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Tumor Discovery Pyroptosis-related genes in breast cancer progression

women over the previous 5 years, making it the world’s most pro-Interleukin-18 are segmented by activated caspase-1,
common malignancy. Although BC can affect women of releasing these cytokines outside the cell to further
any age after puberty, its incidence is higher in older age. mediate pyroptosis. The non-classic caspase-4/5/11
3
Unfortunately, the incidence of BC has been increasing directly binds with lipopolysaccharide; then, through
annually in many countries and regions. In response to this, dimerization-induced autoproteolysis, these caspases are
4
the World Health Organization’s Global BC Initiative aims activated, which, in turn, leads to pyroptosis. In addition
to reduce global BC mortality by 2.5% annually between to the above-mentioned pyroptosis pathways, there are
2020 and 2040, with the goal of preventing 2,500,000 BC caspase-3/8-mediated pathways and serine protease-
deaths worldwide. If successful, this effort could prevent mediated pathways (Figure 1). At present, pyroptosis has
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25% of BC deaths by 2030 and 40% by 2040 among women been widely studied as a new means of treating cancer,
under 70. Achieving these objectives will require three key which suggests a new foundation for the prevention and
components: rapid diagnosis, thorough BC care, and health treatment of this disease.
promotion for early detection. However, there is an urgent
need for new tools for early diagnosis and prognosis to However, although pyroptosis is involved in the
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achieve these goals. 3 physiological and pathological processes of BC, its role
in BC has not been extensively studied. In this study, we
Studies on pyroptosis have revealed its significant aimed to investigate the roles of pyroptosis in patients
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role in tumor mechanisms. This understanding helps with BC, which may provide a new tool for early diagnosis
provide new ideas for a wide range of malignant cancers, and prognosis in BC. A method of BC prognosis was
including stomach, lung, and BCs. Pyroptosis, also established based on the degree of pyroptosis. First,
referred to as inflammatory pyroptosis, is considered the BC clinical data and the RNA sequencing were
to be a new kind of programmed cell death related acquired from The Cancer Genome Atlas (TCGA)
to gasdermin pores in the plasma membrane. The
6,7
main characteristics of pyroptosis include unique DNA database. Thirty-nine differential genes were obtained
damage, preservation of nuclear integrity, and the rapid by analyzing the differences in cell-death-related genes.
formation of membrane pores with diameters of 10 – After identifying these different genes by means of
15 nm. These pores lead to the gradual loss of cell ions, protein-protein interaction (PPI) and correlation network
causing cell edema, membrane rupture, and the release analyses, a pyroptosis-related gene prognostic model was
of cellular contents and pro-inflammatory mediators. developed and validated. Finally, Gene ontology (GO),
The process is faster and more intense than apoptosis. Kyoto Encyclopedia of Genes and Genomes (KEGG),
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The main executor of pyroptosis is the gasdermin family, and ssGESA were utilized for functional and immunity
including pejvakin (PJVK or DFNB59) and gasdermin-A analysis (Figure 2).
to gasdermin-E. Inflammasomes, which are composed
of oligomerized pattern recognition receptors (PRRs), 2. Methods
procaspase-1, and the adaptor apoptosis-associated 2.1. Data acquisition
speck-like protein (ASC), play a crucial role in this In this study, the RNA sequencing and clinical documents of
process. In addition, ASC contains an N-terminal pyrin
domain and C-terminal caspase recruitment domain BC were obtained from the TCGA website on August 19, 2021.
(CARD) to recruit NOD-like proteins (NLRs), or, if it There were 112 cases in the normal group and 1106 cases in
lacks the absent in melanoma 2-like receptor family the tumor group (https://portal.gdc.cancer.gov/).
and pro-caspase-1 for assembling the inflammasome, it 2.2. Identification of differentially expressed
activates caspase-1. According to the detection of damage pyroptosis-related genes
signals by the cytoplasmic protein sensor, the mechanism
of pyroptosis can be classified into two main pathways, Fifty-two pyroptosis-related genes were extracted to
the classic caspase-1-dependent pathway and the non- determine the differential genes between the normal group
classic non-caspase-1-dependent pathway. In the classic and the tumor group. The “limma” package within the R
caspase-1-dependent pathway, inflammasomes cleave package was used to distinguish the differential genes with
the executive protein GSDMD by activating caspase-1, P < 0.05, which was marked as *P < 0.05, **P < 0.01, and
and the resulting GSDMD-N punches holes in the cell ***P < 0.001, respectively (Figure 3A). Utilizing the search
membrane to form non-selective membrane channels, tool for the retrieval of interacting genes, the protein
disrupting the ion balance across the cell membrane. interaction network was obtained (Figure 3B). In addition,
This disruption leads to cell swelling and lysis, and a correlation network was obtained using the “igraph” and
eventually, cell death. Moreover, pro-interleukin-1β and “reshape2” packets (Figure 3C).

Volume 3 Issue 3 (2024) 2 doi: 10.36922/td.3469