title: Effect of the tyrosine kinase inhibitor lapatinib on CUB-domain containing protein (CDCP1)-mediated breast cancer cell survival and migration.
abstract: The surface receptor CUB domain-containing protein 1 (CDCP1) is highly expressed in several adenocarcinomas and speculated to participate in anchorage-independent cell survival and cell motility. Tyrosine kinase phosphorylation seems to be crucial for intracellular signaling of CDCP1. Lapatinib, a tyrosine kinase inhibitor (TKI), is approved for treatment of HER-2/neu overexpressing metastatic breast cancer and functions by preventing autophosphorylation following HER-2/neu receptor activation. This study aimed to investigate the effect of CDCP1 expression on anchorage-independent growth and cell motility of breast cancer cells. Moreover, studies were performed to examine if lapatinib provided any beneficial effect on HER-2/neu((+)/-)/CDCP1(+) breast cancer cell lines. In our studies, we affirmed that CDCP1 prevents cells from undergoing apoptosis when cultured in the absence of cell-substratum anchorage and that migratory and invasive properties of these cells were decreased when CDCP1 was down-regulated. However, only HER-2/neu(+), but not HER-2/neu((+)/-) cells showed decreased proliferation and invasion and an enhanced level of apoptosis towards loss of anchorage when treated with lapatinib. Therefore, we conclude that CDCP1 might be involved in regulating adhesion and motility of breast cancer cells but that lapatinib has no effect on tyrosine kinases regulating CDCP1. Nonetheless, other TKIs might offer therapeutic approaches for CDCP1-targeted breast cancer therapy and should be studied considering this aspect.
authors.affiliation: Charité Campus Mitte, Medizinische Klinik mit Schwerpunkt Onkologie und Hämatologie, Humboldt Universität zu Berlin, Germany.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Seidel
authors.forename: Klaudia
authors.initials: K
authors.lastname: Kunc
authors.forename: Kurt
authors.initials: K
authors.lastname: Possinger
authors.forename: Christian
authors.initials: C
authors.lastname: Jehn
authors.forename: Diana
authors.initials: D
authors.lastname: Lüftner
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D000077341:Lapatinib; D009363:Neoplasm Proteins / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D000077341:Lapatinib; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D013937:Thymidine Kinase; C432044:CDCP1 protein, human; C092717:thymidine kinase 1; C508053:ERBB2 protein, human