Department of Oncology and Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, China.
Department of Foreign Language, Dalian Medical University, Dalian, China.
Cancer Biomark. 2019;25(1):19-27. doi: 10.3233/CBM-182094.
Triple-negative breast cancer (TNBC) is associated with an aggressive phenotype and poor prognosis, and the lack of druggable markers leads to the unavailability of targeted therapies. Thus, there is an urgent need to identify potential targets for triple-negative breast cancer.
In this study, we aimed to explore the expression of LAPTM4B and p27kip1 in triple-negative breast cancer, and its clinical significance.
We analyzed the expression and association of LAPTM4B and p27kip1 in human breast cancer databases. To analyze the role of LAPTM4B in the aggressiveness of the human triple-negative breast cancer, the expressions of LAPTM4B were knocked down in MDA-MB-231 and HCC1187 cell lines. Then, cell proliferation, migration and apoptosis were assessed in vitro. Furthermore, the immunohistochemistry examinations of LAPTM4B and p27kip1 expression were performed using surgical specimens from 188 primary triple-negative breast cancer patients.
Through analyses of several independent breast cancer cohorts, we found the correlation of the LAPTM4B and p27kip1 expression. Remarkably, the knockdown of LAPTM4B restored p27kip1 expression and inhibited the aggressiveness of breast cancer cells. Meanwhile, the knockdown of p27kip1 relieved the suppression of cell migration. Consistent with the analyses of human breast cancer cohorts, the immunohistochemistry results showed that the expression levels of LAPTM4B and p27kip1 were correlated in 188 triple-negative breast cancer samples (p= 0.019). We also validated that the higher LAPTM4B expression, the lower p27kip1 expression (p= 0.0001), and the LAPTM4B+/p27kip1- subgroup (p< 0.0001) were poor prognostic indicators, as well as the higher histologic grade (p= 0.0001). In the multivariate Cox regression, p27kip1 expression was considered as an independent predictor of survival (p< 0.001).
The overexpression of LAPTM4B and the loss of p27kip1 expression are correlated. Meanwhile, the up-regulated expression of LAPTM4B together with the down-regulated expression of p27kip1 could classified a group of breast cancer patients with poor prognosis, consequently considered as a potentially prognostic marker and candidate target for therapeutic intervention of triple-negative breast cancer.
三阴性乳腺癌（TNBC）与侵袭性表型和不良预后相关，缺乏可靶向的标志物导致无法进行靶向治疗。因此，迫切需要确定三阴性乳腺癌的潜在靶点。
本研究旨在探讨 LAPTM4B 和 p27kip1 在三阴性乳腺癌中的表达及其临床意义。
我们分析了人类乳腺癌数据库中 LAPTM4B 和 p27kip1 的表达及其相关性。为了分析 LAPTM4B 在人类三阴性乳腺癌侵袭性中的作用，我们在 MDA-MB-231 和 HCC1187 细胞系中敲低了 LAPTM4B 的表达。然后，在体外评估细胞增殖、迁移和凋亡。此外，使用 188 例原发性三阴性乳腺癌患者的手术标本进行了 LAPTM4B 和 p27kip1 表达的免疫组织化学检查。
通过对几个独立的乳腺癌队列的分析，我们发现了 LAPTM4B 和 p27kip1 表达的相关性。值得注意的是，敲低 LAPTM4B 恢复了 p27kip1 的表达并抑制了乳腺癌细胞的侵袭性。同时，敲低 p27kip1 缓解了细胞迁移的抑制。与人类乳腺癌队列的分析一致，免疫组织化学结果显示，在 188 例三阴性乳腺癌样本中，LAPTM4B 和 p27kip1 的表达水平呈正相关（p=0.019）。我们还验证了较高的 LAPTM4B 表达与较低的 p27kip1 表达（p=0.0001）相关，LAPTM4B+/p27kip1-亚组（p<0.0001）为预后不良的指标，以及较高的组织学分级（p=0.0001）。在多变量 Cox 回归中，p27kip1 表达被认为是生存的独立预测因子（p<0.001）。
LAPTM4B 的过表达和 p27kip1 表达的缺失相关。同时，LAPTM4B 的上调表达与 p27kip1 的下调表达相结合可将一组乳腺癌患者分为预后不良的群体，因此可将其视为潜在的预后标志物和三阴性乳腺癌治疗干预的候选靶点。
