Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
Cancer Cell. 2011 Sep 13;20(3):341-56. doi: 10.1016/j.ccr.2011.07.017.
Breast cancer initiating cells (BCICs), which can fully recapitulate the tumor origin and are often resistant to chemo- and radiotherapy, are currently considered as a major obstacle for breast cancer treatment. Here, we show that BIKDD, a constitutively active mutant form of proapoptotic gene, BIK, effectively induces apoptosis of breast cancer cells and synergizes with lapatinib. Most importantly, BikDD significantly reduces BCICs through co-antagonism of its binding partners Bcl-2, Bcl-xL, and Mcl-1, suggesting a potential therapeutic strategy targeting BCICs. Furthermore, we developed a cancer-specific targeting approach for breast cancer that selectively expresses BikDD in breast cancer cells including BCICs, and demonstrated its potent antitumor activity and synergism with lapatinib in vitro and in vivo.
乳腺癌起始细胞（BCICs）能够完全重现肿瘤起源，并且经常对化疗和放疗产生抗性，目前被认为是乳腺癌治疗的主要障碍。在这里，我们表明，促凋亡基因 BIK 的组成性激活突变体 BIKDD 可有效诱导乳腺癌细胞凋亡，并与拉帕替尼协同作用。最重要的是，BikDD 通过与其结合伙伴 Bcl-2、Bcl-xL 和 Mcl-1 的共同拮抗作用，显著减少了 BCICs，这表明针对 BCICs 的潜在治疗策略。此外，我们开发了一种针对乳腺癌的癌症特异性靶向方法，该方法可选择性地在包括 BCICs 在内的乳腺癌细胞中表达 BikDD，并在体外和体内证明了其强大的抗肿瘤活性和与拉帕替尼的协同作用。
