白表达与ER的相关系数为-0.584，AKR1B10蛋白表达与HER2的相关系数为0.699，AKR1B10与ER负相关，与HER2正相关。作为对照，ER与HER2相关系数为-0.732,与文献报道吻合，证实我们所用方法的可靠性。
综上所述：AKR1B10基因蛋白（aldo-keto reductase family 1 B10，醛糖还原酶家族1成员B10）在大约67%（22/33）乳腺原位癌中高水平表达，与HER2表达成正相关，相关系数为0.699。本发明作为一种人乳腺原位癌的新的肿瘤标志物，用于今后的人乳腺导管原位癌早期诊断、药物靶标和评估预后。
表1：28例人乳腺原位癌免疫组化后AKR1B10、ER和HER2蛋白表达灰度值
病人编号 AKR1B10 ER HER2
1 187 208 166
2 101 211 162
3 172 193 167
4 140 192 122
5 142 215 73
6 169 209 124
7 175 112 211
8 136 212 125
9 171 104 217
10 138 193 101
11 105 196 103
12 188 110 213
13 188 94 220
14 173 116 212
15 172 214 73
16 191 91 215
17 182 111 210
18 206 92 215
19 103 207 108
20 100 210 124
21 201 90 216
22 169 91 218
23 102 213 71
24 108 212 75
25 103 205 122
26 174 91 214
27 184 89 216
28 186 85 212
注：AKR1B10为醛糖还原酶家族1成员B10，ER为雌激素受体，HER2为表皮生长因子受体家族成员2。
表2：免疫组化后导管内癌AKR1B10、ER和HER2蛋白表达灰度值统计分析
组别 AKR1B10 ER HER2
AKR1B10 1  -0.584**  0.699**
ER  -0.584** 1  -0.732**
HER2  0.699**  -0.732** 1
采用SPSS16.0 Spearman相关分析，**P<0.01
实验例2
免疫组化方法检测AKR1B10在乳腺导管原位癌的表达
对选取的长春某医院人乳腺导管原位癌病例28例的蜡块进行连续切片，每个病例切三张，分别使用AKR1B10蛋白、ER和HER2抗体做免疫组化染色。我们的免疫组化方法为：切片脱蜡，滴加3%双氧水，湿盒中孵育10分钟；PBS 洗涤 3次，每次2分钟；高压锅热修复（pH6.0枸橼酸抗原修复液）；PBS 洗涤 3次，每次2分钟；滴加封闭血清，湿盒中37℃孵育10分钟；甩掉封闭血清，擦净组织片周围的液体，勿洗。将兔源和鼠源的两种一抗体各50 ul混合均匀，滴加到组织上，放入湿盒，4 ℃ 孵育过夜；取出4℃孵育过夜的切片，用含0.05% Tween20 的PBS 洗涤3次，每次2分钟；将辣根过氧化物酶标记的羊抗小鼠IgG聚合物和碱性磷酸酶标记的羊抗兔IgG聚合物各70 ul混合均匀，滴加到组织上，放入湿盒，37℃孵育30分钟；取出切片，用含0.05% Tween20 的PBS 洗涤3次，每次2分钟；滴加DAB 5秒至 1分钟（镜下观察显色情况，显色达到要求即用蒸馏水终止反应）；苏木素复染 20秒，氨水发蓝，树胶封片。镜下观察AKR1B10、ER、HER2染色情况。免疫组化结果如图2所示，A为导管原位癌及早期浸润癌AKR1B10蛋白表达阳性，B为正常乳腺上皮AKR1B10蛋白表达为阴性，C和D为100倍镜下结果，AKR1B10蛋白定位于细胞质。
结论：上述实验显示AKR1B10基因表达与HER2有正相关，AKR1B10基因在HER2阳性乳腺癌的化疗失败和癌细胞转移过程中促进癌细胞生存。AKR1B10基因属醛糖还原酶家族，研究表明其抑制剂托瑞司他可特异性地抑制AKR1B10的酶活性，因此醛糖还原酶抑制剂如托瑞司他可应用于HER2阳性乳腺癌临床治疗。
本发明的积极效果在于：提供了AKR1B10基因蛋白在乳腺导管原位癌的表达与HER2表达成正相关，与ER表达成负相关，AKR1B10基因蛋白可作为HER2高表达乳腺癌的标志物和药物靶标，用于病理诊断和治疗靶标。
附图说明
图1为乳腺导管原位癌AKR1B10基因蛋白、ER和HER2在同一标本的免疫组化结果；
图中，A~C、D~F、G~I和J~L分别为4份标本中AKR1B10基因蛋白、ER和HER2的免疫组化结果，其中A~C、D~F为AKR1B10阳性，G~I、J~L为AKR1B10阴性。
图2为AKR1B10基因蛋白表达用于乳腺导管原位癌病理诊断；
图中，A为有微浸灶的导管原位癌中AKR1B10基因蛋白表达于原位癌，B为正常导管中无AKR1B10基因蛋白表达，C~D为100倍镜照片，可见AKR1B10基因蛋白分布于胞质。
具体实施方式
鉴于AKR1B10基因蛋白具有在乳腺导管原位癌的表达与HER2表达成正相关，与ER表达成负相关的特性，应用该基因蛋白通过常规的技术手段可制成乳腺癌诊断制剂；也可在临床上用于乳腺导管原位癌的病理诊断和评估预后，也可作为乳腺癌治疗的潜在的靶标，具体药物制备参见醛糖还原酶抑制剂如托瑞司他的相关剂型制备方法。

Claims (2)

1. AKR1B10基因蛋白在制备乳腺癌诊断标志物中的用途。
2. AKR1B10基因蛋白在制备治疗乳腺癌靶标药物的用途。
CN2011102070768A 2011-07-23 2011-07-23 Akr1b10基因蛋白作为乳腺癌诊断标志物和药物靶标 Pending CN102346193A (zh)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015057175A1 (en) 2013-10-15 2015-04-23 Ústav Experimentálnej Farmakológie A Toxikológie Sav Use of 5-carboxymethyl-3-mercapto-1,2,4-triazino-[5,6-b]indoles and their pharmaceutical composition
CN105177171A (zh) * 2015-10-30 2015-12-23 北京泱深生物信息技术有限公司 Akr1b10在制备急性心肌梗死诊疗制剂中的应用
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