BRCA1 and MAD2 Are Coexpressed and Are Prognostic Indicators in Tubo-ovarian High-Grade Serous Carcinoma

Byrne, Tara; Nelson, Laura L.; Beirne, James; Sharpe, Daniel; Quinn, Jennifer E.; McCluggage, W. Glenn; Robson, Tracy; Furlong, Fiona

doi:10.1097/igc.0000000000001214

Cited by 10 publications

(6 citation statements)

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“…Moreover, the elevated level of BRCA1 in BRCA was an independent prognostic factor of poor OS. Similarly, further studies have discovered that BRCA1 level was a prognostic biomarker of poor survival in some solid tumors patients, including NSCLC [ 20 , 21 ], ovarian cancer [ 22 , 23 ], hepatocellular carcinoma [ 24 ], uterine serous carcinoma [ 25 ], and nasopharyngeal carcinoma [ 26 , 27 ]. One potential explanation for the observed association between high BRCA1 expression and a poor prognosis in patients with BRCA is that elevated levels of BRCA1 could play a protective role in preventing additional DNA damage in cancer cells [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Establishing the role of BRCA1 in the diagnosis, prognosis and immune infiltrates of breast invasive cancer by bioinformatics analysis and experimental validation

Li,

Zhang

et al. 2024

Aging

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Background: Breast cancer susceptibility gene 1 (BRCA1) is a well-known gene that acts a vital role in suppressing the growth of tumors. Previous studies have primarily focused on the genetic mutations of BRCA1 and its association with hereditary breast invasive carcinoma (BRCA). However, little research has been done to investigate the relationship between BRCA1 and immune infiltrates and prognosis in BRCA. Methods: We obtained the expression profiles and clinical information of patients with BRCA from the Cancer Genome Atlas (TCGA) database. The levels of the BRCA1 gene between BRCA tissues and normal breast tissues were compared through the Wilcoxon rank-sum test. Additionally, we performed WB and RT-qPCR techniques to detect the expression of BRCA1. We conducted functional enrichment analyses. Furthermore, we assessed immune cell infiltration using a single-sample gene set enrichment analysis. The methylation status of the BRCA1 gene was analyzed using the UALCAN and MethSurv databases. The Cox regression analysis and (KM) Kaplan-Meier method were employed to determine the prognostic value of BRCA1. In order to provide a practical tool for predicting the overall survival rates at different time points, we also constructed a nomogram. Results: Our analysis revealed that the expression of BRCA1 was significantly higher in BRCA tissues compared to normal tissues. Furthermore, this increased level of BRCA1 was found to be associated with specific BRCA subtypes, including T2, stage II, ER positive, ect. Importantly, the overexpression of BRCA1 was shown to be a negative prognostic marker for the overall survival rates of BRCA patients. Moreover, low methylation status of the BRCA1 gene was related to a poorer prognosis. Furthermore, our results indicated that high levels of BRCA1 are related to a decrease in level of killer immune cells, such as natural killer (NK) cells, macrophages, CD8 + T cells, and plasma-like dendritic cells (pDCs) within the tumor microenvironment. Conclusions: Our study is the first to provide evidence indicating that the presence of BRCA1 can serve as a reliable marker for both diagnosing and determining the prognosis of BRCA. Moreover, BRCA1 acts as a crucial indicator of the cancer’s potential to infiltrate and invade the immune system, which has important implications for developing targeted therapies in BRCA.

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Section: Discussionmentioning

confidence: 99%

Establishing the role of BRCA1 in the diagnosis, prognosis and immune infiltrates of breast invasive cancer by bioinformatics analysis and experimental validation

Li,

Zhang

et al. 2024

Aging

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“…In recent years our group and others have extensively investigated three new prognostic biomarkers, known as toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and mitotic arrest deficient 2 (MAD2) for the most common and lethal form of ovarian cancer; high grade serous ovarian cancer (HGSOC). All three markers have been shown to be involved in the development of chemoresistance to paclitaxel [3][4][5][6][7][8][9][10], one of the first-line chemotherapies used to treat ovarian cancer and their expression levels have been shown to correlate with poor clinical outcome in patients [6,7,[11][12][13][14][15][16]. TLR4 is an innate immune receptor responsible for the recognition of lipopolysaccharide (LPS) on gram-negative bacteria.…”

