Department of Surgical Oncology, Gifu University, Gifu University Graduate School of Medicine, Gifu, Japan.
Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Gifu, Japan.
J Mol Med (Berl). 2019 Feb;97(2):257-268. doi: 10.1007/s00109-018-01732-2. Epub 2019 Jan 3.
LRP1B intracellular domain is released and transported to the nucleus; however, pathological consequences of this nuclear transport are largely unclear. We aimed to unravel the pathobiological significance of nuclear localization of LRP1B intracellular domain in mammary gland carcinogenesis. Immunohistochemical staining using antibodies for LRP1B intracellular domain was performed to determine LRP1B expression in 92 invasive ductal breast carcinomas. LRP1B immunoreactivity was detected in the surface membrane and cytoplasm of 60 of 92 invasive ductal carcinomas and in the nucleus of 15 of 92 carcinomas. Nuclear LRP1B was significantly associated with poor patient prognosis, particularly luminal A type breast cancer, where it was significantly related to nodal metastasis. Doxycycline-dependent nuclear expression of LRP1B intracellular domain was established in cultured breast cancer cells. Enforced nuclear expression significantly increased Matrigel invasion activity in MCF-7 and T47D luminal A breast cancer cells. Moreover, enforced nuclear expression of LRP1B intracellular domain facilitated MCF-7 cells growth in mammary fat pad of nude mice, which was supplemented with estrogen. Comprehensive microarray-based analysis demonstrated that nuclear expression of LRP1B intracellular domain significantly increased long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) expression, which facilitates breast cancer invasion with poor prognosis. Nuclear-localized LRP1B intracellular domain promoted breast cancer progression with poor prognosis, possibly through the NEAT1 pathway. Nuclear transport of LRP1B intracellular domain could be a therapeutic target for breast cancer patients. KEY MESSAGES: Nuclear LRP1B was significantly associated with poor patient prognosis. Nuclear LRP1B increased Matrigel invasion activity of breast cancer cells. Nuclear expression of LRP1B intracellular domain increased NEAT1 expression.
LRP1B 细胞内结构域被释放并转运到细胞核内；然而，这种核转运的病理后果在很大程度上还不清楚。我们旨在揭示 LRP1B 细胞内结构域在乳腺肿瘤发生中的核定位的病理生物学意义。使用针对 LRP1B 细胞内结构域的抗体进行免疫组织化学染色，以确定 92 例浸润性导管乳腺癌中的 LRP1B 表达。在 92 例浸润性导管癌中，有 60 例检测到 LRP1B 免疫反应性位于细胞膜和细胞质中，有 15 例位于细胞核中。核 LRP1B 与患者预后不良显著相关，尤其是腔 A 型乳腺癌，其与淋巴结转移显著相关。在培养的乳腺癌细胞中建立了依赖于多西环素的 LRP1B 细胞内结构域的核表达。强制核表达显著增加了 MCF-7 和 T47D 腔 A 型乳腺癌细胞在 Matrigel 中的侵袭活性。此外，LRP1B 细胞内结构域的强制核表达促进了 MCF-7 细胞在裸鼠乳腺脂肪垫中的生长，而裸鼠乳腺脂肪垫中补充了雌激素。基于微阵列的综合分析表明，LRP1B 细胞内结构域的核表达显著增加了长链非编码 RNA 核斑状组装转录物 1（NEAT1）的表达，从而促进了具有不良预后的乳腺癌侵袭。核定位的 LRP1B 细胞内结构域促进了具有不良预后的乳腺癌进展，可能通过 NEAT1 途径。LRP1B 细胞内结构域的核转运可能成为乳腺癌患者的治疗靶点。关键信息：核 LRP1B 与患者预后不良显著相关。核 LRP1B 增加了乳腺癌细胞的 Matrigel 侵袭活性。LRP1B 细胞内结构域的核表达增加了 NEAT1 的表达。
