Targeting Androgen Receptor in Treating HER2 Positive Breast Cancer.
Targeting Androgen Receptor in Treating HER2 Positive Breast Cancer.
复制标题
靶向雄激素受体治疗 HER2 阳性乳腺癌
DOI：
10.1038/s41598-017-14607-2
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发表时间：
2017-11-06
影响因子：
4.6
通讯作者：
Gu H
中科院分区：
文献类型：
--
作者：
He L;Du Z;Xiong X;Ma H;Zhu Z;Gao H;Cao J;Li T;Li H;Yang K;Chen G;Richer JK;Gu H
雄激素受体（AR）在乳腺癌（BC）的不同亚型中广泛表达。然而，目前尚不清楚AR如何在HER2阳性（+）BC中发挥作用。使用shRNA和新一代抗雄激素药物Enzalutamide敲低AR，以探索AR对HER2 + BC细胞（HCC 1954和SKBR 3）生长的参与。AR shRNA或Enzalutamide抑制SKBR 3细胞生长的程度与曲妥珠单抗（一种获批的HER2靶向药物）相似。Enzalutamide与曲妥珠单抗联合用药与单独用药相比，可进一步抑制HCC 1954和SKBR 3细胞的体外生长。生化分析显示，抑制AR导致HER2磷酸化和Erk和Akt的活化降低，而不影响HER2和HER3的表达。使用HCC 1954异种移植模型进一步检测Enzalutamide的体内疗效。Enzalutamide抑制HCC 1954肿瘤生长的水平与曲妥珠单抗相当。在HCC 1954肿瘤中，与溶剂对照组相比，Enzalutamide可降低Ki 67染色，并增加活化的caspase 3染色。我们的研究结果表明，AR通过与HER2信号转导交叉作用在促进HER2 + BC的生长中起重要作用。AR药物可用作治疗HER2 + BC的替代二线疗法。
Androgen receptor (AR) is widely expressed in different subtypes of breast cancer (BC). However, it is unclear how AR functions in HER2 positive (+) BC. Knockdown of AR with shRNAs and a new generation anti-androgen drug, Enzalutamide, were used to explore the involvement of AR on the growth of HER2 + BC cells (HCC1954 and SKBR3). AR shRNA or Enzalutamide inhibited the growth of SKBR3 cells at a similar extend compared to trastuzumab, an approved HER2 targeted drug. Combining Enzalutamide with trastuzumab further decreased the growth of HCC1954 and SKBR3 cells compared with single agent alonein vitro. Biochemical analysis revealed that inhibiting AR resulted in decreased HER2 phosphorylation and activation of Erk and Akt, without affecting the HER2 and HER3 expression. Thein vivoefficacy of Enzalutamide was further tested using the HCC1954 xenograft model. Enzalutamide impaired the growth of HCC1954 tumor at a level comparable to that by trastuzumab. Enzalutamide decreased Ki67 staining and increased activated caspase3 staining compared with vehicle control in HCC1954 tumors. Our results indicate AR plays an important role in promoting the growth of HER2 + BC by cross-talking with the HER2 signaling. AR drug may be used as an alternative second line therapy for treating HER2 + BC.
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DOI：
10.1186/bcr327
发表时间：
2001
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Olayioye MA
通讯作者：
Olayioye MA
影响因子：
--
作者：
Jiang HS;Kuang XY;Sun WL;Xu Y;Zheng YZ;Liu YR;Lang GT;Qiao F;Hu X;Shao ZM
通讯作者：
Shao ZM
影响因子：
50.5
作者：
Park, S.;Koo, J. S.;Lee, K. S.
通讯作者：
Lee, K. S.
影响因子：
3.7
作者：
Qu Q;Mao Y;Fei XC;Shen KW
通讯作者：
Shen KW
影响因子：
8
作者：
Farmer, P;Bonnefoi, H;Iggo, R
通讯作者：
Iggo, R