Tumor Suppressor In Breast Cancer Research Articles

One-Pot Multicomponent Synthesis of Novel Pyrazole-Linked Thiazolyl-Pyrazolines: Molecular Docking and Cytotoxicity Assessment on Breast and Lung Cancer Cell-lines

Cancer remains a foremost cause of mortality globally, with approximately 20 million new cases and nearly 10 million deaths reported in 2022. Lung and breast cancers are particularly prevalent and deadly, underscoring the critical need for novel therapeutic strategies. This study utilized a one-pot, multicomponent reaction (MCR) approach to synthesize a novel series of pyrazole-linked thiazolyl-pyrazolines. The optimal reaction conditions were determined by systematically varying bases, temperatures, reaction times, and solvents. The best yield was achieved using NaOH as the base at 50°C with 2 hours of stirring in ethanol. The synthesized compounds underwent thorough characterization through IR, mass spectrometry, and NMR spectroscopy. Molecular docking studies indicated strong binding affinities to the ErbB4 kinase, suggesting potential utility as kinase inhibitors. Compounds 5E, 5F, and 5G exhibited significant cytotoxicity against breast cancer cell lines, with IC50 values ranging from 15.79±1.272 to 28.38±1.520 µM. Meanwhile, compounds 5A, 5B, 5D, and 5G demonstrated potent effects against lung cancer cell lines, with IC50 values between 7.945±0.99 and 9.295±1.074 µM. Remarkably, compound 5G showed potent efficacy against both breast and lung cancers, with IC50 values of 28.38±1.520 µM and 9.02±1.07 µM, respectively. This study illuminates the critical role of pyrazole-linked thiazolyl-pyrazoline scaffolds in crafting powerful cancer therapeutics targeting ErbB4 (HER4) kinase. Unique in its dual functionality, ErbB4 can act as either an oncogene or a tumor suppressor in lung and breast cancers, contingent on specific cellular contexts and isoform variations. The dynamic expression of ErbB4 intricately modulates tumor growth and patient outcomes, marking it as a compelling therapeutic target for innovative treatments in both breast and lung cancer.

Unraveling the Role of PCDH9 in Breast Cancer and Identifying Therapeutic Strategies for PCDH9-Deficient Tumors.

Protocadherin 9 (PCDH9), a member of the cadherin superfamily of transmembrane proteins, plays a role in cell adhesion and neural development. Recent studies suggest that PCDH9 may function as a tumor suppressor in certain cancers, though its specific role in breast cancer remains unclear. UALCAN database to retrieve information on PCDH9 expression in breast cancer tissues compared with that in normal tissues. The biological effects of PCDH9 in breast cancer cells were analyzed using the DepMap database. Stable knockdown or overexpression of PCDH9 in breast cancer cell lines and subsequently assessed tumor cell proliferation and migration. Synthetic lethal screening was conducted for breast cancer cells with low PCDH9 expression or deficiency. In this study, we observed significant downregulation of PCDH9 in breast cancer tissues, with its expression negatively correlated with progression-free survival. Further investigations revealed that decreased PCDH9 expression promotes breast cancer cell proliferation and migration, while overexpression of PCDH9 has the opposite effect. Subsequently, we identified the TAS-102, an approved drug for metastatic colorectal cancer, exhibited selective cytotoxicity against breast cancer cells with low PCDH9 expression. In summary, our study identified PCDH9 as a tumor suppressor in breast cancer and highlighted TAS-102 as a potential therapeutic option for tumors with low PCDH9 expression or deficiency. The specific interaction between TAS-102 and PCDH9 warrants further exploration, providing deeper insights into its mode of action in treating PCDH9-deficient breast cancer.

Hypermethylation of the BRCA2 gene promoter and its co-hypermethylation with the BRCA1 gene promoter in patients with breast cancer.

