Pathological and Molecular Significance of HER2/neu Overexpression in Familial Breast Cancer Among Egyptian Women: A Comprehensive Study on Diagnostic and Prognostic Implications

Breast cancer, the most prevalent malignancy among women worldwide, exhibits a high incidence in Egypt, particularly in familial cases. This study investigates the pathological and molecular significance of ERBB2 (HER2/neu) overexpression in 44 Egyptian breast cancer patients, alongside 35 daughters and 24 sisters, recruited from Mansoura University Hospital (2013–2015). Serum biochemical markers, including alanine aminotransferase (ALT; 6.6 ± 0.55 U/mL), lactate dehydrogenase (LDH; 16.8 ± 1.4 U/mL), and cancer antigen 15-3 (CA15-3; 160 ± 13.33 U/mL), were significantly elevated, with reduced aspartate aminotransferase (AST; 2.6 ± 0.22 U/mL) compared to controls (P ≤ 0.05). Histopathological analysis revealed invasive ductal carcinoma with stromal desmoplasia, while immunohistochemical staining confirmed ERBB2 overexpression in >10% of tumor cells, correlating with aggressive tumor phenotypes. Molecularly, ERBB2 amplification was detected in 72% of patients via nested PCR, with daughters (17%) and sisters (20%) showing elevated frequencies. Notably, ERBB2 expression was higher in unmarried and pre-menopausal patients and those with diabetes or hypertension, suggesting hormonal and metabolic influences on ERBB2-driven oncogenesis via PI3K/AKT/mTOR and MAPK/ERK pathways. Additionally, ERBB2 may upregulate PD-L1, promoting immune evasion. These findings highlight ERBB2 as a critical diagnostic and prognostic biomarker in familial breast cancer, emphasizing the need for genetic screening and personalized therapies, such as HER2-targeted treatments combined with immune checkpoint inhibitors, to improve outcomes in high-risk Egyptian populations.