Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function.
Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function.
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DOI：
10.1038/s41418-021-00773-4
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发表时间：
2021-09
影响因子：
12.4
通讯作者：
Tait SWG
中科院分区：
文献类型：
--
作者：
Campbell KJ;Mason SM;Winder ML;Willemsen RBE;Cloix C;Lawson H;Rooney N;Dhayade S;Sims AH;Blyth K;Tait SWG
在乳腺癌中经常发现高水平的抗凋亡的bcl2家族成员mcl1，相应地，针对mcl1的S功能的类似bh3的药物正在开发中作为抗癌治疗。MCL-1也报道了可能与其促进肿瘤作用相关的非典范作用。在这里，我们研究了MCL-1在临床相关乳腺癌模型中的作用，并讨论了MCL-1在细胞凋亡中的典型作用是否是MCL-1在乳腺癌中的主要功能，这种作用可以用BH3模拟药物来靶向。我们发现，MCL-1在基因缺失的已建立的肿瘤中是必不可少的，通过MCL-1特异的BH3模拟药物S63845显着阻碍肿瘤的生长，诱导肿瘤退化和抑制。重要的是，我们发现MCL-1的缺失或抑制所实现的抗肿瘤功能完全依赖于促凋亡的Bax/BAK。有趣的是，我们发现MCL-1对人类乳腺癌细胞中的干细胞活性也是至关重要的，并且MCL1的高表达与肿瘤中的干性标记相关。这有力地支持了MCL-1在乳腺癌中的关键作用是通过其抗凋亡功能的观点。这对未来MCL-1特异性BH3模拟药物在乳腺癌治疗中的应用具有重要意义。
High levels of the anti-apoptotic BCL-2 family member MCL-1 are frequently found in breast cancer and, appropriately, BH3-mimetic drugs that specifically target MCL-1’s function in apoptosis are in development as anti-cancer therapy. MCL-1 also has reported non-canonical roles that may be relevant in its tumour-promoting effect. Here we investigate the role of MCL-1 in clinically relevant breast cancer models and address whether the canonical role of MCL-1 in apoptosis, which can be targeted using BH3-mimetic drugs, is the major function for MCL-1 in breast cancer. We show that MCL-1 is essential in established tumours with genetic deletion inducing tumour regression and inhibition with the MCL-1-specific BH3-mimetic drug S63845 significantly impeding tumour growth. Importantly, we found that the anti-tumour functions achieved by MCL-1 deletion or inhibition were completely dependent on pro-apoptotic BAX/BAK. Interestingly, we find that MCL-1 is also critical for stem cell activity in human breast cancer cells and high MCL1 expression correlates with stemness markers in tumours. This strongly supports the idea that the key function of MCL-1 in breast cancer is through its anti-apoptotic function. This has important implications for the future use of MCL-1-specific BH3-mimetic drugs in breast cancer treatment.
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