Wakahara Makoto, Sakabe Tomohiko, Kubouchi Yasuaki, Hosoya Keiko, Hirooka Yumi, Yurugi Yohei, Nosaka Kanae, Shiomi Tatsushi, Nakamura Hiroshige, Umekita Yoshihisa
Division of Organ Pathology, Department of Pathology, Faculty of Medicine, Tottori University, Tottori, Japan.
Division of General Thoracic Surgery, Department of Surgery, Faculty of Medicine, Tottori University, Tottori, Japan.
Anticancer Res. 2017 Sep;37(9):5071-5077. doi: 10.21873/anticanres.11924.
BACKGROUND/AIM: Maspin is known to be a tumor suppressor protein. Its nuclear localization and endogenous inhibition of histone deacetylase 1 (HDAC1) are considered crucial for its tumor suppressor activity. However, it remains unclear whether subcellular localization of maspin correlates with HDAC1 expression level in human breast cancer.
Immunohistochemical analyses were performed on 164 resected specimens of invasive breast carcinoma using antibodies for maspin and HDAC1. Subcellular localization of maspin protein and HDAC1 mRNA expression level in two human breast cancer cell lines (MCF7, MDA-MB-231) and mammary epithelial cell line (MCF10) were analyzed by immunofluorescence and quantitative polymerase chain reaction, respectively.
The frequency of cytoplasmic-only, pancellular (combined nuclear and cytoplasm) and no staining of maspin were 31%, 14.0% and 55%, respectively. The cytoplasmic-only subgroup showed significantly higher histological grade (p=0.004), negative progesterone receptor status (p=0.003) and shorter disease-free survival compared to the pancellular subgroup (p=0.043). High HDAC1 expression was observed in 60% of cases and was significantly correlated with cytoplasmic-only staining compared to pancellular (p<0.001) or no staining (p=0.004). Immunofluorescence analysis revealed that maspin protein was localized mainly in the cytoplasm in MCF7 and MDA-MB-231 cells, while in both the nucleus and cytoplasm in MCF10A cells. HDAC1 mRNA levels were significantly up-regulated in MCF7 and MDA-MB-231 cells compared to MCF10A cells (p<0.001).
High HDAC1 expression may contribute to the aggressiveness of human breast cancer with cytoplasmic-only expression of maspin.
背景/目的：已知乳腺丝抑蛋白是一种肿瘤抑制蛋白。其核定位以及对组蛋白脱乙酰基酶1（HDAC1）的内源性抑制作用被认为对其肿瘤抑制活性至关重要。然而，在人类乳腺癌中，乳腺丝抑蛋白的亚细胞定位是否与HDAC1表达水平相关仍不清楚。
使用针对乳腺丝抑蛋白和HDAC1的抗体，对164例浸润性乳腺癌切除标本进行免疫组织化学分析。分别通过免疫荧光和定量聚合酶链反应分析了两种人类乳腺癌细胞系（MCF7、MDA-MB-231）和乳腺上皮细胞系（MCF10）中乳腺丝抑蛋白的亚细胞定位和HDAC1 mRNA表达水平。
仅细胞质、全细胞（细胞核和细胞质均有）以及无乳腺丝抑蛋白染色的频率分别为31%、14.0%和55%。与全细胞亚组相比，仅细胞质亚组的组织学分级显著更高（p = 0.004）、孕激素受体状态为阴性（p = 0.003）且无病生存期更短（p = 0.043）。60%的病例观察到HDAC1高表达，与全细胞染色（p < 0.001）或无染色（p = 0.004）相比，HDAC1高表达与仅细胞质染色显著相关。免疫荧光分析显示，在MCF7和MDA-MB-231细胞中，乳腺丝抑蛋白主要定位于细胞质，而在MCF10A细胞中则定位于细胞核和细胞质。与MCF10A细胞相比，MCF7和MDA-MB-231细胞中HDAC1 mRNA水平显著上调（p < 0.001）。
HDAC1高表达可能导致仅细胞质表达乳腺丝抑蛋白的人类乳腺癌具有侵袭性。
