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As a crucial amino acid, glutamine can provide the nitrogen and carbon sources needed to support cancer cell proliferation, invasion, and metastasis. Interestingly, different types of breast cancer have different dependences on glutamine. This research shows that basal-like breast cancer depends on glutamine, while the other types of breast cancer may be more dependent on glucose. Glutamine transporter ASCT2 is highly expressed in various cancers and significantly promotes the growth of breast cancer. However, the key regulatory mechanism of ASCT2 in promoting basal-like breast cancer progression remains unclear. Our research demonstrates the significant change in fatty acid levels caused by ASCT2, which may be a key factor in glutamine sensitivity. This phenomenon results from the mutual activation between ASCT2-mediated glutamine transport and lipid metabolism via the nuclear receptor PPARα. ASCT2 cooperatively promoted PPARα expression, leading to the upregulation of lipid metabolism. Moreover, we also found that C118P could inhibit lipid metabolism by targeting ASCT2. More importantly, this research identifies a potential avenue of evidence for the prevention and early intervention of basal-like breast cancer by blocking the glutamine-lipid feedback loop.
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Breast cancer treatment has evolved drastically with the addition of immunotherapy and novel targeted drugs to the current treatment options. However, achieving long-term responses with minimal adverse events remains challenging. Cancer testis antigens (CTAs) offer novel opportunities for drug development thanks to their tumor specificity, immunogenicity, pro-tumorigenic functions, and negative prognostic connotations. We previously reported that lactate dehydrogenase C (LDHC) plays a key role in regulating genomic stability and that targeting LDHC significantly improved treatment response to DNA damage response drugs in breast cancer. Here, we explored the molecular mechanisms associated with LDHC silencing in two basal-like breast cancer cell lines, MDA-MB-468 and BT-549, and a Her2-enriched breast cancer cell line, HCC-1954. Transcriptomic analyses identified the cell line-dependent differential activation of the pro-survival STAT3 pathway following LDHC depletion. While LDHC silencing significantly compromised cell survival in basal-like breast cancer cells in conjunction with a downregulation of STAT3 signaling, the opposite effect was observed in Her2-enriched breast cancer cells, which demonstrated the enhanced activation of the pro-survival STAT3 signaling pathway. The inhibition of STAT3 not only reversed the unfavorable effect of LDHC silencing in the Her2-enriched cancer cells but also demonstrated significant anti-cancer activity when used as a single agent. Our findings suggest that the LDHC-STAT3 signaling axis plays a role in regulating breast tumor cell survival in a subtype-dependent manner. Thus, LDHC-targeted therapy could be a viable therapeutic approach for a subset of breast cancer patients, particularly patients with basal-like breast cancer, whereas patients carrying Her2-enriched tumors may likely benefit more from monotherapy with STAT3 inhibitors.
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The TOR1B gene is known to play a pivotal role in maintaining cellular homeostasis and responding to endoplasmic reticulum stress. However, its involvement in cancer remains relatively understudied. This study seeks to explore the prognostic implications of TOR1B across various cancers, with a specific focus on Basal-like Breast Cancer (BLBC) and its underlying cellular mechanisms. Through comprehensive analysis of data from TCGA, TARGET, GEO, and GTEx, we investigated TOR1B expression and its correlation with patient outcomes. Furthermore, in vitro experiments conducted on BLBC cell lines examined the impact of TOR1B modulation on cell viability, apoptosis, and metabolic activity under varying oxygen levels. Our statistical analysis encompassed differential expression analysis, survival analysis, and multivariate Cox regression. Our findings indicate that TOR1B is overexpressed in BLBC and other cancers, consistently correlating with poorer prognosis. Elevated TOR1B levels were significantly associated with reduced overall and disease-free survival in BLBC patients. In vitro experiments further revealed that TOR1B knockdown augmented apoptosis and influenced metabolic activity, particularly under hypoxic conditions, highlighting its potential role in cancer cell adaptation to stress. Overall, our study underscores the importance of TOR1B in cancer progression, particularly in BLBC, where it serves as a notable prognostic indicator. The interaction between TOR1B and metabolic pathways, as well as its regulation by HIF-1α, suggests its significance in adapting to hypoxia, thereby positioning TOR1B as a promising therapeutic target for aggressive breast cancer subtypes.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Pronóstico , Línea Celular Tumoral , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , ApoptosisRESUMEN
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.
