title: ABCB1/MDR1 contributes to the anticancer drug-resistant phenotype of IPH-926 human lobular breast cancer cells.
abstract: Contribution of the ABCB1/MDR1/P-glycoprotein drug transporter to breast cancer resistance has been controversial. One issue is that ABCB1-dependent drug-resistance has primarily been investigated in mammary epithelial cell models technically manipulated to overexpress ABCB1, either by gene transfer using appropriate expression vectors or by chronic anticancer drug-selection. However, an unmodified human breast cancer cell line with an endogenous overexpression of ABCB1 has not been described thus far. Using Affymetrix microarray analyses, we identified an endogenous overexpression of several tumor-biologically relevant transcripts including ABCB1, BCAR4, CCL28, SCGB2A2 and PIP in IPH-926, an anticancer drug-resistant human lobular breast cancer cell line derived from a chemo-refractory mammary carcinoma patient. In a panel of twenty breast cancer cell lines examined, overexpression of ABCB1 mRNA and protein was exclusively detected in IPH-926. This was further validated using chronically in vitro drug-selected KB-V-1 cells as a widely used reference model to accurately define an ABCB1 overexpression. IPH-926 and KB-V-1 displayed a similar overexpression of ABCB1. Flow cytometric analyses showed that IPH-926 but not ABCB1-negative breast cancer cells extruded the anticancer agent doxorubicin, a classical substrate of the ABCB1 drug transporter. PSC-833 (valspodar), a selective ABCB1 inhibitor, blocked this efflux, restored apoptotic PARP cleavage and increased doxorubicin sensitivity in IPH-926 and KB-V-1. To our knowledge, IPH-926 represents the first human breast cancer cell line with a genuine, endogenous overexpression of ABCB1. IPH-926 provides evidence that ABCB1 can occasionally cause anticancer drug-resistance in breast cancer patients and offers a new tool for the evaluation of compounds to overcome drug-resistance.
authors: Institute of Pathology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors: Till
authors: T
authors: Krech
authors: Elisa
authors: E
authors: Scheuerer
authors: Robert
authors: R
authors: Geffers
authors: Hans
authors: H
authors: Kreipe
authors: Ulrich
authors: U
authors: Lehmann
authors: Matthias
authors: M
authors: Christgen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000503:physiopathology; D018275:Carcinoma, Lobular / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D010641:Phenotype; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents