972

CD74

CD74 molecule, major histocompatibility complex, class II invariant chain;CD74;CD74 molecule, major histocompatibility complex, class II invariant chain

CD74 antigen (invariant polypeptide of major histocompatibility complex, class II antigen-associated)|HLA class II histocompatibility antigen gamma chain|HLA-DR antigens-associated invariant chain|HLA-DR-gamma|Ia-associated invariant chain|MHC HLA-DR gamm

5q32

protein-coding

Triple-negative breast cancer is difficult to treat because of the lack of rationale-based therapies. There are no established markers and targets that can be used for stratification of patients and targeted therapy. Here we report the identification of novel molecular features, which appear to augment metastasis of triple negative breast tumors. We found that triple-negative breast tumors can be segregated into 2 phenotypes based on their genome-wide protein abundance profiles. The first is characterized by high expression of Stat1, Mx1, and CD74. Seven out of 9 tumors from this group had invaded at least 2 lymph nodes while only 1 out of 10 tumors in group 2 was lymph node positive. In vitro experiments showed that the interferon-induced increase in Stat1 abundance correlates with increased migration and invasion in cultured cells. When CD74 was overexpressed, it increased cell adhesion on matrigel. This effect was accompanied with a marked increase in the membrane expression of beta-catenin, MUC18, plexins, integrins, and other proteins involved in cell adhesion and cancer metastasis. Taken together, our results show that Stat1/CD74 positive triple-negative tumors are more aggressive and suggest an approach for development of better diagnostics and more targeted therapies for triple negative breast cancer. This article is part of a Special Issue entitled: Proteomics: The clinical link.

The expression status of CD74 in breast cancer stem cells and its clinical implications was evaluated in order to lay a foundation for managing breast cancer. Five hundred and eighty breast cancer specimens were enrolled in the study. The relationship between the CD74 protein and clinicopathological parameters as well as prognosis was subsequently determined. In total, 468 (80.69 %) of the 580 breast cases showed CD74-positive expression. After universal analysis, CD74 was observed to be related to lymph node metastasis and triple-negative breast cancer (P = 0.01 and 0.001). Moreover, CD74 expression has a line correlation with lymph node metastasis and triple-negative breast cancer (P = 0.02 and 0.001). Furthermore, periostin was shown to attain a significantly more distant liver metastasis and worse disease-specific survival than those with none or low-expressed CD74 protein (P = 0.001). In the Cox regression test, CD74 protein was detected as an independent prognostic factor (P = 0.001). CD74 is consistently expressed in triple-negative subgroups of breast cancer and might be a new potential marker for triple-negative breast cancer.

Elevation of CD74 is associated with a number of human cancers, including clear cell renal cell carcinoma (ccRCC). To understand the role of CD74 in the oncogenic process of ccRCC, we ectopically expressed CD74 in human embryonic kidney 293 cells (HEK/CD74) and evaluated its oncogenic potential. Through overexpression of CD74 in HEK293 and Caki-2 cells and down-regulation of CD74 in Caki-1 cells, we show that vascular endothelial growth factor-D (VEGF-D) expression is modified accordingly. A significant, positive correlation between CD74 and VEGF-D is found in human ccRCC tissues (Pearson's correlation, r = 0.65, p < 0.001). In HEK/CD74 xenograft mice, CD74 significantly induced the formation of tumor masses, increased tumor-induced angiogenesis, and promoted cancer cell metastasis. Blockage of VEGF-D expression by small interference RNA resulted in a decrease in cell proliferation, invasion, and cancer cell-induced HUVEC migration enhanced by CD74. Furthermore, we provide evidence that the intracellular signaling cascade responsible for VEGF-D up-regulation by CD74 is both PI3K/AKT- and MEK/ERK-dependent, both of which are associated with NF-kappaB nuclear translocation and DNA-binding activity. These results suggest that VEGF-D is crucial for CD74-induced human renal carcinoma cancer cell tumorigenesis.