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BACKGROUND: Basal-like breast cancer (BLBC) is the most aggressive subtype of breast cancer due to its aggressive characteristics and lack of effective therapeutics. However, the mechanism underlying its aggressiveness remains largely unclear. S-adenosylmethionine decarboxylase proenzyme (AMD1) overexpression occurs specifically in BLBC. Here, we explored the potential molecular mechanisms and functions of AMD1 promoting the aggressiveness of BLBC. METHODS: The potential effects of AMD1 on breast cancer cells were tested by western blotting, colony formation, cell proliferation assay, migration and invasion assay. The spermidine level was determined by high performance liquid chromatography. The methylation status of CpG sites within the AMD1 promoter was evaluated by bisulfite sequencing PCR. We elucidated the relationship between AMD1 and Sox10 by ChIP assays and quantitative real-time PCR. The effect of AMD1 expression on breast cancer cells was evaluated by in vitro and in vivo tumorigenesis model. RESULTS: In this study, we showed that AMD1 expression was remarkably elevated in BLBC. AMD1 copy number amplification, hypomethylation of AMD1 promoter and transcription activity of Sox10 contributed to the overexpression of AMD1 in BLBC. AMD1 overexpression enhanced spermidine production, which enhanced eIF5A hypusination, activating translation of TCF4 with multiple conserved Pro-Pro motifs. Our studies showed that AMD1-mediated metabolic system of polyamine in BLBC cells promoted tumor cell proliferation and tumor growth. Clinically, elevated expression of AMD1 was correlated with high grade, metastasis and poor survival, indicating poor prognosis of breast cancer patients. CONCLUSION: Our work reveals the critical association of AMD1-mediated spermidine-eIF5A hypusination-TCF4 axis with BLBC aggressiveness, indicating potential prognostic indicators and therapeutic targets for BLBC.
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Neoplasias de la Mama , Proliferación Celular , Factor 5A Eucariótico de Iniciación de Traducción , Regulación Neoplásica de la Expresión Génica , Lisina/análogos & derivados , Factores de Iniciación de Péptidos , Proteínas de Unión al ARN , Espermidina , Factor de Transcripción 4 , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Factores de Iniciación de Péptidos/metabolismo , Factores de Iniciación de Péptidos/genética , Ratones , Animales , Espermidina/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Factor de Transcripción 4/metabolismo , Factor de Transcripción 4/genética , Línea Celular Tumoral , Regiones Promotoras Genéticas , Adenosilmetionina Descarboxilasa/metabolismo , Adenosilmetionina Descarboxilasa/genética , Movimiento Celular/genética , Metilación de ADN , Pronóstico , Factores de Transcripción SOXE/metabolismo , Factores de Transcripción SOXE/genéticaRESUMEN
Basal-like breast cancer (BLBC) is the most aggressive molecular subtype of breast cancer with worse prognosis and fewer treatment options. The underlying mechanisms upon BLBC transcriptional dysregulation and its upstream transcription factors (TFs) remain unclear. Here, among the hyperactive candidate TFs of BLBC identified by bioinformatic analysis, POU4F1 is uniquely upregulated in BLBC and is associated with poor prognosis. POU4F1 is necessary for the tumor growth and malignant phenotypes of BLBC through regulating G1/S transition by direct binding at the promoter of CDK2 and CCND1. More importantly, POU4F1 maintains BLBC identity by repressing ERα expression through CDK2-mediated EZH2 phosphorylation and subsequent H3K27me3 modification in ESR1 promoter. Knocking out POU4F1 in BLBC cells reactivates functional ERα expression, rendering BLBC sensitive to tamoxifen treatment. In-depth epigenetic analysis reveals that the subtype-specific re-configuration and activation of the bivalent chromatin in the POU4F1 promoter contributes to its unique expression in BLBC, which is maintained by DNA demethylase TET1. Together, these results reveal a subtype-specific epigenetically activated TF with critical role in promoting and maintaining BLBC, suggesting that POU4F1 is a potential therapeutic target for BLBC.
