| Critical Roles of Molecular Signaling Pathways in Multiple Primary Tumors; A Missing Piece in the Puzzle of Breast Cancer Precision Medicine |
| Paper ID : 1325-IGA |
| Authors |
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Nazila Bahmaie *1, Mojgan Karimi2, Farhad Fallah Shojaei Mardomakdehi3, Ardalan Salehi4, Kamyar Bagheri4, Ali Zehtab Salehi5, Maryam Sadat Jamadi6, Parisa Salmani Khormalou7, Pouya Paidar8, Fatemeh Heydari9, Melika Ansarin2, Samin Rahimi10 1Department of Medical Biology, Faculty of Medicine, Ankara Yildirim Beyazit University (AYBU), 06800 Ankara, Turkey. 2Department of Obstetrics and Gynecology, Faculty of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran. 3Department of Medicine, Faculty of Medicine, Ankara Yildirim Beyazit University (AYBU), Ankara, Turkey (Türkiye). 4Student Research Committee, Department of Medical Laboratory Sciences, Abadan University of Medical Sciences, Abadan, Iran. 5Department of Naturopathy, Faculty of Natural Medicine, Turkish International University of Technofest Institute of Technology (TITU), Turkey (Türkiye) Branch. 6Department of Obstetrics and Gynecology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. 7Department of Midwifery, Faculty of Nursing and Midwifery, Tabriz Medical Sciences Center (TaMS.C.), Islamic Azad University, Tabriz, East Azerbaijan, Iran 8Department of Computer Engineering, Faculty of Engineering, Graduate School of Natural and Applied Sciences, Gazi University, Ankara, Turkey (Türkiye). 9Student Research Committee, Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 10Department of Genetics, Faculty of Natural Sciences, Tabriz University, Tabriz, Iran. |
| Abstract |
| Despite advances in state-of-the-art technologies for diagnosis, prognosis, and clinical management, breast cancer remains a malignancy with high morbidity, and a remarked tumor heterogeneity, among which, germline-driven Multiple Primary Tumors (MPTs) represent distinct molecular entities with critical implications. Frequently, MPTs are misclassified as metastatic lesions by gynecologists or gyneco-oncologists, leading to diagnostic inaccuracies, unoptimized clinical outcomes, as well as recurrence. Approximately 5–10% of breast cancers arise from BRCA1/2-related Hereditary Breast and Ovarian Cancer (HBOC), TP53-mutated Li-Fraumeni syndrome, PTEN-associated Cowden syndrome, STK11-driven Peutz-Jeghers syndrome, and CHEK2 or ATM-mediated susceptibility. These germline alterations converge on central molecular pathways—DNA Damage Response (DDR), Homologous Recombination Repair (HRR), PI3K/AKT/mTOR, and p53 signaling—governing genomic integrity, cell survival, and apoptosis resistance. At the molecular level, BRCA1/2 mutations disrupt HRR and sensitize tumors to synthetic lethality through PARP inhibition, while TP53 alterations deregulate cell-cycle checkpoints, augmenting tumorigenesis under an oxidative stress. Loss of PTEN hyperactivates PI3K/AKT/mTOR signaling, enhancing oncogenic transcriptional programs and metabolic reprogramming. Likewise, CHEK2 and ATM mutations attenuate DNA damage sensing, leading to chromosomal fragility and cooperative oncogenic signaling. These signaling perturbations not only underpin hereditary tumor initiation, but also lessen the responsiveness to targeted therapeutics and immunomodulatory strategies. The evolution of translational and molecular medicine has revolutionized breast cancer precision oncology by bridging germline genomics with functional proteogenomics, transcriptomics, and spatial multi-omics. Integrative molecular profiling enables early identification of mutation carriers, dynamic risk prediction, and therapy optimization based on pathway vulnerabilities. Moreover, the convergence of Next-Generation Sequencing (NGS), liquid biopsy technologies, and artificial intelligence-driven modeling is refining the molecular taxonomy of hereditary breast cancer, enabling the transition from genotypic categorization to pathway-oriented, patient-specific clinical interventions, integrating these insights into translational frameworks to establish a paradigm shift in breast cancer care, from population-based management toward molecularly-guided breast cancer precision oncology. |
| Keywords |
| Breast Cancer, Immunopathophysiology, Metastasis, Molecular Medicine, Precision Medicine, Multiple Primary Tumors. |
| Status: Accepted |
