Integrative transcriptome analysis of triple negative breast cancer profiles for identification of druggable targets.

As triple negative breast cancer (TNBC) lacks a specific target, exploration of abnormally expressed genes during the progression of TNBC is important for a better understanding of tumorigenesis and to find a specific target. We intended to figure out genes associated with TNBC, which can provide unique insights into gene dysregulation in TNBC while also pointing to new possible therapeutic targets for TNBC. A meta-analysis of multiple TNBC mRNA profiles was performed to identify consistently differentially expressed genes (CDGs). The pathways involved in modulating these genes were analyzed by MsigDB, and the interaction map was constructed. These CDGs were evaluated for their expression in cell lines, and drugs that could modulate the expression of CDGs were obtained using the connectivity map. CDGs were docked with doxorubicin and anethole, which is a phytocompound. The expression of selected CDGs was analyzed in MDA-MB-231 cells after treatment with doxorubicin and anethole. We found 45 CDGs, out of which 36 were upregulated and 9 were downregulated. MDA-MB-231 cell line was found to have high expression of CDGs, and drug that could modulate the expression of CDGs was doxorubicin. Docking results revealed that anethole and doxorubicin had good interaction with the CDGs especially with the genes AURKA, CDC6, DEPDC1, KIF23, KPNA2, MELK, CTNNB1, FLI1 and E2F1. Gene expression studies of the selected CDGs showed that the synergistic effect of anethole and doxorubicin effectively downregulated the expression. The CDGs identified from multiple cohorts have clinical significance and may be effectively exploited in the targeted therapy for TNBC.Communicated by Ramaswamy H. Sarma.

Reverse Screening Bioinformatics Approach to Identify Potential Anti Breast Cancer Targets Using Thymoquinone from Neutraceuticals Black Cumin Oil.

BACKGROUND: Functional foods, neutraceuticals and natural antioxidants have established their potential roles in the protection of human health and diseases. Thymoquinone (TQ), the main bioactive component of Nigella sativa seeds (black cumin seeds), a plant derived neutraceutical was used by ancient Egyptians because of their ability to cure a variety of health conditions and used as a dietary food supplement. Owing to its multi targeting nature, TQ interferes with a wide range of tumorigenic processes and counteracts carcinogenesis, malignant growth, invasion, migration, and angiogenesis. Additionally, TQ can specifically sensitize tumor cells towards conventional cancer treatments (e.g., radiotherapy, chemotherapy, and immunotherapy) and simultaneously minimize therapy-associated toxic effects in normal cells besides being cost effective and safe. TQ was found to play a protective role when given along with chemotherapeutic agents to normal cells. METHODS: In the present study, reverse in silico docking approach was used to search for potential molecular targets for cancer therapy. Various metastatic and apoptotic targets were docked with the target ligand. TQ was also tested for its anticancer activities for its ability to cause cell death, arrest cell cycle and ability to inhibit PARP gene expression. RESULTS: In silico docking studies showed that TQ effectively docked metastatic targets MMPs and other apoptotic and cell proliferation targets EGFR. They were able to bring about cell death mediated by apoptosis, cell cycle arrest in the late apoptotic stage and induce DNA damage too. TQ effectively down regulated PARP gene expression which can lead to enhanced cancer cell death. CONCLUSION: Thymoquinone a neutraceutical can be employed as a new therapeutic agent to target triple negative breast cancer which is otherwise difficult to treat as there are no receptors on them. Can be employed along with standard chemotherapeutic drugs to treat breast cancer as a combinatorial therapy.

Cytotoxic activity of the methanolic extract of leaves and rhizomes of Curcuma amada Roxb against breast cancer cell lines.

OBJECTIVES: To evaluate the methanol extract of both the leaves and the rhizomes of Curcuma amada (C. amada) for their cytotoxic activity against breast cancer cell lines MCF-7 and MDA MB 231. METHODS: Viability and cytotoxicity induced by the extracts were assessed using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, sulforhodamine B, and lactate dehydrogenase release assays. Various staining techniques such as acridine orange/ethidium bromide, Giemsa, ethidium bromide, propidium iodide, and Hoechst 33342 staining were employed to study the mechanism of cell death induced by the extract. RESULTS: The results indicated that the methanol extract of both the leaves and the rhizomes of C. amada exhibited strong cytotoxicity towards breast cancer cell lines MCF-7 and MDA MB 231. The extract also showed less cytotoxicity towards non-cancerous breast cell line HBL-100. The results of staining revealed that the extracts induced cell death in cancer cells which are mediated through apoptotic pathway. CONCLUSIONS: The results indicated that the methanol extract of leaves and rhizomes of C. amada possess anticancer and cytotoxic activity.