title: Amplification and overexpression of the ABCC3 (MRP3) gene in primary breast cancer.
abstract: The ATP-binding cassette (ABC) of active transporters comprises a group of proteins that which facilitate efflux of anticancer drugs from cancer cells. We focused on the gene amplification and protein expression of ABCC3 (also known as MRP3) in breast cancer cell lines and clinical tumor samples. Fluorescence and chromogenic in situ hybridization, using an ABCC3-specific probe, was used to analyze 11 breast cancer cell lines and 112 clinical tumor samples. The results of ABCC3 were correlated with the amplification status of HER2 and topoisomerase II alpha (TOP2A), which are located close to ABCC3 at 17q12-q21. Immunohistochemistry was used to assess ABCC3 protein overexpression. Of the cell lines studied 6 HER2-positive lines and 1 HER2-negative line exhibited amplification of ABCC3. In the HER-2-negative clinical tumor samples, only 4/55 (7.3%) exhibited ABCC3 amplification. In the HER2-positive tumors, ABCC3 was amplified in 16/57 tumors (28.1%, P=0.0059). TOP2A did not exhibit any consistent coamplification pattern. ABCC3 (MRP3) protein overexpression was more common in tumors with gene amplification (P=0.069). In silico analysis of 804 breast cancers with matched gene expression and copy number microarray data revealed significant differences ABCC3 across the molecular subtypes. Specifically, increased ABCC3 mRNA and gene copy numbers were most prominent in HER2 amplified and/or HER2-enriched classified tumors. Moreover, differential ABCC3 mRNA levels were found within the HER-2 amplified subset when stratified by the estrogen receptor status. We conclude that ABCC3 is frequently amplified and overexpressed in HER2-positive breast cancer, and something that warrants further studies correlating the results with therapeutic outcome.
authors.affiliation: Institute of Biomedical Technology, University of Tampere, and Department of Oncology, Tampere University Hospital, Tampere, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Partanen
authors.forename: Johan
authors.initials: J
authors.lastname: Staaf
authors.forename: Minna
authors.initials: M
authors.lastname: Tanner
authors.forename: Vilppu J
authors.initials: VJ
authors.lastname: Tuominen
authors.forename: Åke
authors.initials: Å
authors.lastname: Borg
authors.forename: Jorma
authors.initials: J
authors.lastname: Isola
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D055028:Comparative Genomic Hybridization; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C114462:multidrug resistance-associated protein 3; C000618811:TOP2A protein, human