Computational Biology of BRCA2 in Male Breast Cancer, through Prediction of Probable nsSNPs, and Hit Identification

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.