Department of Radiation Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA.
Breast Cancer Res Treat. 2012 Jun;133(2):417-26. doi: 10.1007/s10549-011-1755-0. Epub 2011 Sep 7.
The purpose is to evaluate sensitivity of basal-like breast cancer to treatment with anti-DR5 alone and in combination with chemotherapy. Cytotoxicity of TRA-8 anti-DR5 alone and in combination with doxorubicin or paclitaxel was examined. The role of a DR5-associated molecule (DDX3) in the regulation of apoptosis by recruitment of cIAP1 to the DR5/DDX3 complex was studied. SUM159 and 2LMP orthotopic xenografts were treated with TRA-8 alone and in combination with Abraxane or doxorubicin, and tumor growth inhibition determined. Diffusion-weighted magnetic resonance imaging was used to monitor early tumor response. The majority (12/15) of basal-like cell lines were very sensitive to TRA-8-induced cytotoxicity (IC(50) values of 1.0-49 ng/ml). In contrast, 8/11 luminal or HER2-positive cell lines were resistant (IC(50) > 1,000 ng/ml). Enhanced killing of basal-like cell lines was produced by combination treatment with TRA-8 and doxorubicin. Majority of basal cell lines expressed lower levels of DR5-associated DDX3 and cIAP1 than luminal and HER2-positive cell lines. TRA-8 inhibited growth of basal xenografts and produced 20% complete 2LMP tumor regressions. TRA-8 and chemotherapy produced greater 2LMP growth inhibition than either alone. An increase in apparent diffusion coefficient in 2LMP tumors was measured in a week of therapy with TRA-8 and Abraxane. Basal-like cell lines were more sensitive to TRA-8-mediated cytotoxicity than HER2-over-expressing and luminal cell lines, and chemotherapy enhanced cytotoxicity. High sensitivity of basal cells to TRA-8 correlated with low expression of DR5/DDX3/cIAP1 complex. Treatment with TRA-8 and chemotherapy may be an effective therapy for basal-like breast cancer.
目的是评估基底样乳腺癌对单独使用抗 DR5 和与化疗联合治疗的敏感性。检测了 TRA-8 单独使用以及与阿霉素或紫杉醇联合使用的细胞毒性。研究了 DR5 相关分子（DDX3）在通过将 cIAP1 募集到 DR5/DDX3 复合物中来调节细胞凋亡中的作用。用 TRA-8 单独以及与 Abraxane 或阿霉素联合治疗 SUM159 和 2LMP 原位异种移植瘤，并确定肿瘤生长抑制率。扩散加权磁共振成像用于监测早期肿瘤反应。大多数（12/15）基底样细胞系对 TRA-8 诱导的细胞毒性非常敏感（IC50 值为 1.0-49ng/ml）。相比之下，8/11 个管腔或 HER2 阳性细胞系具有抗性（IC50＞1000ng/ml）。TRAE8 与阿霉素联合治疗可增强基底样细胞系的杀伤作用。大多数基底细胞系表达的 DR5 相关 DDX3 和 cIAP1 水平低于管腔和 HER2 阳性细胞系。TRAE8 抑制了基底异种移植瘤的生长，并产生了 20%的 2LMP 肿瘤完全消退。与单独使用相比，TRAE8 和化疗可产生更大的 2LMP 生长抑制作用。在 TRAE8 和 Abraxane 治疗一周后，在 2LMP 肿瘤中测量到表观扩散系数的增加。与 HER2 过表达和管腔细胞系相比，基底样细胞系对 TRAE8 介导的细胞毒性更敏感，并且化疗增强了细胞毒性。基底细胞对 TRAE8 的高敏感性与 DR5/DDX3/cIAP1 复合物的低表达相关。TRAE8 和化疗的联合治疗可能是基底样乳腺癌的有效治疗方法。
