Department Of Human Genetics And Molecular Medicine

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    High levels of unfolded protein response component CHAC1 associates with cancer progression signatures in malignant breast cancer tissues
    (Springer Science and Business Media Deutschland GmbH, 2022-08-05T00:00:00) Mehta, Vikrant; Suman, Prabhat; Chander, Harish
    Purpose: The aberrant mRNA expression of a UPR component Cation transport regulator homolog 1 (CHAC1) has been reported to be associated with poor survival in breast and ovarian cancer patients, however, the expression of CHAC1 at protein levels in malignant breast tissues is underreported. The following study aimed at analyzing CHAC1 protein expression in malignant breast cancer tissues. Methods: Evaluation of CHAC1 expression in invasive ductal carcinomas (IDCs) with known ER, PR, and HER2 status was carried out using immunohistochemistry (IHC) with CHAC1 specific antibody. The Human breast cancer tissue microarray (TMA, cat# BR1503f, US Biomax, Inc., Rockville, MD) was used to determine CHAC1 expression. The analysis of CHAC1 IHC was done to determine its expression in terms of molecular subtypes of breast cancer, lymph node status, and proliferation index using Qu-Path software. Survival analysis was studied with a Kaplan�Meier plotter. Results: Immunohistochemical analysis of CHAC1 in breast cancer tissues showed significant up-regulation of CHAC1 as compared to the adjacent normal and benign tissues. Interestingly, CHAC1 immunostaining revealed high expression in tumor tissues with high proliferation and positive lymph node metastasis suggesting that CHAC1 might have an important role to play in breast cancer progression. Furthermore, high CHAC1 expression is associated with poor overall survival (OS) in large breast cancer patient cohorts. Conclusion: As a higher expression of CHAC1 was observed in tissue cores with high Ki67 index and positive lymph node metastasis it may be concluded that enhanced CHAC1 expression correlates with proliferation and metastasis. The further analysis of breast cancer patients� survival data through KM plot indicated that high CHAC1 expression is associated with a bad prognosis hinting that CHAC1 may have a possible prognostic significance in breast cancer. � 2022, The Author(s), under exclusive licence to Federaci�n de Sociedades Espa�olas de Oncolog�a (FESEO).
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    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, Harish
    Background: 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.
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    Expression of CHAC1 in Breast Cancer Cell Lines
    (Central University of Punjab, 2018) Sharma, Ankita; Chander, Harish
    Breast cancer is the commonly diagnosed type of cancer in women and is a major cause of deaths in women. Unfolded Protein Response Pathway is a signaling pathway induced in endoplasmic reticulum as a stress response. This type of stress signaling has been seen to be activated in many tumors including breast cancer. CHAC1 (Glutathione specific gamma- glutamylcyclotransferas-1) is a member of UPR Pathway. It was first discovered as a component of the ATF4 arm of the UPR pathway in a co-regulated group of genes. CHAC1 expression is necessary and sufficient to induce well-characterized markers of apoptosis. CHAC1 is involved in the inhibition of TNFRS6B via ATF4-ATF3-CHOP signaling. This sensitizes cells to commit to apoptosis following induction of UPR pathway. Although CHAC1 is a pro-apoptotic component of the UPR pathway, its expression in breast cancers have been noted to be remarkably high. To study the role of CHAC1 in breast cancer, we analyzed the expression of CHAC1 at mRNA level by using Real-Time PCR and further checked its' protein expression by Western-blotting. Its expression was found to be higher in ER positive cells as compared to the ER negative cells. Further investigations were performed by transfecting MDA-MB-231 cells by ER-alpha, which confirmed that presence of ER-alpha leads to the higher expression cHAC1 in breast cancer cells.