The BRCA2 gene is an important tumour suppressor in breast cancer, and alterations in BRCA2 may lead to cancer progression. The aim of the study was to investigate the association of hypermethylation of the BRCA2 gene promoter and its co-hypermethylation with the BRCA1 gene promoter with the development and course of breast cancer in women. This study included 74women with breast cancer (tumour tissue samples and peripheral blood) and 62women without oncological pathology (peripheral blood)- control group. Hypermethylation of the BRCA2 gene was significantly more frequently detected in the tumour tissue of women with breast cancer compared to their peripheral blood and peripheral blood of control subjects (p= 0.0006 and p= 0.00001, respectively). Hypermethylation of BRCA2 was more frequently detected in patients with breast cancer over the age of 50 and in patients with higher Ki67 expression levels (p= 0.045 and p= 0.045, respectively). There was a high frequency of unmethylated BRCA1 and BRCA2 gene combination in women of the control group compared to women with breast cancer, both in blood samples and tumour tissue samples (p= 0.014 and p= 0.00001, respectively). Our study confirms the hypothesis that BRCA2 hypermethylation plays an important role in the pathogenesis of breast cancer and the importance of assessing its co-hypermethylation with BRCA1 in predicting the course of the disease.

Unveiling FRG1’s DNA repair role in breast cancer

The FRG1(FSHD region gene 1) gene has emerged as a pivotal tumor suppressor in both breast and prostate cancer. HPF1 (Histone PARylation Factor 1), a gene crucial in the base excision repair (BER) mechanism for single-stranded DNA (ssDNA) lesions, showcases a robust correlation with FRG1. This implies that FRG1 might have the capacity to influence BER via HPF1, potentially playing a role in tumorigenesis. Using a comprehensive approach that integrates in-silico analyses involving differential gene expression, KEGG (Kyoto Encyclopedia of Genes and Genomes), GO (Gene Ontology), and STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) databases, we unravelled the intricate network of genes and pathways influenced by FRG1, which includes BER. Our linear regression analysis unveiled a positive relationship between FRG1 and key genes crucial for BER. Notably, breast cancer patients with low FRG1 expression exhibited a significantly higher frequency of mutation in TP53. To enhance the accuracy of our analysis, we conducted qRT-PCR assays, which demonstrated that FRG1 affects the transcription of DNA base excision repair genes, showing differential expression in breast cancer cells. Moreover, through the Alkaline Comet Assay, a technique that quantifies DNA damage at the single-cell level, we observed diminished DNA repair capabilities when FRG1 levels are low. Risk scores were calculated using the Cox regression coefficients, and we found notable differences in Overall Survival (OS) and mRNA expression of DEGs in the low and high-risk groups. In summary, our findings shed light on the pivotal role of FRG1 in maintaining DNA repair efficiency within breast cancer cells.

RGS10 deficiency facilitates distant metastasis by inducing epithelial–mesenchymal transition in breast cancer

Distant metastasis is the major cause of death in patients with breast cancer. Epithelial–mesenchymal transition (EMT) contributes to breast cancer metastasis. Regulator of G protein-signaling (RGS) proteins modulates metastasis in various cancers. This study identified a novel role for RGS10 in EMT and metastasis in breast cancer. RGS10 protein levels were significantly lower in breast cancer tissues compared to normal breast tissues, and deficiency in RGS10 protein predicted a worse prognosis in patients with breast cancer. RGS10 protein levels were lower in the highly aggressive cell line MDA-MB-231 than in the poorly aggressive, less invasive cell lines MCF7 and SKBR3. Silencing RGS10 in SKBR3 cells enhanced EMT and caused SKBR3 cell migration and invasion. The ability of RGS10 to suppress EMT and metastasis in breast cancer was dependent on lipocalin-2 and MIR539-5p. These findings identify RGS10 as a tumor suppressor, prognostic biomarker, and potential therapeutic target for breast cancer.

RGS10 deficiency facilitates distant metastasis by inducing epithelial-mesenchymal transition in breast cancer.

