CRUK Beatson Institute, Glasgow, UK.
Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Cell Death Differ. 2021 Sep;28(9):2589-2600. doi: 10.1038/s41418-021-00773-4. Epub 2021 Mar 31.
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.
高水平的抗凋亡 BCL-2 家族成员 MCL-1 经常在乳腺癌中发现，因此，专门针对 MCL-1 在凋亡中功能的 BH3 模拟药物正在开发中作为抗癌治疗。MCL-1 也有报道称具有非典型作用，这可能与其在肿瘤促进作用中有关。在这里，我们研究了 MCL-1 在临床相关乳腺癌模型中的作用，并探讨了 MCL-1 在凋亡中的典型作用（可以使用 BH3 模拟药物靶向）是否是 MCL-1 在乳腺癌中的主要功能。我们表明，MCL-1 在具有遗传缺失的已建立肿瘤中是必不可少的，该缺失会导致肿瘤消退，并且 MCL-1 特异性 BH3 模拟药物 S63845 的抑制显着阻碍肿瘤生长。重要的是，我们发现 MCL-1 缺失或抑制所实现的抗肿瘤功能完全依赖于促凋亡 BAX/BAK。有趣的是，我们发现 MCL-1 对于人乳腺癌细胞中的干细胞活性也是至关重要的，并且高 MCL1 表达与肿瘤中的干细胞标志物相关。这强烈支持了 MCL-1 在乳腺癌中的关键功能是通过其抗凋亡功能的观点。这对未来使用 MCL-1 特异性 BH3 模拟药物治疗乳腺癌具有重要意义。