Section: Introductionmentioning

confidence: 99%

The role of the MAD2-TLR4-MyD88 axis in paclitaxel resistance in ovarian cancer

et al. 2020

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Despite the use of front-line anticancer drugs such as paclitaxel for ovarian cancer treatment, mortality rates have remained almost unchanged for the past three decades and the majority of patients will develop recurrent chemoresistant disease which remains largely untreatable. Overcoming chemoresistance or preventing its onset in the first instance remains one of the major challenges for ovarian cancer research. In this study, we demonstrate a key link between senescence and inflammation and how this complex network involving the biomarkers MAD2, TLR4 and MyD88 drives paclitaxel resistance in ovarian cancer. This was investigated using siRNA knockdown of MAD2, TLR4 and MyD88 in two ovarian cancer cell lines, A2780 and SKOV-3 cells and overexpression of MyD88 in A2780 cells. Interestingly, siRNA knockdown of MAD2 led to a significant increase in TLR4 gene expression, this was coupled with the development of a highly paclitaxel-resistant cell phenotype. Additionally, siRNA knockdown of MAD2 or TLR4 in the serous ovarian cell model OVCAR-3 resulted in a significant increase in TLR4 or MAD2 expression respectively. Microarray analysis of SKOV-3 cells following knockdown of TLR4 or MAD2 highlighted a number of significantly altered biological processes including EMT, complement, coagulation, proliferation and survival, ECM remodelling, olfactory receptor signalling, ErbB signalling, DNA packaging, Insulin-like growth factor signalling, ion transport and alteration of components of the cytoskeleton. Cross comparison of the microarray data sets identified 7 overlapping genes including MMP13, ACTBL2, AMTN, PLXDC2, LYZL1, CCBE1 and CKS2. These results demonstrate an important link between these biomarkers, which to our knowledge has never before been shown in ovarian cancer. In the future, we hope that triaging patients into alterative treatment groups based on the expression of these three biomarkers or therapeutic targeting of the mechanisms they are involved in will lead to improvements in patient outcome and prevent the development of chemoresistance.

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“…En esta revisión, también en varios artículos muestran la relación de MAD2 y otras proteínas como BRCA1, esta proteína se puede unir a OCT-1 y regula positivamente a MAD2 (R.-H. Wang, Yu, & Deng, 2004b). En cáncer de ovario se demostró que BRCA1 estaba fuertemente correlacionada con MAD2 en tejidos tumorales (Byrne et al, 2018).…”

Section: Discussionunclassified

“…La expresión de la proteína MAD2 está asociada con la metástasis hacia ganglios linfáticos (L. . En 13 artículos obtenidos en esta revisión, reportan un aumento en la expresión de la proteína MAD2, sin embargo, también es importante mencionar que hay tres trabajos en los cuales la expresión de MAD2 disminuye, uno de estos trabajos fue el reportado por McGrogan et al, los cuales demuestran que la proteína MAD2 se correlaciona con el aumento de la proliferación celular y localizándola principalmente en el núcleo pero en menor proporción en los tejidos tumorales, asociando esto con una menor sobrevida libre de recurrencia (McGrogan et al, 2014), mientras que el trabajo publicado por Byrne et al, mencionan que existe una baja intensidad nuclear de la proteína MAD2, la cual se asoció en los carcinomas de ovario seroso de alto grado con una mejor sobrevida específica de la enfermedad y hubo una correlación positiva significativa entre la expresión de BRCA1 y MAD2, (Byrne et al, 2018).…”

Section: La Participación De Mad2 En Diferentes Tipos De Cáncerunclassified

“…oncogén Si (Byrne et al, 2018) IHQ: inmunohistoquímica; WB: Western blot; qRT-PCR: reacción en cadena de la polimerasa en tiempo real; NR: no reportado; MDS: síndrome mielodisplásico; NSCLC: carcinoma de pulmón de células no pequeñas; SCLC: carcinoma de pulmón de células pequeñas; SCC: carcinoma de células escamosas.…”

Section: La Participación De Mad2 En Diferentes Tipos De Cáncerunclassified

BRCA1 and MAD2 Are Coexpressed and Are Prognostic Indicators in Tubo-ovarian High-Grade Serous Carcinoma

Abstract: BRCA1 and MAD2 expressions are strongly correlated in EOC, but BRCA1 expression remains the stronger prognostic factor in HGSC.

Cited by 10 publications

References 44 publications

Establishing the role of BRCA1 in the diagnosis, prognosis and immune infiltrates of breast invasive cancer by bioinformatics analysis and experimental validation

Establishing the role of BRCA1 in the diagnosis, prognosis and immune infiltrates of breast invasive cancer by bioinformatics analysis and experimental validation

The role of the MAD2-TLR4-MyD88 axis in paclitaxel resistance in ovarian cancer

La proteína MAD2 como posible biomarcador diagnóstico en cáncer

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