PI3K/Akt/mTOR pathway expression profiling reveals age- and subtype-specific molecular heterogeneity in the Nigerian breast cancer landscape

Introduction: Breast cancer (BC) is a molecularly heterogeneous disease, and treatment outcomes are strongly shaped by subtype-specific signalling dependencies. However, there is paucity of data on the molecular pathways that drive breast cancer in African women. This study aimed to identify PI3K/AkT/mTOR pathway alterations in distinct BC age groups and subtypes to provide insights on personalized and more effective BC therapies. Methods: A total of 102 formalin-fixed paraffin-embedded malignant breast tissues from Nigerian women were collected from Abuja, Nigeria. The Expression of PI3K/AkT/mTOR pathway proteins was quantified using immunohistochemistry across age groups: Young-adults (YA: 20-39 years), Middle-Aged (MA: 40-59 years) and Older-Adults (OA: 60-79 years), also among BC subtypes: Estrogen Receptor-positive (ER+), Estrogen Receptor-positive/Progesterone Receptor-Positive (ER+/PR+), Human Epidermal Receptor 2-positive (HER2-positive), and triple-negative breast cancers (TNBC) tumors. Expression quantification was performed using IMAGE-J-WIN 64 and Statistical analysis was carried out using Graphpad Prism. Results: This study reveals profound molecular heterogeneity in Nigerian breast cancer, defined by distinct age- and subtype-specific signaling profiles. Proliferative markers PI3K and AKT peak in ER+, ER+/PR+, and TNBC subtypes, but significantly suppressed in HER2-positive tumors. A critical age-dependent transition was identified: young adults exhibit peak AKT, MDM2, and hTERT expression, whereas middle-aged patients show peak mTOR levels, and older-adult cohorts shift toward MAPK and PDK1 dominance. Genomic stability markers, such as BRCA1 and BRCA2, alongside luminal regulators like GATA3, decline progressively with both advancing age and tumor aggressiveness, reaching their lowest levels in TNBC. Conversely, the apoptotic and inflammatory landscapes evolve significantly across age-groups; executioner caspase activity is highest in younger patients, while older cohorts and TNBC subtypes demonstrate a marked enrichment of anti-apoptotic BCL2, pro-apoptotic BAX, and the inflammatory mediator NF-κB. Conclusion: Nigerian breast cancer exhibits profound molecular heterogeneity governed by both subtype and age. ER+ and ER+/PR+ tumors maintain DNA repair and apoptotic competence despite high proliferative signaling, HER2+ and TNBC subtypes display genomic instability and apoptotic evasion. Critically, the study identifies an evolving biological "engine, " transitioning from AKT/hTERT-driven growth in young patients to a MAPK/NF-κB-dominant inflammatory profile and genomic collapse in older cohorts, necessitating age-tailored precision oncology and targeted inhibitors.