Advances in the field of breast cancer (BC) biomarkers discovery facilitate diagnosis and treatment of BC in its pre-invasive state. While the genetic tissue markers are making significant advances in understanding the molecular basis of BC, serum has long been considered a rich source for biomarkers. So, integrated genomic and proteomic strategies play a huge role in the analytical validation of BC biomarkers and represent a true milestone in the areas of diagnostics and personalized medicine. This study included 60 cases (BC), 30 patients with fibroadenoma and 30 healthy women. Histidine-rich glycoprotein RNA (HRG) tissue expression was analyzed through gene expression-based outcome for breast cancer online algorithm (GOBO) bioinformatic analysis. To confirm our informatics analysis, HRG RNA was detected in breast tissue samples by RT-PCR, and HRG serum protein was estimated by ELISA. GOBO analysis revealed increased HRG RNA expression in all subtypes of BC with relative higher expression in basal subtype and grade 2. We confirmed these findings by HRG tissue RNA with 71.7% sensitivity and 93.3% specificity. HRG serum protein was 86.7% sensitivity and 80% specificity. HRG tissue RNA and serum protein could be considered as promising novel markers for prediction of BC prognosis.