Distant metastasis is the major cause of death in patients with breast cancer. Epithelial-mesenchymal transition (EMT) contributes to breast cancer metastasis. Regulator of G protein-signaling (RGS) proteins modulates metastasis in various cancers. This study identified a novel role for RGS10 in EMT and metastasis in breast cancer. RGS10 protein levels were significantly lower in breast cancer tissues compared to normal breast tissues, and deficiency in RGS10 protein predicted a worse prognosis in patients with breast cancer. RGS10 protein levels were lower in the highly aggressive cell line MDA-MB-231 than in the poorly aggressive, less invasive cell lines MCF7 and SKBR3. Silencing RGS10 in SKBR3 cells enhanced EMT and caused SKBR3 cell migration and invasion. The ability of RGS10 to suppress EMT and metastasis in breast cancer was dependent on lipocalin-2 and MIR539-5p. These findings identify RGS10 as a tumor suppressor, prognostic biomarker, and potential therapeutic target for breast cancer.

The Roles of Cytoplasmic Polyadenylation Element Binding Protein 1 in Tumorigenesis.

CPEB1 is an alternative polyadenylation binding protein that promotes or suppresses the expression of related mRNAs and proteins by binding to a highly conserved Cytoplasmic Polyadenylation Element (CPE) in the mRNAs 3'UTR. It is found to express abnormally in multiple tumors and affect tumorigenesis through many pathways. This review summarizes the functions and mechanisms of CPEB1 in a variety of cancers and suggests new directions for future related treatments. A total of 95 articles were eligible for inclusion based on the year, quality of the research, and the strength of association with CPEB1. In this review, current research about how CPEB1 affects the initiation and progression of glioblastoma, breast cancer, hepatocellular carcinoma, gastric cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, and melanoma are dissected, and the biomedical functions and mechanisms are summarized. CPEB1 mostly presents as a tumor suppressor for breast cancer, endometrial carcinoma, hepatocellular carcinoma, non-small cell lung cancer, prostate cancer, and melanoma. However, glioblastoma, gastric cancer, and colorectal cancer it exhibit two opposing properties of tumorigenesis, either promoting or inhibiting it. CPEB1 is likely to serve as a target and dynamic detection index or prognostic indicator for its function of apoptosis, activity, proliferation, migration, invasion, stemness, drug resistance, and even ferroptosis in various cancers.

Long non-coding RNAs PTENP1, GNG12-AS1, MAGI2-AS3 and MEG3 as tumor suppressors in breast cancer and their associations with clinicopathological parameters.

Breast cancer is the most commonly occurring cancer worldwide and is the main cause of death from cancer in women. Novel biomarkers are highly warranted for this disease. Evaluation of novel long non-coding RNAs biomarkers for breast cancer. The study comprised the analysis of the expression of 71 candidate lncRNAs via screening, six of which (four underexpressed, two overexpressed) were validated and analyzed by qPCR in tumor tissues associated with NST breast carcinomas, compared with the benign samples and with respect to their clinicopathological characteristics. The results indicated the tumor suppressor roles of PTENP1, GNG12-AS1, MEG3 and MAGI2-AS3. Low levels of both PTENP1 and GNG12-AS1 were associated with worsened progression-free and overall survival rates. The reduced expression of GNG12-AS1 was linked to the advanced stage. A higher grade was associated with the lower expression of PTENP1, GNG12-AS1 and MAGI2-AS3. Reduced levels of both MEG3 and PTENP1 were linked to Ki-67 positivity. The NRSN2-AS1 and UCA1 lncRNAs were overexpressed; higher levels of UCA1 were associated with multifocality. The results suggest that the investigated lncRNAs may play important roles in breast cancer and comprise a potential factor that should be further evaluated in clinical studies.

