title: Impact of intertumoral heterogeneity on predicting chemotherapy response of BRCA1-deficient mammary tumors.
abstract: The lack of markers to predict chemotherapy responses in patients poses a major handicap in cancer treatment. We searched for gene expression patterns that correlate with docetaxel or cisplatin response in a mouse model for breast cancer associated with BRCA1 deficiency. Array-based expression profiling did not identify a single marker gene predicting docetaxel response, despite an increase in Abcb1 (P-glycoprotein) expression that was sufficient to explain resistance in several poor responders. Intertumoral heterogeneity explained the inability to identify a predictive gene expression signature for docetaxel. To address this problem, we used a novel algorithm designed to detect differential gene expression in a subgroup of the poor responders that could identify tumors with increased Abcb1 transcript levels. In contrast, standard analytical tools, such as significance analysis of microarrays, detected a marker only if it correlated with response in a substantial fraction of tumors. For example, low expression of the Xist gene correlated with cisplatin hypersensitivity in most tumors, and it also predicted long recurrence-free survival of HER2-negative, stage III breast cancer patients treated with intensive platinum-based chemotherapy. Our findings may prove useful for selecting patients with high-risk breast cancer who could benefit from platinum-based therapy.
authors.affiliation: Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. s.rottenberg@nki.nl
authors.forename: Sven
authors.initials: S
authors.lastname: Rottenberg
authors.forename: Marieke A
authors.initials: MA
authors.lastname: Vollebergh
authors.forename: Bas
authors.initials: B
authors.lastname: de Hoon
authors.forename: Jorma
authors.initials: J
authors.lastname: de Ronde
authors.forename: Philip C
authors.initials: PC
authors.lastname: Schouten
authors.forename: Ariena
authors.initials: A
authors.lastname: Kersbergen
authors.forename: Serge A L
authors.initials: SA
authors.lastname: Zander
authors.forename: Marina
authors.initials: M
authors.lastname: Pajic
authors.forename: Janneke E
authors.initials: JE
authors.lastname: Jaspers
authors.forename: Martijn
authors.initials: M
authors.lastname: Jonkers
authors.forename: Martin
authors.initials: M
authors.lastname: Lodén
authors.forename: Wendy
authors.initials: W
authors.lastname: Sol
authors.forename: Eline
authors.initials: E
authors.lastname: van der Burg
authors.forename: Jelle
authors.initials: J
authors.lastname: Wesseling
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gillet
authors.forename: Michael M
authors.initials: MM
authors.lastname: Gottesman
authors.forename: Joost
authors.initials: J
authors.lastname: Gribnau
authors.forename: Lodewyk
authors.initials: L
authors.lastname: Wessels
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Linn
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.forename: Piet
authors.initials: P
authors.lastname: Borst
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology; D000077143:Docetaxel; D005260:Female; D020869:Gene Expression Profiling; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016032:Randomized Controlled Trials as Topic; D043823:Taxoids / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin