Computational Biology of BRCA2 in Male Breast Cancer, through Prediction of Probable nsSNPs, and Hit Identification
Sangita Dattatray Shinde1, Dinesh Parshuram Satpute1, Santosh Kumar Behera2
1Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmadabad, Palaj, Gandhinagar 382355, Gujarat, India.
Abstract:
Male breast cancer (MBC) is a relatively rare disease, but emerging data recommend the development of novel therapeutics considering its alarming threats. Compared to female breast cancer (FBC), MBC is reportedly associated with inferior outcomes (poor survival) owing to their late diagnosis and lack of adequate treatment. Treatment typically correlates with FBC, involving surgical removal of the breast tissue along with chemo/hormonal/radiation therapy, the tamoxifen being a standard adjuvant. Considering the distinct immunophenotypic (implying different pathogenesis and progression) differences from FBC, the identification of diagnostics, prognostics, and therapeutics for MBC is highly desirable. In this context, we have analyzed the most deleterious nsSNPs of BRCA2, a human tumor suppressor gene constituting the potential biomarker for tumors including MBC, to predict the structural changes associated with the mutants hampering the normal protein-protein and protein-ligand interactions, resulting in MBC progression. Among 27 nsSNPs confined to 21 rsIDs pertaining to MBC, the 19 nsSNPs constituting 14 rsIDs have been predicted as highly deleterious. We believe that these nsSNPs could serve as potential biomarkers for diagnostic and prognostic purposes and could be the pivotal target for MBC drug discovery. Subsequently, the study highlights the exploration of the key nsSNPs (of BRCA2 associated with the MBC) and its applications toward the identification of therapeutic hit TIP006136 following the homology modeling, virtual screening of 5284 phytochemicals retrieved from the TIPdb (a database of phytochemicals from indigenous plants in Taiwan) database, molecular docking (against native and mutant BRCA2), dynamic simulations (against native and mutant BRCA2), density functional theory (DFT), and molecular electrostatic potential. To the best of our knowledge, this is the first report to use diverse computational modules to investigate the important nsSNPs of BRCA2 related to MBC, implying that TIP006136 could be a potential hit and must be studied further (in vitro and in vivo) to establish its anticancer property and efficacy against MBC.
Insights
Male breast cancer (MBC) research identifies harmful BRCA2 gene mutations. These mutations may serve as biomarkers and drug targets, with TIP006136 showing potential as a novel therapeutic agent.
Area of Science:
- Oncology
- Genetics
- Computational Biology
Background:
- Male breast cancer (MBC) is rare but has poor outcomes due to late diagnosis and limited treatments.
- Distinct immunophenotypic differences from female breast cancer (FBC) necessitate specific diagnostics and therapeutics for MBC.
- The BRCA2 tumor suppressor gene is a potential biomarker for MBC, with mutations influencing disease progression.
Purpose of the Study:
- To analyze deleterious nsSNPs in BRCA2 associated with male breast cancer.
- To predict the structural impact of BRCA2 mutations on protein interactions.
- To identify potential diagnostic, prognostic, and therapeutic targets for MBC.
Main Methods:
- Analysis of 27 nsSNPs in BRCA2 related to MBC.
- Prediction of deleterious nsSNPs using computational tools.
- Homology modeling, virtual screening of phytochemicals, molecular docking, and dynamic simulations.
- Density functional theory (DFT) and molecular electrostatic potential calculations.
Main Results:
- 19 out of 27 nsSNPs (in 14 rsIDs) were predicted as highly deleterious in BRCA2.
- TIP006136 was identified as a potential therapeutic hit through virtual screening and molecular docking against native and mutant BRCA2.
- This study is the first to use diverse computational modules to investigate BRCA2 nsSNPs in MBC.
Conclusions:
- Deleterious BRCA2 nsSNPs can serve as potential biomarkers for MBC diagnosis and prognosis.
- TIP006136 shows promise as a novel therapeutic agent for MBC and requires further in vitro and in vivo validation.
- Targeting specific BRCA2 mutations offers a new avenue for MBC drug discovery.
