Department Of Human Genetics And Molecular Medicine
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Item Brain metastasis in breast cancer: focus on genes and signaling pathways involved, blood�brain barrier and treatment strategies(Springer Science and Business Media Deutschland GmbH, 2023-03-10T00:00:00) Chhichholiya, Yogita; Ruthuparna, Malayil; Velagaleti, Harini; Munshi, AnjanaBreast cancer�(BC) is one of the most prevalent types of cancer in women. Despite advancement in early detection and efficient treatment, recurrence and metastasis continue to pose a significant risk to the life of BC patients. Brain metastasis�(BM) reported in 17�20 percent of BC patients is considered as a major cause of mortality and morbidity in these patients. BM includes various steps from primary breast tumor to secondary tumor formation. Various steps involved are primary tumor formation, angiogenesis, invasion, extravasation, and brain colonization. Genes involved in different pathways have been reported to be associated with BC cells metastasizing to the brain. ADAM8 gene, EN1 transcription factor, WNT, and VEGF signaling pathway have been associated with primary breast tumor; MMP1, COX2, XCR4, PI3k/Akt, ERK and MAPK pathways in angiogenesis; Noth, CD44, Zo-1, CEMIP, S0X2 and OLIG2 are involved in invasion, extravasation and colonization, respectively. In addition, the blood�brain barrier is also a key factor in BM. Dysregulation of cell junctions, tumor microenvironment and loss of function of microglia leads to BBB disruption ultimately resulting in BM. Various therapeutic strategies are currently used to control the BM in BC. Oncolytic virus therapy, immune checkpoint inhibitors, mTOR-PI3k inhibitors and immunotherapy have been developed to target various genes involved in BM in BC. In addition, RNA interference (RNAi) and CRISPR/Cas9 are novel interventions in the field of BCBM where research to validate these and clinical trials are being carried out. Gaining a better knowledge of metastasis biology is critical for establishing better treatment methods and attaining long-term therapeutic efficacies against BC. The current review has been compiled with an aim to evaluate the role of various genes and signaling pathways involved in multiple steps of BM in BC. The therapeutic strategies being used currently and the novel ones being explored to control BM in BC have also been discussed at length. � 2023, The Author(s), under exclusive licence to Federaci�n de Sociedades Espa�olas de Oncolog�a (FESEO).Item Differential molecular mechanistic behavior of HDACs in cancer progression(Springer, 2022-08-16T00:00:00) Singh, Tashvinder; Kaur, Prabhsimran; Singh, Paramdeep; Singh, Sandeep; Munshi, AnjanaGenetic aberration including mutation in oncogenes and tumor suppressor genes transforms normal cells into tumor cells. Epigenetic modifications work concertedly with genetic factors in controlling cancer development. Histone acetyltransferases (HATs), histone deacetylases (HDACs), DNA methyltransferases (DNMTs) and chromatin structure modifier are prospective epigenetic regulators. Specifically, HDACs are histone modifiers regulating the expression of genes implicated in cell survival, growth, apoptosis, and metabolism. The majority of HDACs are highly upregulated in cancer, whereas some have a varied function and expression in cancer progression. Distinct HDACs have a positive and negative role in controlling cancer progression. HDACs are also significantly involved in tumor cells acquiring metastatic and angiogenic potential in order to withstand the anti-tumor microenvironment. HDACs� role in modulating metabolic genes has also been associated with tumor development and survival. This review highlights and discusses the molecular mechanisms of HDACs by which they regulate cell survival, apoptosis, metastasis, invasion, stemness potential, angiogenesis, and epithelial to mesenchymal transitions (EMT) in tumor cells. HDACs are the potential target for anti-cancer drug development and various inhibitors have been developed and FDA approved for a variety of cancers. The primary HDAC inhibitors with proven anti-cancer efficacy have also been highlighted in this review. � 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item Prognostic significance of CHAC1 expression in breast cancer(Springer Science