An Autoimmune Response Signature Associated with the Development of Triple-Negative Breast Cancer Reflects Disease Pathogenesis

Abstract

The repertoire of antigens associated with the development of an autoimmune response in breast cancer has relevance to detection and treatment strategies. We have investigated the occurrence of autoantibodies associated with the development of triple-negative breast cancer (TNBC) in the before diagnosis setting and in samples collected at the time of diagnosis of TNBC. Lysate arrays containing protein fractions from the TNBC MDA-MB-231 cell line were hybridized with TNBC plasmas from the Women's Health Initiative cohort, collected before clinical diagnosis and with plasmas from matched controls. An immune response directed against spliceosome and glycolysis proteins was observed with case plasmas as previously reported in estrogen receptor+ breast cancer. Importantly, autoantibodies directed against networks involving BRCA1, TP53, and cytokeratin proteins associated with a mesenchymal/basal phenotype were distinct to TNBC before diagnosis samples. Concordant autoantibody findings were observed with mouse plasma samples collected before occurrence of palpable tumors from a C3(1)-T triple negative mouse model. Plasma samples collected at the time of diagnosis of stage II TNBC and from matched healthy controls were subjected to proteomic analysis by mass spectrometry to identify Ig-bound proteins yielding a predominance of cytokeratins, including several associated with a mesenchymal/basal phenotype among cases compared with controls. Our data provide evidence indicative of a dynamic repertoire of antigens associated with a humoral immune response reflecting disease pathogenesis in TNBC.

Proteome Profiling Uncovers an Autoimmune Response Signature That Reflects Ovarian Cancer Pathogenesis

“…Consistent with our findings, we uncovered TP53 and MYC as major nodes for antigens associated with autoantibodies, suggesting an intrinsic relationship between established drivers of serous ovarian cancer pathogenesis and autoantibody targets [28]. We previously reported on a triple-negative breast cancer (TNBC) autoimmune response signature that was also mainly contributed by TP53 and MYC [15]. According to the Cancer Genome Atlas (TCGA), serous ovarian carcinoma and the basal type of breast cancer have molecular phenotype similarity that include MYC high expression and high frequency of TP53 inactivation [29].…”

“…The combined performance of these three markers resulted in an AUC of 0.9576 ( Figure 1C). Released antigens may occur in circulation bound to Ig [15,[19][20][21]. We profiled ovarian cancer circulating Ig-bound proteins in ovarian cancer subjects compared to controls using tandem mass tag (TMT)-based liquid chromatography mass spectrometry (LCMS).…”

“…cDNA expression libraries [8], phage display [9] and recombinant protein arrays [10][11][12] have been utilized to identify antigens associated with autoantibodies. Other approaches include natural protein arrays that utilize fractionated tumor cell lysates as the source of antigens to preserve post-translational modifications (PTMs) and other protein alterations associated with immune reactivity [13][14][15]. Recently we have reported on the use of whole-genome derived peptide arrays as an approach for identification of pre-diagnostic autoantibodies associated with lung cancer, which provides a comprehensive coverage of peptide epitopes encoded in the genome [16].…”

Integrated Analysis Identifies Molecular Signatures and Specific Prognostic Factors for Different Gastric Cancer Subtypes

“…Molecular signatures associated with distinct prognosis have been illustrated in many different cancers [24], [25], [26], [27], [28]. For breast cancer, a 21-gene signature has even been approved by the FDA for application in bedside decisions [24], [29].…”

Immunization against HIF-1α Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells In Vivo

“…Whether these data indicate the inherent immunogenicity of TNBC as compared to other breast cancer subtypes or reflect an increased incidence of HIF-1α overexpression in TNBC as compared to other breast cancers is unknown. However, the high incidence and levels of tumor associated autoantibodies in TNBC suggest this subtype manifests an active tumor specific Type II immune response (30). …”