title: BRCA2-deficient sarcomatoid mammary tumors exhibit multidrug resistance.
abstract: Pan- or multidrug resistance is a central problem in clinical oncology. Here, we use a genetically engineered mouse model of BRCA2-associated hereditary breast cancer to study drug resistance to several types of chemotherapy and PARP inhibition. We found that multidrug resistance was strongly associated with an EMT-like sarcomatoid phenotype and high expression of the Abcb1b gene, which encodes the drug efflux transporter P-glycoprotein. Inhibition of P-glycoprotein could partly resensitize sarcomatoid tumors to the PARP inhibitor olaparib, docetaxel, and doxorubicin. We propose that multidrug resistance is a multifactorial process and that mouse models are useful to unravel this.
authors.affiliation: Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Janneke E
authors.initials: JE
authors.lastname: Jaspers
authors.affiliation: Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Wendy
authors.initials: W
authors.lastname: Sol
authors.affiliation: Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Ariena
authors.initials: A
authors.lastname: Kersbergen
authors.affiliation: Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlicker
authors.affiliation: Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Guyader
authors.affiliation: Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Guotai
authors.initials: G
authors.lastname: Xu
authors.affiliation: Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Lodewyk
authors.initials: L
authors.lastname: Wessels
authors.affiliation: Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Piet
authors.initials: P
authors.lastname: Borst
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.affiliation: Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland. sven.rottenberg@vetsuisse.unibe.ch.
authors.forename: Sven
authors.initials: S
authors.lastname: Rottenberg
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D024682:BRCA2 Protein / Q000172:deficiency / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D024682:BRCA2 Protein; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D004317:Doxorubicin; C507084:Abcb1b protein, mouse