and Business Media B.V., 2022-06-21T00:00:00) Mehta, Vikrant; Meena, Jaipal; Kasana, Harit; Munshi, Anjana; Chander, HarishBackground: An emerging component of Unfolded Protein Response (UPR) pathway, cation transport regulator homolog 1 (CHAC1) has been conferred with the ability to degrade intracellular glutathione and induce apoptosis, however, many reports have suggested a role of CHAC1 in cancer progression. Our study aimed to investigate CHAC1 mRNA levels in large breast cancer datasets using online tools and both mRNA and protein levels in different breast cancer cell lines. Methods and results: Analysis of clinical information from various online tools (UALCAN, GEPIA2, TIMER2, GENT2, UCSCXena, bcGenExMiner 4.8, Km Plotter, and Enrichr) was done to elucidate the CHAC1 mRNA expression in large breast cancer patient dataset and its correlation with disease progression. Later, in vitro techniques were employed to explore the mRNA and protein expression of CHAC1 in breast cancer cell lines. Evidence from bioinformatics analysis as well as in vitro studies indicated a high overall expression of CHAC1 in breast tumor samples and had a significant impact on the prognosis and survival of patients. Enhanced CHAC1 levels in the aggressive breast tumor subtypes such as Human Epidermal growth factor receptor 2 (HER2) and Triple Negative Breast Cancer (TNBC) were evident. Our findings hint toward the possible role of CHAC1 in facilitating the aggressiveness of breast cancer and the disease outcome. Conclusion: In summary, CHAC1 is constantly up-regulated in breast cancer leading to a poor prognosis. CHAC1, therefore, could be a promising candidate in the analysis of breast cancer diagnosis and prognosis. � 2022, The Author(s), under exclusive licence to Springer Nature B.V.Item The genomic architecture of metastasis in breast cancer: focus on mechanistic aspects, signalling pathways and therapeutic strategies(Springer, 2021-07-16T00:00:00) Chhichholiya, Yogita; Suman, Prabhat; Singh, Sandeep; Munshi, AnjanaBreast cancer is a multifactorial, heterogeneous disease and the second most frequent cancer amongst women worldwide. Metastasis is one of the most leading causes of death in these patients. Early-stage or locally advanced breast cancer is limited to the breast or nearby lymph nodes. When breast cancer spreads to farther tissues/organs from its original site, it is referred to as metastatic or stage IV breast cancer. Normal breast development is regulated by specific genes and signalling pathways controlling cell proliferation, cell death, cell differentiation and cell motility. Dysregulation of genes involved in various signalling pathways not only leads to the formation of primary tumour but also to the metastasis as well. The metastatic cascade is represented by a multi-step process including invasion of the local tumour cell followed by its entry into the vasculature, exit of malignant cells from the circulation and ultimately their colonization at the distant sites. These stages are referred to as formation of primary tumour, angiogenesis, invasion, intravasation and extravasation, respectively. The major sites of metastasis of breast cancer are the lymph nodes, bone, brain and lung. Only about 28% five-year survival rate has been reported for stage IV breast cancer. Metastasis is a serious concern for breast cancer and therefore, various therapeutic strategies such as tyrosine kinase inhibitors have been developed to target specific dysregulated genes and various signalling pathways involved in different steps of metastasis. In addition, other therapies like hyperbaric oxygen therapy, RNA interference and CRISPR/Cas9 are also being explored as novel strategies to cure the stage IV/metastatic breast cancer. Therefore, the current review has been compiled with an aim to evaluate the genetic basis of stage IV breast cancer with a focus on the molecular mechanisms. In addition, the therapeutic strategies targeting these dysregulated genes involved in various signalling pathways have also been discussed. Genome editing technologies that can target specific genes in the affected areas by making knock-in and knock-out alternations and thereby bring significant treatment outcomes in breast cancer have also been summarized. � 2021, Springer Science+Business Media, LLC, part of Springer Nature.