title: HB-EGF orchestrates the complex signals involved in triple-negative and trastuzumab-resistant breast cancer.
abstract: A number of therapeutic strategies targeting epidermal growth factor receptor (EGFR) have not always led to success in the present state of breast cancer therapy. Notably, there is currently no way to treat trastuzumab-resistant and triple-negative breast cancer (TNBC). Here, we found that heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGFR ligands, was predominantly expressed in breast cancer and that treatment with crossreacting material 197 (CRM197), a specific inhibitor of HB-EGF, blocked ERK as well as AKT activation via complexes of EGFR and unknown growth factor receptors in TNBC or through complexes of EGFR and human epidermal growth factor receptor-2 in trastuzumab-resistant breast cancer, caused significant cell apoptosis and inhibited tumor growth. Accordingly, we can provide a novel concept that a certain EGFR ligand is recognized as a rational target against breast cancer. In addition, it is plausible that CRM197 could be an effective anticancer agent for molecularly targeted therapies.
authors.affiliation: Department of Biochemistry, School of Medicine, Fukuoka University, Jonan-ku, Fukuoka, Japan.
authors.forename: Fusanori
authors.initials: F
authors.lastname: Yotsumoto
authors.forename: Eiji
authors.initials: E
authors.lastname: Oki
authors.forename: Eriko
authors.initials: E
authors.lastname: Tokunaga
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
authors.forename: Masahide
authors.initials: M
authors.lastname: Kuroki
authors.forename: Shingo
authors.initials: S
authors.lastname: Miyamoto
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D000068818:Cetuximab; D016503:Drug Delivery Systems / Q000379:methods; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051058:Oncogene Protein v-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D000068818:Cetuximab; D066246:ErbB Receptors; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D051058:Oncogene Protein v-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000068878:Trastuzumab; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; C028581:CRM197 (non-toxic variant of diphtheria toxin)