Analysis Of Differential Proteins And The Phosphorylation In Different Tissue Subtypes Of Luminal A Breast Cancer

Breast cancer is one of the most frequently occurring malignant cancers worldwide.Invasive ductal carcinoma(IDC)and Invasive lobular carcinoma(ILC)are the two most common histological subtypes of breast cancer.The current treatment of breast cancer is only based on its molecular type,in which IDC and ILC are often treated with the same method.This leads to differences in the prognosis and five-year survival rates of breast cancer patients with different histological subtypes.In this study,we aimed to deeply explore molecular characteristics and the relationship between IDC and ILC subtypes in same molecular subgroup of breast cancer using comprehensive analysis of proteome and phosphoproteome,and provide potential biomarkers for the rapid diagnosis and targeted treatment of breast cancer.At first,Cancer tissues and noncancerous adjacent tissues(NATs)with the luminal A subtype(ER-and PR-positive,HER-2-negative)were obtained from paired IDC and ILC patients respectively.Label-free quantitative proteomics and phosphoproteomics methods were used to detect differentially expressed proteins and the phosphorylation between 10 paired breast cancer and NATs.Then,the data were normalized,visualized and bioinformatic analyzed to explore the difference between IDC and ILC subtypes,including the difference in protein expression levels,the degree of phosphorylation,the protein function and pathway.A total of5,044 high-confidence proteins and 3,808 phosphoproteins were identified from breast cancer tissues.The protein phosphorylation level in ILC tissues was higher than that in IDC tissues.From the quantitative analysis of 1,259 proteins and 560 phosphoproteins with high patient coverage,Histone H1.10,Complement C4-B and Crk-like protein were found to be significantly differentially expressed in the two subtype tissues from the proteomics analysis.Moreover,the differences in protein expression of Septin-2,Septin-9,Heterogeneous nuclear ribonucleoprotein A1 and Kinectin and their phosphorylation clearly distinguished IDC from ILC.In addition,functional enrichment analysis found that differentially expressed proteins and differentially expressed phosphoproteins in ILC subtypes were much closely involved in the PI3K-Akt signaling pathway and the ECM receptor pathway,these functions were associated with the susceptibility of ILC to metastasize.While IDC were primarily related to energy metabolism and the Mitochondrial related pathway,which were associated with higher tumor grade.Meanwhile,Kinase-Substrate Enrichment Analysis(KSEA)revealed that the activation difference of kinases and their substrates between IDC and ILC.Furthermore,the results of KSEA analysis showed that ILC related kinomes were much closely involved in AGC groups,while the kinomes from IDC were primarily significantly activated in the CMGC groups.These results represent that the molecular functions,pathways and kinases of IDC and ILC are different.Conclusions: Our research provided insights into the molecular characterization of IDC and ILC and contributed to discovering novel targets for further drug development and targeted treatment.