Proteomic Analysis Identifies FNDC1, A1BG, and Antigen Processing Proteins Associated with Tumor Heterogeneity and Malignancy in a Canine Model of Breast Cancer

Abstract

New insights into the underlying biological processes of breast cancer are needed for the development of improved markers and treatments. The complex nature of mammary cancer in dogs makes it a great model to study cancer biology since they present a high degree of tumor heterogeneity. In search of disease-state biomarkers candidates, we applied proteomic mass spectrometry imaging in order to simultaneously detect histopathological and molecular alterations whilst preserving morphological integrity, comparing peptide expression between intratumor populations in distinct levels of differentiation. Peptides assigned to FNDC1, A1BG, and double-matching keratins 18 and 19 presented a higher intensity in poorly differentiated regions. In contrast, we observed a lower intensity of peptides matching calnexin, PDIA3, and HSPA5 in poorly differentiated cells, which enriched for protein folding in the endoplasmic reticulum and antigen processing, assembly, and loading of class I MHC. Over-representation of collagen metabolism, coagulation cascade, extracellular matrix components, cadherin-binding and cell adhesion pathways also distinguished cell populations. Finally, an independent validation showed FNDC1, A1BG, PDIA3, HSPA5, and calnexin as significant prognostic markers for human breast cancer patients. Thus, through a spatially correlated characterization of spontaneous carcinomas, we described key proteins which can be further validated as potential prognostic biomarkers.

Protein disulfide isomerase A3 activity promotes extracellular accumulation of proteins relevant to basal breast cancer outcomes in human MDA-MB-A231 breast cancer cells

“…For example, proteomic analyses of breast cancers identified PDIA3 to be elevated in the tumors versus normal breast tissue ( 15 , 16 , 76 ) and to be upregulated in invasive ductal breast cancers compared with lobular cancers ( 17 ). PDIA3 has also been identified on the surface of tumor-associated macrophages in triple-negative breast cancer specimens ( 18 ) and has been suggested as a possible new prognostic marker ( 19 ).…”

Research of Prostate Cancer Urinary Diagnostic Biomarkers by Proteomics: The Noteworthy Influence of Inflammation

“…A1BG, another glycoprotein belonging to the immunoglobulin superfamily, was found overexpressed by proteomics in various forms of cancer, such as pancreatic ductal adenocarcinoma [ 41 ], cervical intraepithelial neoplasia [ 42 ] and bladder cancer [ 43 ]. Additionally, A1BG has been found to be associated with tumor heterogeneity and malignancy in an animal model of breast cancer [ 44 ]. Recently, its key role in tumorigenesis has been confirmed, suggesting that A1BG could be a promising target for cancer diagnosis, prognosis, and therapy [ 40 ].…”

“…Moreover, they could discriminate cancer from BPH. Some of these proteins have already been reported in the literature as possible targets of PCa [ 32 , 39 , 46 ], while others are thought to be promising biomarkers for different types of malignant diseases [ 33 , 34 , 41 , 42 , 43 , 44 ]. In the future, once validated and endorsed for clinical practice, these new biomarkers could be proposed as a complementary analysis after a PSA-positive scenario to differentiate between PCa and BPH.…”

Identification of alpha 1B glycoprotein and haptoglobin 1 as probable biomarkers for early diagnosis of leprosy

“…It is known to be highly expressed in the adult and foetal liver however found in minute level in the blood, brain, lung, lymph node etc. Cordeiro et al [24] identi ed it as a strong predictive factor for human breast cancer patients.…”