Department of Neuro-Oncology and Neurosurgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Thorac Cancer. 2020 Sep;11(9):2493-2505. doi: 10.1111/1759-7714.13561. Epub 2020 Jul 20.
Brain metastasis is an unsolved clinical problem in breast cancer patients due to its poor prognosis and high fatality rate. Although accumulating evidence has shown that some pan-histone deacetylase (HDAC) inhibitors can relieve breast cancer brain metastasis, the specific HDAC protein involved in this process is unclear. Thus, identifying a specific HDAC protein closely correlated with breast cancer brain metastasis will not only improve our understanding of the functions of the HDAC family but will also help develop a novel target for precision cancer therapy.
Immunohistochemical staining of HDAC1, HDAC2, and HDAC3 in 161 samples from breast invasive ductal carcinoma patients, including 63 patients with brain metastasis, was performed using the standard streptavidin-peroxidase method. The relationships between HDAC1, HDAC2, and HDAC3 and overall survival/brain metastasis-free survival/post-brain metastatic survival were evaluated using Kaplan-Meier curves and Cox regression analyses.
HDAC1, HDAC2, and cytoplasmic HDAC3 all displayed typical oncogenic characteristics and were independent prognostic factors for the overall survival of breast cancer patients. Only cytoplasmic HDAC3 was an independent prognostic factor for brain metastasis-free survival. Cytoplasmic expression of HDAC3 was further upregulated in the brain metastases compared with the matched primary tumors, while nuclear expression was downregulated. The HDAC1, HDAC2, and HDAC3 expression levels in the brain metastases were not correlated with survival post-brain metastasis.
Our studies first demonstrate a critical role for HDAC3 in the brain metastasis of breast cancer patients and it may serve as a promising therapeutic target for the vigorously developing field of precision medicine.
Significant findings of the study Cytoplasmic HDAC3 is an independent prognostic factor for the overall survival and brain metastasis-free survival of breast cancer patients. What this study adds Cytoplasmic expression of HDAC3 was further upregulated in the brain metastases compared with the matched primary tumours, while nuclear expression was downregulated.
脑转移是乳腺癌患者尚未解决的临床问题，因为其预后较差且死亡率较高。尽管越来越多的证据表明，一些泛组蛋白去乙酰化酶（HDAC）抑制剂可以缓解乳腺癌脑转移，但涉及该过程的特定 HDAC 蛋白尚不清楚。因此，鉴定与乳腺癌脑转移密切相关的特定 HDAC 蛋白不仅可以提高我们对 HDAC 家族功能的理解，还有助于为精准癌症治疗开发新的靶标。
使用标准链霉亲和素-过氧化物酶法对 161 例乳腺癌浸润性导管癌患者（包括 63 例脑转移患者）的 HDAC1、HDAC2 和 HDAC3 进行免疫组织化学染色。使用 Kaplan-Meier 曲线和 Cox 回归分析评估 HDAC1、HDAC2 和 HDAC3 与总生存/无脑转移生存/脑转移后生存之间的关系。
HDAC1、HDAC2 和细胞质 HDAC3 均表现出典型的致癌特征，是乳腺癌患者总生存的独立预后因素。只有细胞质 HDAC3 是脑转移无复发生存的独立预后因素。与配对的原发性肿瘤相比，脑转移中细胞质 HDAC3 的表达进一步上调，而核表达下调。脑转移中 HDAC1、HDAC2 和 HDAC3 的表达水平与脑转移后生存无关。
我们的研究首次证明了 HDAC3 在乳腺癌患者脑转移中的关键作用，它可能成为精准医学这一快速发展领域的有前途的治疗靶标。
本研究的重要发现细胞质 HDAC3 是乳腺癌患者总生存和无脑转移生存的独立预后因素。本研究的新增内容与配对的原发性肿瘤相比，脑转移中细胞质 HDAC3 的表达进一步上调，而核表达下调。
