Department of Pathology, University of Nevada School of Medicine, Reno, NV 89557, USA.
Anticancer Res. 2010 Oct;30(10):3903-10.
E-Cadherin functions as a tumor suppressor in some invasive breast carcinomas and metastasis is promoted when its expression is lost. It has been observed, however, that in one of the most aggressive human breast cancers, inflammatory breast cancer (IBC), E-cadherin is overexpressed and this accounts for the formation of the lymphovascular embolus, a structure efficient at metastasis and resistant to chemotherapy through unknown cytoprotective mechanisms. Studies using a human xenograft model of IBC, MARY-X, indicate that the mechanism of E-cadherin overexpression is not transcriptional but related to altered protein trafficking. By real-time RT-PCR, E-cadherin transcript levels in MARY-X were 3- to 11-fold less than in other E-cadherin positive human breast carcinoma lines but the protein levels were 5- to 10-fold greater. In addition, several smaller E-cadherin protein fragments, e.g. 95 kDa, were present. To explain these observations, it was hypothesized that there may be altered protein trafficking. A real-time RT-PCR screen of candidate molecules generally known to regulate protein trafficking was conducted. The screen revealed 3.5- to 7-fold increased ExoC5 level and 10 to 20 fold decreased HRS and RAB7 levels, which was confirmed in human microdissected lymphovascular emboli. Since these alterations may only be correlative with E-cadherin overexpression, one of the molecules, Rab7, was selectively knocked down in MCF-7 cells. An increase in the full length 120 kDa E-cadherin and the de novo appearance of the 95 KD band were observed. These findings suggest that it is the altered E-cadherin trafficking that contributes to its oncogenic rather than suppressive role in IBC.
E-钙黏蛋白在一些侵袭性乳腺癌中作为肿瘤抑制因子发挥作用，而当其表达丢失时会促进转移。然而，已经观察到，在最具侵袭性的人类乳腺癌之一，炎性乳腺癌（IBC）中，E-钙黏蛋白过表达，这导致了淋巴管栓子的形成，这种结构有利于转移，并且通过未知的细胞保护机制对化疗具有抗性。使用 IBC 的人异种移植模型 MARY-X 的研究表明，E-钙黏蛋白过表达的机制不是转录的，而是与改变的蛋白转运有关。通过实时 RT-PCR，MARY-X 中的 E-钙黏蛋白转录本水平比其他 E-钙黏蛋白阳性的人乳腺癌系低 3-11 倍，但蛋白水平高 5-10 倍。此外，还存在几个较小的 E-钙黏蛋白蛋白片段，例如 95kDa。为了解释这些观察结果，假设可能存在改变的蛋白转运。对通常已知调节蛋白转运的候选分子进行了实时 RT-PCR 筛选。该筛选揭示了 ExoC5 水平增加 3.5-7 倍，HRS 和 RAB7 水平降低 10-20 倍，在人微解剖的淋巴管栓子中得到了证实。由于这些改变可能仅与 E-钙黏蛋白过表达相关，因此在 MCF-7 细胞中选择性敲低了一种分子 Rab7。观察到全长 120kDa E-钙黏蛋白增加和新出现的 95KD 带。这些发现表明，正是改变的 E-钙黏蛋白转运导致其在 IBC 中具有致癌而非抑制作用。
