Abstract
In contrast to various signatures that predict the prognosis of breast cancer patients, markers that predict chemotherapy response are still elusive. To detect such predictive biomarkers, we investigated early changes in protein expression using two mouse models for distinct breast cancer subtypes who have a differential knock-out status for the breast cancer 1, early onset (Brca1) gene. The proteome of cisplatin-sensitive BRCA1-deficient mammary tumors was compared with that of cisplatin-resistant mammary tumors resembling pleomorphic invasive lobular carcinoma. The analyses were performed 24 h after administration of the maximum tolerable dose of cisplatin. At this time point, drug-sensitive BRCA1-deficient tumors showed DNA damage, but cells were largely viable. By applying paired statistics and quantitative filtering, we identified highly discriminatory markers for the sensitive and resistant model. Proteins up-regulated in the sensitive model are involved in centrosome organization, chromosome condensation, homology-directed DNA repair, and nucleotide metabolism. Major discriminatory markers that were up-regulated in the resistant model were predominantly involved in fatty acid metabolism, such as fatty-acid synthase. Specific inhibition of fatty-acid synthase sensitized resistant cells to cisplatin. Our data suggest that exploring the functional link between the DNA damage response and cancer metabolism shortly after the initial treatment may be a useful strategy to predict the efficacy of cisplatin.
Highlights
From the ‡OncoProteomics Laboratory, Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081HV Amsterdam and the ¶Division of Molecular Oncology and Division of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121 Amsterdam, 1066 CX, The Netherlands
BRCA1-proficient/CDH1-deficient Mammary Tumors Respond Poorly to Cisplatin—We have previously shown that BRCA1-deficient mammary tumors, which contain large intragenic deletions of the Brca1 and p53 genes, are highly sensitive to the maximum tolerable dose of cisplatin [3]
When we treated CDH1-deficient tumors, we found that these hardly responded to the same regimen (Fig. 1A). This difference in cisplatin response between the models is not unexpected, because CDH1-deficient tumors are still capable of repairing cisplatin-induced DNA damage by homologous recombination (HR), in contrast to BRCA1-deficient tumors
Summary
Unless otherwise specified, were obtained from Sigma-Aldrich. HPLC solvents, LC-MS grade water, acetonitrile, and formic acid were obtained from Biosolve (Biosolve B.V., Valkenswaard, The Netherlands). Porcine sequence-grade modified trypsin was obtained from Promega (Promega Benelux B.V., Leiden, The Netherlands)
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