A human monoclonal autoantibody to breast cancer identifies the PDZ domain containing protein GIPC1 as a novel breast cancer-associated antigen

Rudchenko, Sergei; Scanlan, Matthew J.; Kalantarov, Gavreel F.; Yavelsky, Victoria; Levy, Chen; Estabrook, Alison; Old, Lloyd J.; Chan, Gloria; Lobel, Leslie; Trakht, Ilya

doi:10.1186/1471-2407-8-248

Cited by 21 publications

(19 citation statements)

References 55 publications

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“…GIPC is overexpressed both in pancreatic and breast cancers, 6–9 and abnormal activation of GIPC-mediated interactions has been shown to cause or contribute to pancreatic and breast cancers. Several studies including ours have implicated the PDZ domain of GIPC (“GIPC PDZ”) as a critical player in the biology of normal and malignant cells.…”

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confidence: 99%

Chemically Modified Peptides Targeting the PDZ Domain of GIPC as a Therapeutic Approach for Cancer

et al. 2012

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GIPC (GAIP-interacting protein, C terminus) represents a new target class for the discovery of chemotherapeutics. While many of the current generation of anticancer agents function by directly binding to intracellular kinases or cell surface receptors, the disruption of cytosolic protein-protein interactions mediated by non-enzymatic domains is an underdeveloped avenue for inhibiting cancer growth. One such example is the PDZ domain of GIPC. Previously we developed a molecular probe, the cell permeable octapeptide CR1023 (N-myristoyl-PSQSSSEA), which diminished proliferation of pancreatic cancer cells. We have expanded upon that discovery using a chemical modification approach, and here report a series of cell permeable, side chain-modified lipopeptides that target the GIPC PDZ domain in vitro and in vivo. These peptides exhibit significant activity against pancreatic and breast cancers, both in vitro and in animal models. CR1166 (N-myristoyl-PSQSK(εN-4-bromobenzoyl)SK(εN-4-bromobenzoyl)A), bearing two halogenated aromatic units on alternate side chains, was found to be the most active compound, with pronounced down-regulation of EGFR/1GF-1R expression. We hypothesize that these organic acid-modified residues extend the productive reach of the peptide beyond the canonical binding pocket, which defines the limit of accessibility for the native proteinogenic sequences that the PDZ domain has evolved to recognize. Cell permeability is achieved with N-terminal lipidation using myristate, rather than a larger CPP (cell-penetrating peptide) sequence. This, in conjunction with optimization of targeting through side chain modification, has yielded an approach that will allow the discovery and development of next-generation cellular probes for GIPC PDZ as well as other PDZ domains.

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confidence: 99%

Chemically Modified Peptides Targeting the PDZ Domain of GIPC as a Therapeutic Approach for Cancer

et al. 2012

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“…They are biochemically well-characterized, and many reagents and techniques are available for their detection, simplifying assay development. Until very recently, several specific autoantibodies have been detected in the sera of patients with advanced-stage breast cancer (14,(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58). However, very few studies have attempted to identify and/or evaluate autoantibodies in node-negative earlystage PBC ( 2 cm) or, more importantly, in preinvasive breast cancer, for which mammography's sensitivity is decreased.…”

Section: Discussionmentioning

confidence: 99%

A Multiparametric Serum Marker Panel as a Complementary Test to Mammography for the Diagnosis of Node-Negative Early-Stage Breast Cancer and DCIS in Young Women

Lacombe

Mangé

Bougnoux

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: The sensitivity of mammography for the detection of small lesions, including node-negative early-stage (T1N0) primary breast cancer (PBC) and ductal carcinoma in situ (DCIS), is significantly decreased in young patients. From a clinical standpoint, an inconclusive mammogram reflects the inability of clinicians to confidently decide whether patients should be referred for biopsy or for follow-up with repeat imaging.Methods: Specific ELISAs were developed for a panel of 13 well-recognized breast autoantigens (HSP60, FKBP52, PRDX2, PPIA, MUC1, GAL3, PAK2, P53, CCNB1, PHB2, RACK1, RUVBL1, and HER2). Circulating autoantibody levels were measured in a cohort of 396 serum samples from histologically confirmed DCIS (n ¼ 87) or T1N0 PBC (n ¼ 153) and healthy controls (n ¼ 156).Results: Individually, antibodies against CCNB1, FKBP52, GAL3, PAK2, PRDX2, PPIA, P53, and MUC1 demonstrated discriminatory power between breast cancer and healthy control groups. At 90% sensitivity, the overall combined specificity of the autoantibody serum screening test was 42%. Adjustment for higher sensitivities of 95% and 99% resulted in 30% and 21% specificities, respectively (33% and 18% in T1N0 PBC and 28% and 21% in DCIS). Finally, in patients with node-negative early-stage breast cancer younger than 50 years, the autoantibody assay exhibited 59% specificity with a fixed sensitivity at 90%.Conclusions: Our autoantibody panel allows accurate detection of early breast cancer and DCIS, notably in younger patients.Impact: Clinical assessment of this autoantibody panel displays a potential to facilitate clinical management of early-stage breast cancer detection in cases of inconclusive mammogram. Cancer Epidemiol Biomarkers Prev; 23(9); 1834-42. Ó2014 AACR.

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“…AAb to the signal transduction related protein replication protein A (RPA32) have been detected in 87/801 patients with invasive breast cancer and 4/39 patients with ductal carcinoma in situ (DCIS) [93]. Using a novel approach of directly cloning monoclonal antibodies representing the native B cell repertoire from breast cancer patients, GIPC1 was identified as a breast cancer AAb [75].…”

Section: Other Markersmentioning

confidence: 99%

Autoantibody profiles as biomarkers of breast cancer

Tabernero

Anderson

2010

CBM

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Breast cancer is the second leading cause of cancer death in women in the United States. While mammography and breast magnetic resonance imaging (MRI) improve detection of early disease, there remains an unmet need for biomarkers for risk stratification, early detection, prediction, and disease prognosis. Sera from patients with breast cancer contain specific autoantibodies (AAb) to tumor antigens that develop as part of the natural immune response to cancer-associated changes in protein structure and expression. The recent development of proteomic tools for AAb detection, including protein microarrays, reverse-phase protein immunoblots, and phage display have identified a number of potential AAb biomarkers for clinical development. Immune response signatures have been identified that are highly specific, but with variable sensitivities for cancer detection. This review focuses on the detection and application of AAb signatures as biomarkers for breast cancer detection and monitoring.

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A human monoclonal autoantibody to breast cancer identifies the PDZ domain containing protein GIPC1 as a novel breast cancer-associated antigen

Cited by 21 publications

References 55 publications

Chemically Modified Peptides Targeting the PDZ Domain of GIPC as a Therapeutic Approach for Cancer

Chemically Modified Peptides Targeting the PDZ Domain of GIPC as a Therapeutic Approach for Cancer

A Multiparametric Serum Marker Panel as a Complementary Test to Mammography for the Diagnosis of Node-Negative Early-Stage Breast Cancer and DCIS in Young Women

Autoantibody profiles as biomarkers of breast cancer

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