Gene Editing for Unraveling the Regulatory Role of a HER2-Associated Enhancer with lncRNA GAS5 and Related Genes in Breast Cancer Cells

Background: The HER2/neu gene belongs to the epidermal growth factor receptor (EGFR) family and encodes a 185 kDa protein with tyrosine kinase activity. HER2 amplification or overexpression has been associated with tumorigenesis and cancer progression, notably in breast cancer (BC). The long non-coding RNA GAS5 has been recognized as a tumor suppressor in BC, promoting apoptosis and inhibiting cell proliferation. Moreover, GAS5 regulates key signaling pathways in breast cancer, including PI3K/AKT/mTOR and PTEN signaling. The PI3K/AKT pathway is critical in various cancer processes, such as proliferation, apoptosis, invasion, and drug resistance. Breast cancer stem cells (BCSCs) and stemness genes also contribute to tumor growth and therapy resistance. Therefore, targeting key regulatory regions in the HER2 gene could offer potential therapeutic strategies. Objectives: In this study, we aimed to investigate the regulatory role of a putative enhancer located in the HER2 gene in the 17q12 region (GH17J039694; we referred to it as Her2-Enhancer1 in our previous study) on HER2 variants and genes that are connected to it through different pathways. Methods: We analyzed the effects of enhancer knockout on HER2 variants, GAS5, PTEN, and stemness genes in HER2-positive and HER2-negative breast cancer cells using the CRISPR/Cas9 system and real-time PCR. Results: Our results showed significantly reduced HER2 variant expression in both cell lines after genetic editing. Furthermore, the expression of some other target genes was affected, including GAS5, P53, and PTEN. Interestingly, we observed altered expression of stemness genes like NANOG, SOX2, and OCT4, indicating possible implications for cancer stem cell properties. Conclusions: Our study highlights the potential regulatory role of the studied region as an enhancer in the HER2 gene and sheds light on its influence on various cancer-related pathways, providing valuable insights into breast cancer pathogenesis and potential therapeutic targets.

CEBPA Restrains the Malignant Progression of Breast Cancer by Prompting the Transcription of SOCS2.

The suppressor of cytokine signaling 2 (SOCS2) has been identified to act as a tumor suppressor in breast cancer (BC) progression. However, the action of SOCS2 in macrophage polarization in BC cells has not been reported yet. The qRT-PCR and western blotting were adopted for detecting the levels of mRNAs and proteins. The macrophage M2 polarization was analyzed by flow cytometry. Analyses of cell oncogenic phenotypes and tumor growth were conducted using 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, scratch, Transwell, tube formation assays in vitro, and tumor xenograft assay in vivo, respectively. The interaction between CEBPA (CCAAT Enhancer Binding Protein Alpha) and SOCS2 was confirmed using bioinformatics analysis and dual-luciferase reporter assay. SOCS2 was lowly expressed in BC tissues and cells. Functionally, overexpression of SOCS2 inhibited macrophage M2 polarization, and impaired BC cell proliferation, angiogenesis, and metastasis. Mechanistically, CEBPA bound to the promoter region of SOCS2, and promoted its transcription. A low CEBPA expression was observed in BC tissues and cells. Forced expression of CEBPA also suppressed macrophage M2 polarization, BC cell proliferation, angiogenesis, and metastasis. Moreover, the anticancer effects mediated by CEBPA were abolished by SOCS2 knockdown. In addition, CEBPA overexpression impeded BC growth in nude mice by regulating SOCS2. CEBPA suppressed macrophage M2 polarization, BC cell proliferation, angiogenesis, and metastasis by promoting SOCS2 transcription in a targeted manner.

MEF2D Functions as a Tumor Suppressor in Breast Cancer.

The myocyte enhancer factor 2 (MEF2) gene family play fundamental roles in the genetic programs that control cell differentiation, morphogenesis, proliferation, and survival in a wide range of cell types. More recently, these genes have also been implicated as drivers of carcinogenesis, by acting as oncogenes or tumor suppressors depending on the biological context. Nonetheless, the molecular programs they regulate and their roles in tumor development and progression remain incompletely understood. The present study evaluated whether the MEF2D transcription factor functions as a tumor suppressor in breast cancer. The knockout of the MEF2D gene in mouse mammary epithelial cells resulted in phenotypic changes characteristic of neoplastic transformation. These changes included enhanced cell proliferation, a loss of contact inhibition, and anchorage-independent growth in soft agar, as well as the capacity for tumor development in mice. Mechanistically, the knockout of MEF2D induced the epithelial-to-mesenchymal transition (EMT) and activated several oncogenic signaling pathways, including AKT, ERK, and Hippo-YAP. Correspondingly, a reduced expression of MEF2D was observed in human triple-negative breast cancer cell lines, and a low MEF2D expression in tissue samples was found to be correlated with a worse overall survival and relapse-free survival in breast cancer patients. MEF2D may, thus, be a putative tumor suppressor, acting through selective gene regulatory programs that have clinical and therapeutic significance.

