title: Deficient HER3 expression in poorly-differentiated colorectal cancer cells enhances gefitinib sensitivity.
abstract: Poorly-differentiated colorectal cancers (PD-CRC) show high metastatic potential and poor prognosis. However, molecular characteristics of PD-CRC remain unknown to date, particularly in molecular targeting therapy for patients with PD-CRC. In this study, we examined the expression of EGFR, HER2 and HER3 in PD-CRC by immunohistochemical analysis of archived clinical specimens of primary tumors and investigated the sensitivity of PD-CRC cell lines to gefitinib, a tyrosine kinase inhibitor for EGFR in vitro. We found that HER3 expression of PD-CRC among members of the HER family was significantly lower than that of well to moderately differentiated CRC (WMD-CRC) and 37% of the PD cases showed a EGFR+/HER2+/HER3- expression pattern. COLM-5 cells, a PD-CRC-derived cell line, which exhibits EGFR+/HER2+/HER3- expression pattern and recapitulates the typical histology of PD-CRC in xenografted tumors, showed high gefitinib sensitivity both in vitro and in vivo, compared with WMD-CRC cell line (COLM-2). Treatment with gefitinib resulted in the upregulation of p27Kip1 expression and induction of G1 cell cycle arrest, concomitantly associated with inactivation of PI3K/Akt signaling in COLM-5 cells and marked inhibition of xenografted tumors in nude mice, but not evident in COLM-2 cells. Treatment with sodium butyrate, an HDAC inhibitor that induces differentiation, upregulated the expression of HER3 associated with enhancement of the PI3K/Akt signaling, attenuated gefitinib-mediated p27Kip1 upregulation and reduced gefitinib sensitivity in COLM-5 cells in vitro. Furthermore, enforced expression of HER3 in COLM-5 cells resulted in significant resistance to gefitinib treatment both in vitro and in vivo. These findings suggest that deficient HER3 expression plays an important role in gefitinib sensitivity and that a malignant subset of PD with EGFR+/HER2+/HER3- phenotype is a potential candidate for a target of anti-EGFR molecular therapy such as gefitinib.
authors.affiliation: Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakata
authors.affiliation: Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
authors.forename: Harunari
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Nagoya 464-8681, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Gastroenterological Surgery, Nagoya City University, Nagoya 464-8681, Japan.
authors.forename: Masayasu
authors.initials: M
authors.lastname: Hara
authors.affiliation: Department of Microbiology, Kinki University, Graduate School of Medical Sciences, Osaka 589-8511, Japan.
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Fujita
authors.affiliation: Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
authors.forename: Eisaku
authors.initials: E
authors.lastname: Kondo
authors.affiliation: Colorectal Surgery Division, National Cancer Center Hospital, Tokyo 104-0045, Japan.
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Kanemitsu
authors.affiliation: Department of Pathology and Molecular Medicine, Aichi Cancer Center Central Hospital, Nagoya 464-8681, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.affiliation: Laboratory of Pathology and Clinical Research, Aichi Cancer Center Aichi Hospital, Okazaki 444-0011, Japan.
authors.forename: Hayao
authors.initials: H
authors.lastname: Nakanishi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D020148:Butyric Acid / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011799:Quinazolines / Q000008:administration & dosage* / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D020148:Butyric Acid; D066246:ErbB Receptors; D000077156:Gefitinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human