Autoantibody signatures involving glycolysis and splicesome proteins precede a diagnosis of breast cancer among postmenopausal women - PubMed (original) (raw)

. 2013 Mar 1;73(5):1502-13.

doi: 10.1158/0008-5472.CAN-12-2560. Epub 2012 Dec 26.

Timothy Chao, Melissa M Johnson, Ji Qiu, Alice Chin, Rebecca Israel, Sharon J Pitteri, Jianning Mao, Mei Wu, Lynn M Amon, Martin McIntosh, Christopher Li, Ross Prentice, Nora Disis, Samir Hanash

Affiliations

Autoantibody signatures involving glycolysis and splicesome proteins precede a diagnosis of breast cancer among postmenopausal women

Jon J Ladd et al. Cancer Res. 2013.

Abstract

We assessed the autoantibody repertoire of a mouse model engineered to develop breast cancer and the repertoire of autoantibodies in human plasmas collected at a preclinical time point and at the time of clinical diagnosis of breast cancer. In seeking to identify common pathways, networks, and protein families associated with the humoral response, we elucidated the dynamic nature of tumor antigens and autoantibody interactions. Lysate proteins from an immortalized cell line from a MMTV-neu mouse model and from MCF7 human breast cancers were spotted onto nitrocellulose microarrays and hybridized with mouse and human plasma samples, respectively. Immunoglobulin-based plasma immunoreactivity against glycolysis and spliceosome proteins was a predominant feature observed both in tumor-bearing mice and in prediagnostic human samples. Interestingly, autoantibody reactivity was more pronounced further away than closer to diagnosis. We provide evidence for dynamic changes in autoantibody reactivity with tumor development and progression that may depend, in part, on the extent of antigen-antibody interactions.

©2012 AACR.

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Figures

Figure 1

Figure 1

a) Experimental design. Identification of immunogenic proteins was based on b) autoantibody reactivity to arrayed MCF7 fractions. Peaks were determined qualitatively from microarray data. c) Western blots of individual fractions within a cluster with individual plasma samples were used to determine the molecular weight of reactive bands whose pattern qualitatively matches the microarray response pattern. d) Mass spectrometry analysis of fractions within a cluster identifies proteins by total peptide counts that match microarray and western blot data.

Figure 2

Figure 2

Subcellular localization of immunogenic proteins identified in a) mouse and b) human samples. c) Immunogenic proteins identified in the glycolysis pathway. Purple indicates autoantibodies were elevated in cases compared to controls for both pre-diagnostic mouse and human samples, while red indicates autoantibodies were elevated only in pre-diagnostic human cases compared to controls. No color indicates autoantibodies to these proteins were not identified.

Figure 3

Figure 3

Receiver operator characteristic (ROC) analysis of proteins identified in glycolysis and spliceosome signatures for a) all samples, b) cases collected within 150 days prior to diagnosis compared to controls and c) cases collected more than 150 days prior to diagnosis of breast cancer compared to controls. d) Case-to-control ratios based on time-to-diagnosis for a subset of immunogenic proteins assayed in a cohort of newly diagnosed, post-menopausal women.

Figure 4

Figure 4

a) Normalized ELISA results for PKM2 in pre-diagnostic samples from the WHI separated by days prior to diagnosis of blood draw. b) Normalized autoantibody response from natural protein arrays for PKM2 separated by days prior to diagnosis. * indicates p<0.05. c) Distribution of positive autoantibody responses for each of the identified glycolysis pathway proteins as a function of time before diagnosis in case samples. d) Distribution of positive autoantibody responses for each of the identified spliceosome proteins as a function of time before diagnosis in case samples. In c & d, individual proteins are marked by unique symbols.

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