Resf1 is a compound G4 quadruplex-associated tumor suppressor for triple negative breast cancer.

Patients with ER-negative breast cancer have the worst prognosis of all breast cancer subtypes, often experiencing rapid recurrence or progression to metastatic disease shortly after diagnosis. Given that metastasis is the primary cause of mortality in most solid tumors, understanding metastatic biology is crucial for effective intervention. Using a mouse systems genetics approach, we previously identified 12 genes associated with metastatic susceptibility. Here, we extend those studies to identify Resf1, a poorly characterized gene, as a novel metastasis susceptibility gene in ER- breast cancer. Resf1 is a large, unstructured protein with an evolutionarily conserved intron-exon structure, but with poor amino acid conservation. CRISPR or gene trap mouse models crossed to the Polyoma Middle-T antigen genetically engineered mouse model (MMTV-PyMT) demonstrated that reduction of Resf1 resulted in a significant increase in tumor growth, a shortened overall survival time, and increased incidence and number of lung metastases, consistent with patient data. Furthermore, an analysis of matched tail and primary tissues revealed loss of the wildtype copy in tumor tissue, consistent with Resf1 being a tumor suppressor. Mechanistic analysis revealed a potential role of Resf1 in transcriptional control through association with compound G4 quadruplexes in expressed sequences, particularly those associated with ribosomal biogenesis. These results suggest that loss of Resf1 enhances tumor progression in ER- breast cancer through multiple alterations in both transcriptional and translational control.

Novel role of LLGL2 silencing in autophagy: reversing epithelial-mesenchymal transition in prostate cancer

PurposeProstate cancer (PCa) is a major urological disease that is associated with significant morbidity and mortality in men. LLGL2 is the mammalian homolog of Lgl. It acts as a tumor suppressor in breast and hepatic cancer. However, the role of LLGL2 and the underlying mechanisms in PCa have not yet been elucidated. Here, we investigate the role of LLGL2 in the regulation of epithelial-mesenchymal transition (EMT) in PCa through autophagy in vitro and in vivo.MethodsPC3 cells were transfected with siLLGL2 or plasmid LLGL2 and autophagy was examined. Invasion, migration, and wound healing were assessed in PC3 cells under autophagy regulation. Tumor growth was evaluated using a shLLGL2 xenograft mouse model.ResultsIn patients with PCa, LLGL2 levels were higher with defective autophagy and increased EMT. Our results showed that the knockdown of LLGL2 induced autophagy flux by upregulating Vps34 and ATG14L. LLGL2 knockdown inhibits EMT by upregulating E-cadherin and downregulating fibronectin and α-SMA. The pharmacological activation of autophagy by rapamycin suppressed EMT, and these effects were reversed by 3-methyladenine treatment. Interestingly, in a shLLGL2 xenograft mouse model, tumor size and EMT were decreased, which were improved by autophagy induction and worsened by autophagy inhibition.ConclusionDefective expression of LLGL2 leads to attenuation of EMT due to the upregulation of autophagy flux in PCa. Our results suggest that LLGL2 is a novel target for alleviating PCa via the regulation of autophagy.

Estrogen Signals through ERβ in Breast Cancer; What We Have Learned since the Discovery of the Receptor.

