Epidermal growth factor receptor (EGFR)–related protein inhibits multiple members of the EGFR family in colon and breast cancer cells

Abstract

Inactivation of epidermal growth factor receptor (EGFR) family members represents a promising strategy for the development of selective therapies against epithelial cancers. Current anti-EGFR therapies, such as cetuximab (Erbitux), gefitinib (Iressa), or trastuzumab (Herceptin), target EGFR or HER-2 but not both. Because solid tumors express different EGFRs, identification of inhibitor(s) targeting multiple EGFR family members may provide a therapeutic benefit to a broader patient population. We have identified a natural inhibitor of EGFRs called EGFRrelated protein (ERRP), a 53 to 55 kDa protein that is present in most, if not all, normal human epithelial cells. The growth of colon (HCT-116, Caco2, and HT-29) and breast (MDA-MB-468 and SKBR-3) cancer cells expressing varying levels of EGFR, HER-2, and/or HER-4 was inhibited by recombinant ERRP in a dose-dependent manner. In contrast, ERRP caused no inhibition of growth of normal mouse fibroblast cell lines (NIH-3T3, NIH-3T3/PT-67), and the growth of nontransformed rat small intestinal IEC-6 cells expressing relatively low levels of EGFRs was inhibited only at high doses of ERRP. Transforming growth factor-A or heparin-binding epidermal growth factorinduced activation of EGFR and HER-2 was inhibited by ERRP in colon and breast cancer cells expressing high levels of EGFR or HER-2. In contrast, cetuximab inhibited the growth-and ligand-induced activation of EGFR in cell lines expressing high levels of EGFR, whereas trastuzumab was effective only in HER-2 -overexpressing cells. ERRP and trastuzumab, but not cetuximab, attenuated heregulin-A -induced activation of colon and breast cancer cells that expressed high levels of HER-2. Furthermore, ERRP, but not cetuximab or trastuzumab, significantly induced apoptosis of colon and breast cancer cells. None of these agents induced apoptosis of either NIH-3T3 mouse fibroblast or normal rat small intestinal IEC cells. Our results suggest that ERRP is an effective pan-erbB inhibitor and, thus, may be a potential therapeutic agent for a wide variety of epithelial cancers expressing different levels and subclasses of EGFRs.

Acrolein Contributes to Human Colorectal Tumorigenesis Through the Activation of RAS/MAPK Pathway.

“…Major restriction of this study is that NIH/3T3 is a mouse broblast cell model and the genetic background may not be correlated with epithelia, though NIH/3T3 has been recognized as a cell line for tumorigenesis study in vitro and in vivo 17 . We could not observe EGFR expression in NIH/3T3 which is similar to previous studies showing that NIH/3T3 is lack of EGFR 55,56 . Therefore, we tried to use a normal colon cell, CCD-841CoN as a model and found that acrolein indeed induce activation of RAS/MAPK pathway which was similar to NIH/3T3 (Fig.…”

Acrolein contributes to human colorectal tumorigenesis through the activation of RAS-MAPK pathway

“…The major restriction of this study is that NIH/3T3 is a mouse fibroblast cell model, and the genetic background may not be correlated with epithelia, although NIH/3T3 has been recognized as a cell line for tumorigenesis studies in vitro and in vivo 17 , 55 , 56 . We could not observe EGFR expression in NIH/3T3 cells, which is similar to previous studies showing that NIH/3T3 cells lack EGFR 57 , 58 . Therefore, we tried to use a normal colon cell line, CCD-841CoN, as a model and found that acrolein indeed induced activation of the RAS/MAPK pathway, which was similar to NIH/3T3 (Fig.…”

Targeted Micellar Phthalocyanine for Lymph Node Metastasis Homing and Photothermal Therapy in an Orthotopic Colorectal Tumor Model

“…HT-29, a human colorectal cancer cell line with strong HER2 expression (Fig. 2 b) [ 22 , 23 ], was used in this study. Micelles labeled with iFluor 594 were used for the cell uptake assay.…”

“…Next, trastuzumab, a human anti-HER2 antibody, was conjugated to the micelle surface through EDS/NHS chemistry to generate trastuzumab-conjugated targeted micellar phthalocyanine (T-MP). T-MP would enable targeting to HER2 expressed on the surface of tumor cells, such as HT-29 colorectal cancer cells [ 22 , 23 ]. An orthotopic HT-29 colorectal tumor model was established [ 24 ], and metastasis to the mesenteric sentinel LN was observed.…”