Identification of a NACC1-Regulated Gene Signature Implicated in the Features of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC), characterized by a deficiency in estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor2 (HER2), is among the most lethal subtypes of breast cancer (BC). Nevertheless, the molecular determinants that contribute to its malignant phenotypes such as tumor heterogeneity and therapy resistance, remain elusive. In this study, we sought to identify the stemness-associated genes involved in TNBC progression. Using bioinformatics approaches, we found 55 up- and 9 downregulated genes in TNBC. Out of the 55 upregulated genes, a 5 gene-signature (CDK1, EZH2, CCNB1, CCNA2, and AURKA) involved in cell regeneration was positively correlated with the status of tumor hypoxia and clustered with stemness-associated genes, as recognized by Parametric Gene Set Enrichment Analysis (PGSEA). Enhanced infiltration of immunosuppressive cells was also positively correlated with the expression of these five genes. Moreover, our experiments showed that depletion of the transcriptional co-factor nucleus accumbens-associated protein 1 (NAC1), which is highly expressed in TNBC, reduced the expression of these genes. Thus, the five genes signature identified by this study warrants further exploration as a potential new biomarker of TNBC heterogeneity/stemness characterized by high hypoxia, stemness enrichment, and immune-suppressive tumor microenvironment

Unveiling the dark side of glucose-regulated protein 78 (GRP78) in cancers and other human pathology: a systematic review

Abstract Glucose-Regulated Protein 78 (GRP78) is a chaperone protein that is predominantly expressed in the lumen of the endoplasmic reticulum. GRP78 plays a crucial role in protein folding by assisting in the assembly of misfolded proteins. Under cellular stress conditions, GRP78 can translocate to the cell surface (csGRP78) were it interacts with different ligands to initiate various intracellular pathways. The expression of csGRP78 has been associated with tumor initiation and progression of multiple cancer types. This review provides a comprehensive analysis of the existing evidence on the roles of GRP78 in various types of cancer and other human pathology. Additionally, the review discusses the current understanding of the mechanisms underlying GRP78's involvement in tumorigenesis and cancer advancement. Furthermore, we highlight recent innovative approaches employed in downregulating GRP78 expression in cancers as a potential therapeutic target