Estrogen receptor (ER) β (ERβ) is the second ER subtype that mediates the effects of estrogen in target tissues along with ERα that represents a validated biomarker and target for endocrine therapy in breast cancer. ERα was the only known ER subtype until 1996 when the discovery of ERβ opened a new chapter in endocrinology and prompted a thorough reevaluation of the estrogen signaling paradigm. Unlike the oncogenic ERα, ERβ has been proposed to function as a tumor suppressor in breast cancer, and extensive research is underway to uncover the full spectrum of ERβ activities and elucidate its mechanism of action. Recent studies have relied on new transgenic models to capture effects in normal and malignant breast that were not previously detected. They have also benefited from the development of highly specific synthetic ligands that are used to demonstrate distinct mechanisms of gene regulation in cancer. As a result, significant new information about the biology and clinical importance of ERβ is now available, which is the focus of discussion in the present article.

MEIS2 suppresses breast cancer development by downregulating IL10.

Breast cancer (BC) is the most commonly diagnosed female cancer. Homeobox protein MEIS2, a key transcription factor, is involved in the regulation of many developmental and cellular processes. However, the role of MEIS2 in the development of breast cancer is still unclear. We aimed to examine the role of myeloid ecotropic insertion site (MEIS2) in breast cancer and the association of MEIS2 with breast cancer clinical stages and pathological grades. We revealed the underlying mechanism by which MEIS2 affected breast cancer cell growth and tumor development. Using human BC cell lines, clinical samples and animal xenograft model, we reveal that MEIS2 functions as a tumor suppressor in breast cancer. The expression of MEIS2 is inversely correlated with BC clinical stages and pathological grades. MEIS2 knockdown (MEIS2-KD) promotes while MEIS2 overexpression suppresses breast cancer cell proliferation and tumor development in vitro and in animal xenograft models, respectively. To determine the biological function of MEIS2, we screen the expression of a group of MEIS2 potential targeting genes in stable-established cell lines. Results show that the knockdown of MEIS2 in breast cancer cells up-regulates the IL10 expression, but MEIS2 overexpression opposed the effect on IL10 expression. Furthermore, the suppressive role of MEIS2 in breast cancer cell proliferation is associated with the IL10 expression and myeloid cells infiltration. Our study demonstrates that the tumor suppressor of MEIS2 in breast cancer progression is partially via down regulating the expression of IL10 and promoting myeloid cells infiltration. Targeting MEIS2 would be a potentially therapeutic avenue for BC.

Apolipoprotein A-1 downregulation promotes basal-like breast cancer cell proliferation and migration associated with DNA methylation.

Apolipoprotein A-I (APOA1) performs different roles in different subtypes of breast cancer. It is hypothesized to function as a tumor suppressor in basal-like breast cancer (BLBC). However, the specific role of APOA1 in BLBC and its underlying mechanisms remain unknown. The findings of the present study demonstrated a positive correlation between the expression level of APOA1 and the overall survival of patients with BLBC. Ectopic expression of APOA1 effectively inhibits the proliferation and metastasis of BLBC cells in vitro, and these effects are closely related to DNA methylation. To the best of our knowledge, the present study is the first to report increased methylation of the promoter region and decreased methylation of the structural genes of APOA1 in BLBC cells. These alterations resulted in the downregulation of APOA1 expression and suppression of BLBC tumor growth. Collectively, the results of the present study suggested that APOA1 mRNA expression is negatively regulated by DNA methylation in BLBC. Therefore, low expression of APOA1 may be a potential risk biomarker to predict survival in patients with BLBC.

Emerging roles of FOXK2 in cancers and metabolic disorders.

FOXK2, a member of the Forkhead box K (FOXK) transcription factor family, is widely expressed in various tissues and organs throughout the body. FOXK2 plays crucial roles in cell proliferation, differentiation, autophagy, de novo nucleotide biosynthesis, DNA damage response, and aerobic glycolysis. Although FOXK2 is recognized as an oncogene in colorectal cancer and hepatocellular carcinoma, it acts as a tumor suppressor in breast cancer, cervical cancer, and non-small cell lung cancer (NSCLC). This review provides an overview of the recent progress in understanding the regulatory mechanisms of FOXK2 and its downstream targets, highlights the significant impact of FOXK2 dysregulation on cancer etiology, and discusses the potential of targeting FOXK2 for cancer treatment.

