Proteomics-Based Identification of Dysregulated Proteins and Biomarker Discovery in Invasive Ductal Carcinoma, the Most Common Breast Cancer Subtype

Abstract

Invasive ductal carcinoma (IDC) is the most common histological subtype of malignant breast cancer (BC), and accounts for 70–80% of all invasive BCs. IDC demonstrates great heterogeneity in clinical and histopathological characteristics, prognoses, treatment strategies, gene expressions, and proteomic profiles. Significant proteomic determinants of the progression from intraductal pre-invasive malignant lesions of the breast, which characterize a ductal carcinoma in situ (DCIS), to IDC, are still poorly identified, validated, and clinically applied. In the era of “6P” medicine, it remains a great challenge to determine which patients should be over-treated versus which need to be actively monitored without aggressive treatment. The major difficulties for designating DCIS to IDC progression may be solved by understanding the integrated genomic, transcriptomic, and proteomic bases of invasion. In this review, we showed that multiple proteomics-based techniques, such as LC–MS/MS, MALDI-ToF MS, SELDI-ToF-MS, MALDI-ToF/ToF MS, MALDI-MSI or MasSpec Pen, applied to in-tissue, off-tissue, BC cell lines and liquid biopsies, improve the diagnosis of IDC, as well as its prognosis and treatment monitoring. Classic proteomics strategies that allow the identification of dysregulated protein expressions, biological processes, and interrelated pathway analyses based on aberrant protein–protein interaction (PPI) networks have been improved to perform non-invasive/minimally invasive biomarker detection of early-stage IDC. Thus, in modern surgical oncology, highly sensitive, rapid, and accurate MS-based detection has been coupled with “proteome point sampling” methods that allow for proteomic profiling by in vivo “proteome point characterization”, or by minimal tissue removal, for ex vivo accurate differentiation and delimitation of IDC. For the detection of low-molecular-weight proteins and protein fragments in bodily fluids, LC–MS/MS and MALDI-MS techniques may be coupled to enrich and capture methods which allow for the identification of early-stage IDC protein biomarkers that were previously invisible for MS-based techniques. Moreover, the detection and characterization of protein isoforms, including posttranslational modifications of proteins (PTMs), is also essential to emphasize specific molecular mechanisms, and to assure the early-stage detection of IDC of the breast.

Recent Contributions of Mass Spectrometry-Based “Omics” in the Studies of Breast Cancer

“…Estimates of the sensitivity and specificity of this protein panel using an independent breast tumor proteome data set supported the potential of these proteins as biomarkers for stratifying BC subtypes into luminal, HER2, and TNBC . Likewise, invasive ductal carcinoma, a most frequent histological presentation of BC, is increasingly characterized and identified based on proteomic profiles …”

“…28 Likewise, invasive ductal carcinoma, a most frequent histological presentation of BC, is increasingly characterized and identified based on proteomic profiles. 53 A correlation was derived with IHC categories to proteomes reported in data sets for obtaining a link through proteomics with IHC expression of these markers. Integration was also done of proteome data to validate independent markers of prognosis in four proteome data sets.…”

“…Neagu (2023) reviewed proteomics based on dysregulated proteins in DCIs (ductal carcinoma in situ), a highly occurring histologic presentation. Reviews in this context approach to understand the pathophysiological markers of this incredibly heterogeneous disease . Revelations of BC through proteomic applications are reviewed by Neagu (2021) .…”

“…Reviews in this context approach to understand the pathophysiological markers of this incredibly heterogeneous disease. 53 Revelations of BC through proteomic applications are reviewed by Neagu (2021). 13 Drug therapy-resistant biomarkers are reviewed by Yang (2020).…”

“…Numerous studies that attempted to derive various biomarkers are integrated under different sections of the review. Such publications of biomarkers are discussed which include proteome markers of drug resistance, identifiers of radiotherapy response, metabolic tissue markers for disease for screening and diagnosis, phosphoproteome-based signaling cascade identifiers for an aggressive disease type, biomarkers from archival samples for prediction of overall survival, protein markers of benign mammogram findings, androgen receptors as diagnosis markers, serum metabolomic fingerprinting, novel volatile organic compounds (VOCs) in urine as biomarkers for diagnosis, , overall survival predictors and immune phenotype related biomarkers, lymph node markers to flag metastasis, interactive marginal tissue biomarkers regulating neoplasm, markers for diagnosis through rapid lipid profiling, endocrine therapy resistance identifiers like aromatase inhibitor resistance (promoted by a RNA DIO3OS), glycan-profile-based markers, specific progression markers, plasma proteome-based prognostic markers, epithelial-mesenchymal transition (EMT) markers, extracellular matrix (ECM) markers like cytokeratin-19, E-cadherin gene expression as metastasis indicators, predictive biomarkers for immunotherapy, retrospective investigation panels based on drug responses and metastasis, tumor microenvironment related target markers implicated in evasion of immunity and drug evasion strategies, extracellular vesicle-based biomarkers for expansion of liquid biopsies, drug resistance linked to tissue environment like hypoxia in BC tumors, proteome signatures of drug resistance in BC cells, biomarkers of invasive ductal carcinoma as novel phenotypes and better classifiers of disease, heterogeneity panel identifiers in subtypes, additional markers for disease subtype conforming to conventional subtypes, glycan biomarkers, and progression identifiers through the salivary proteome . Cell lines are probed for drug-resistant proteomes, and potential drug responsive proteins are identified .…”