title: Modular anti-EGFR and anti-Her2 targeting of SK-BR-3 and BT474 breast cancer cell lines in the presence of ErbB receptor-specific growth factors.
abstract: Over the last decade, a number of monoclonal antibodies and small molecule inhibitors emerged as potent therapeutic agents in the treatment of Her2/neu overexpressing breast cancer. Numerous patients, however, do not adequately respond to anti-epidermal growth factor receptor (EGFR)/Her2 receptor targeting. Receptor- and, in turn, growth-stimulating effects, which potentially hamper antiproliferative cell treatment, have barely been investigated. BT474 and SK-BR-3 breast cancer cell lines were treated with Trastuzumab, Pertuzumab, and Lapatinib alone using different combinations and concentrations. Moreover, epidermal growth factor (EGF) or heregulin (HRG) was added to reveal potential growth factor-mediated compensatory effects. Receptor and intracellular signaling were analyzed as a function of cell treatment. Read-out parameters were cell proliferation and apoptosis. BT474 cells were efficiently driven into quiescence by Trastuzumab, but not by Pertuzumab treatment. Simultaneous EGF or HRG administration, however, restored the BT474 cell proliferation capacity. In contrast, neither therapeutic antibody treatment caused a profound inhibition of SK-BR-3 cell-cycle progress. Lapatinib turned out to be the most potent cell-cycle inhibitor in both cell lines even though its impact was significantly abrogated in the presence of EGF and HRG. The compensatory effect of EGF on Lapatinib-induced cell-cycle inhibition was reversed by Trastuzumab as well as by Pertuzumab treatment. Most importantly, HRG-caused compensation of Lapatinib-induced cell-cycle exit was reversed by Pertuzumab but not by Trastuzumab. Apparently, multiple anti-EGFR/Her2 targeting by using Trastuzumab, Pertuzumab, and Lapatinib more efficiently affects receptor function (interaction and activation) and consequently enhances their antiproliferative capacity. Growth inhibition by anticancer drugs targeted to Her/ErbB receptors, however, can be significantly undermined in the presence of EGF and in particular by HRG treatment, which suggests that specific therapeutic growth factor sequestration might further enhance anti-EGFR/Her2 targeting.
authors.affiliation: Department of Gynecology and Obstetrics, University of Regensburg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Diermeier-Daucher
authors.forename: Stefanie
authors.initials: S
authors.lastname: Breindl
authors.forename: Stefan
authors.initials: S
authors.lastname: Buchholz
authors.forename: Olaf
authors.initials: O
authors.lastname: Ortmann
authors.forename: Gero
authors.initials: G
authors.lastname: Brockhoff
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy; D002453:Cell Cycle; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006801:Humans; D000077341:Lapatinib; D020890:Neuregulin-1 / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004815:Epidermal Growth Factor; D000077341:Lapatinib; D020890:Neuregulin-1; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C485206:pertuzumab