title: P27(kip1) down-regulation is associated with trastuzumab resistance in breast cancer cells.
abstract: Trastuzumab (Herceptin) is a recombinant humanized monoclonal antibody directed against HER-2. The objective response rate to trastuzumab monotherapy is 12-34% for a median duration of 9 months, by which point most patients become resistant to treatment. We created two trastuzumab-resistant (TR) pools from the SKBR3 HER-2-overexpressing breast cancer cell line to study the mechanisms by which breast cancer cells escape trastuzumab-mediated growth inhibition. Both pools maintained her-2 gene amplification and protein overexpression. Resistant cells demonstrated a higher S-phase fraction by flow cytometry and a faster doubling time of 24-36 h compared with 72 h for parental cells. The cyclin-dependent kinase inhibitor p27(kip1) was decreased in TR cells, and cyclin-dependent kinase 2 activity was increased. Importantly, exogenous addition of p27(kip1) increased trastuzumab sensitivity. Additionally, resistant cells displayed heightened sensitivity to the proteasome inhibitor MG132, which induced p27(kip1) expression. Thus, we propose that trastuzumab resistance may be associated with decreased p27(kip1) levels and may be susceptible to treatments that induce p27(kip1) expression.
authors.affiliation: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Nahta
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Naoto T
authors.initials: NT
authors.lastname: Ueno
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Esteva
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068878:Trastuzumab; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D000068878:Trastuzumab