Division of Breast Surgery, Department of Surgery, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung, 807, Taiwan, ROC.
Department of Surgery, Kaohsiung Municipal Ta-Tung Hospital, No. 68, Zhonghua 3rd Rd., Qianjin Dist., Kaohsiung, 801, Taiwan, ROC.
Breast Cancer Res Treat. 2020 Aug;183(1):61-70. doi: 10.1007/s10549-020-05729-9. Epub 2020 Jun 29.
Mitochondrial unfolding protein are abundant in breast cancer cells, but the mechanism by which breast cancer cells resist apoptosis is still not fully elucidated. In this study, we explored the role of mitochondrial unfolded protein response (mtUPR)-related proteins in four types of breast cancer tissues.
Mitochondrial fractions were taken from four breast cancer tissues (luminal A, luminal B, Her2 -overexpression, and TNBC) and the expression of mitochondrial polyubiquitinated proteins was observed by western blot and ELISA. In addition, the expression of hsp10, hsp60, and clpp in mitochondria was observed by western blot in breast cancer tissues and adjacent tissues, and confirmed by ELISA. The expression levels of hsp10 and hsp60 were correlated with clinicopathological parameters in 114 breast cancer patients.
We found an increase in the performance of mitochondrial polyubiquitinated proteins in breast cancer tissues of luminal A, luminal B, Her2-overexpression, and TNBC. The mitochondrial hsp10, hsp60, and clpp are abundantly expressed in breast cancer tissues rather than adjacent noncancerous tissues. The expression levels of mitochondrial hsp10 and hsp60 were highest in histological grade 3 breast cancer tissues. Additionally, mitochondria with high hsp60 expression were more present in Her2-positive tumors.
We observed that mtUPR was specifically activated in breast cancer tissues but inactivated in normal mammary tissue. MtUPR had also exhibited a particular increase in Her2-overexpression tumors but not in ER- or PR-positive tumors. Taken together, we suggested that mtUPR may act as a potential candidate for developing novel Her2-overexpression breast cancer therapy.
乳腺癌细胞中富含线粒体解折叠蛋白，但乳腺癌细胞抵抗细胞凋亡的机制仍未完全阐明。在本研究中，我们探讨了线粒体未折叠蛋白反应（mtUPR）相关蛋白在四种乳腺癌组织中的作用。
从四种乳腺癌组织（管腔 A、管腔 B、Her2 过表达和三阴性乳腺癌）中提取线粒体部分，通过 Western blot 和 ELISA 观察线粒体多泛素化蛋白的表达。此外，通过 Western blot 在乳腺癌组织和相邻组织中观察线粒体中 hsp10、hsp60 和 clpp 的表达，并通过 ELISA 进行验证。在 114 例乳腺癌患者中，hsp10 和 hsp60 的表达水平与临床病理参数相关。
我们发现管腔 A、管腔 B、Her2 过表达和三阴性乳腺癌组织中线粒体多泛素化蛋白的表达增加。乳腺癌组织中大量表达线粒体 hsp10、hsp60 和 clpp，而非相邻非癌组织。组织学分级 3 级的乳腺癌组织中线粒体 hsp10 和 hsp60 的表达水平最高。此外，hsp60 表达较高的线粒体在 Her2 阳性肿瘤中更为常见。
我们观察到 mtUPR 特异性激活于乳腺癌组织而失活于正常乳腺组织。mtUPR 在 Her2 过表达肿瘤中也表现出特殊的增加，而在 ER 或 PR 阳性肿瘤中则没有。综上所述，我们认为 mtUPR 可能成为开发新型 Her2 过表达乳腺癌治疗方法的潜在候选物。
