Abstract:
Breast cancer is the second leading cause of cancer-related mortalities among females worldwide. It is genetically heterogeneous disease caused by various environmental and genetic factors. Abnormal expression of various genes/proteins such as chemokine C-X-C motif (receptor 4), insulin like growth factor-1 receptor and estrogen growth factor receptor and their associated biological regulatory networks are linked with breast cancer. In this study, the crosstalk interaction between these genes/proteins and their associated signaling networks involved in breast cancer metastasis were studied by using both in-silico (qualitative modeling, hybrid PetriNet modeling, pharmacophore modeling and virtual screening) and in-vitro approaches (genotyping, cell viability assay, quantitative real time polymerase chain reaction and western blotting). The association of rs1801157 single nucleotide polymorphism, located within the C-X-C motif ligand 12 (CXCL12) gene, with the development of breast cancer was assessed. The results of genotyping showed the significant prevalence of genotype GG (p<0.05) with a number of variables including patient’s age, weight, lymph nodes status, hormonal imbalances (ER and PR) and family history using multivariable logistic regression among Pakistani breast cancer patients as compared to AA genotype. Our in-silico results suggested that rs1801157 single nucleotide polymorphism identified in CXCL12 gene has crosstalk link with insulin like growth factor-1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR) signaling and is an important factor in predicting the outcomes of breast cancer therapy, which can also result in multidrug resistance due to induction of insulin like growth factor-1.
xxviFurthermore, to address the problem of multidrug resistance in breast cancer cells, an effective and non-toxic biologically synthesized silver nanoparticles (drug delivery vehicles) were conjugated with anti-cancer inhibitors such as fulvestrant and gefitinib to inhibit the activity of multiple genes and proteins such as estrogen growth factor receptor, C-X-C motif (ligand 12), phosphoinositide 3 kinase, insulin receptor substrate-1, insulin like growth factor-1 receptor, PDZ domain containing 1 and estrogen receptor-α to treat breast cancer cells. In conclusion, for a multifactorial disease like breast cancer, more than one therapeutic targets should be inhibited with an effective drug delivery vehicle to induce apoptosis in cancer cells.