Identifying SLC2A6 as the novel protective factor in breast cancer by TP53-related genes affecting M1 macrophage infiltration.

The high heterogeneity of breast cancer (BC) caused by pathogenic gene mutations poses a challenge to immunotherapy, but the underlying mechanism remains unknown. The difference in the infiltration of M1 macrophages induced by TP53 mutations has a significant impact on BC immunotherapy. The aim of this study was to develop a TP53-related M1 macrophage infiltration molecular typing risk signature in BC and evaluate the biological functions of the key gene to find new immunotherapy biomarkers. Weighted correlation network analysis (WGCNA) and negative matrix factorization (NMF) were used for distinguishing BC subtypes. The signature and the nomogram were both constructed and evaluated. Biological functions of the novel signature gene SLC2A6 were confirmed through in vitro and in vivo experiments. RNA-Sequencing and protein profiling were used for detecting the possible mechanism of SLC2A6. The results suggested that four BC subtypes were distinguished by TP53-related genes that affect M1 macrophage infiltration. The signature constructed by molecular typing characteristics could evaluate BC's clinical features and tumor microenvironment. The nomogram could accurately predict the prognosis. The signature gene SLC2A6 was found to have an abnormally low expression in tumor tissues. Overexpression of SLC2A6 could inhibit proliferation, promote mitochondrial damage, and result in apoptosis of tumor cells. The HSP70 family member protein HSPA6 could bind with SLC2A6 and increase with the increased expression of SLC2A6. In summary, the risk signature provides a reference for BC risk assessment, and the signature gene SLC2A6 could act as a tumor suppressor in BC.

Abstract 6281: Context dependent role of glucocorticoids in breast cancer

Abstract Glucocorticoids bind to the transcription factor glucocorticoid receptor (GR) and regulate genes in response to cellular metabolism, inflammation, and stress. Although GR has been extensively evaluated in inflammation and metabolic diseases, its role as a therapeutic target in cancer has not been thoroughly studied. Results from studies with another member of the steroid receptor family, androgen receptor (AR), demonstrated that the AR is an oncogene in estrogen receptor (ER)-negative breast cancer, but a tumor suppressor in ER-positive breast cancer. We expected a comparable mechanism with GR in different breast cancer subtypes. In this study, we evaluated the role of GR in various breast cancer subtypes and discerned the mechanism of action. Six breast cancer cell lines and seven patient-derived xenografts (PDXs) were characterized by Western blot for their expression of GR, ER and AR. Proliferation assays were performed in cell lines with a dose-response of a synthetic glucocorticoid, dexamethasone. Subsequently, we performed xenograft studies in cell line xenografts (CDXs) and PDXs. GR was ubiquitously expressed in various cell lines and PDX models. Dexamethasone reduced cell proliferation in ER-positive models, while it increased the proliferation in ER-negative cell lines, suggesting that the GR might have a mechanism of action that is similar to AR. GR antagonist, mifepristone, reversed the effects of dexamethasone. CDX studies in an ER-positive cell line, MCF7 suggested that dexamethasone (10 mpk) inhibited the tumor growth significantly that was better than the standard of care fulvestrant. This result was confirmed in an ER positive PDX model HCI013. Study by Obradović et al, indicates that glucocorticoids have an oncogenic role and furthermore promote breast cancer metastasis in TNBC model thereby validating the subtype and context dependent role of the glucocorticoid receptor. We are currently exploring the mechanism of GR’s context-dependent tumor suppressor and oncogenic role in distinct breast cancer subtypes. Citation Format: Wendy Effah, Suriyan Ponnusamy, Sarah Asemota, Yekta Khosrosereski, Ramesh Narayanan. Context dependent role of glucocorticoids in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6281.

More Evidences for the Possible Role of Err Beta (ERRβ) as a Tumor Suppressor in Estrogen Receptor Positive and Negative Breast Cancer

More Evidences for the Possible Role of Err Beta (ERRβ) as a Tumor Suppressor in Estrogen Receptor Positive and Negative Breast Cancer