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Neoplasias de la Mama , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Humanos , Femenino , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/genética , Ratones , Animales , Factor de Transcripción Brn-3A/genética , Factor de Transcripción Brn-3A/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Modelos Animales de Enfermedad , Regiones Promotoras Genéticas/genéticaRESUMEN
The majority of triple negative breast cancers (TNBCs) are basal-like breast cancers (BLBCs), which tend to be more aggressive, proliferate rapidly, and have poor clinical outcomes. A key prognostic biomarker and regulator of BLBC is the Forkhead box C1 (FOXC1) transcription factor. However, because of its functional placement inside the cell nucleus and its structural similarity with other related proteins, targeting FOXC1 for therapeutic benefit, particularly for BLBC, continues to be difficult. We envision targeted nonviral delivery of CRISPR/Cas9 plasmid toward the efficacious knockdown of FOXC1. Keeping in mind the challenges associated with the use of CRISPR/Cas9 in vivo, including off-targeting modifications, and effective release of the cargo, a nanoparticle with context responsive properties can be designed for efficient targeted delivery of CRISPR/Cas9 plasmid. Consequently, we have designed, synthesized, and characterized a zwitterionic amino phospholipid-derived transfecting nanoparticle for delivery of CRISPR/Cas9. The construct becomes positively charged only at low pH, which encourages membrane instability and makes it easier for nanoparticles to exit endosomes. This has enabled effective in vitro and in vivo downregulation of protein expression and genome editing. Following this, we have used EpCAM aptamer to make the system targeted toward BLBC cell lines and to reduce its off-target toxicity. The in vivo efficacy, biodistribution, preliminary pharmacokinetics, and biosafety of the optimized targeted CRISPR nanoplatform is then validated in a rodent xenograft model. Overall, we have attempted to knockout the proto-oncogenic FOXC1 expression in BLBC cases by efficient delivery of CRISPR effectors via a context-responsive nanoparticle delivery system derived from a designer lipid derivative. We believe that the nonviral approach for in vitro and in vivo delivery of CRISPR/Cas9 targeted toward FOXC1, studied herein, will greatly emphasize the therapeutic regimen for BLBC.
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Nanopartículas , Neoplasias de la Mama Triple Negativas , Humanos , Sistemas CRISPR-Cas , Fosfolípidos , Distribución Tisular , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genéticaRESUMEN
Vestigial-like family member 1 (VGLL1) is one of the X-linked genes whose expression is elevated in basal-like breast cancer (BLBC) because of X-chromosome isodisomy. As an approach towards understanding its function, we performed correlation study using transcript data of breast cancer patients from cBioPortal for Cancer Genomics. Our analysis identified EGFR as the most correlated transcript with VGLL1. We demonstrate that VGLL1 promotes EGFR expression and increases the frequency of breast tumor initiating cells (CD44high/+CD24low/-). These findings are crucial because an elevated EGFR expression and high frequency of CD44high/+CD24low/- cells are defining features of BLBC, and we provide a new mechanistic insight into how their expressions are controlled. Importantly, VGLL1 regulation of EGFR and CD44high/+CD24low/- population is mediated by the hippo-transducer TAZ which exerts its oncogenic roles by binding and activating TEAD transcription factors. A crucial finding is that TEAD-binding domain of TAZ is dispensable for its regulation of EGFR and CD44high/+CD24low/- cells. Instead, VGLL1 stabilization of cytoplasmic TAZ is essential for these functions. Also, we show that VGLL1/TAZ restricts the surface expression of CD24 which contributes to the increased number of CD44high/+CD24low/- cells. In addition, we observed that VGLL1 represses AXL expression and suppresses claudin-low phenotype, and that is caused by the VGLL1 mediated nuclear expulsion of TAZ. Therefore, EGFR and AXL seem to represent two different breast tumor subtypes, and their differential expressions is controlled by VGLL1.
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Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/patología , Antígeno CD24/metabolismo , Citoplasma/metabolismo , Proteínas de Unión al ADN/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Receptores de Hialuranos/metabolismo , Células Madre Neoplásicas/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Basal-like breast cancer (BLBC) is the most aggressive subtype with poor prognosis; however, the mechanisms underlying aggressiveness in BLBC remain poorly understood. In this study, we showed that in contrast to other subtypes, inositol monophosphatase 2 (IMPA2) was dramatically increased in BLBC. Mechanistically, IMPA2 expression was upregulated due to copy number amplification, hypomethylation of IMPA2 promoter and MYC-mediated transcriptional activation. IMPA2 promoted MI-PI cycle and IP3 production, and IP3 then elevated intracellular Ca2+ concentration, leading to efficient activation of NFAT1. In turn, NFAT1 up-regulated MYC expression, thereby fulfilling a positive feedback loop that enhanced aggressiveness of BLBC cells. Knockdown of IMPA2 expression caused the inhibition of tumorigenicity and metastasis of BLBC cells in vitro and in vivo. Clinically, high IMPA2 expression was strongly correlated with large tumor size, high grade, metastasis and poor survival, indicating poor prognosis in breast cancer patients. These findings suggest that IMPA2-mediated MI-PI cycle allows crosstalk between metabolic and oncogenic pathways to promote BLBC progression.
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Neoplasias de la Mama , Humanos , Femenino , Retroalimentación , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Regiones Promotoras GenéticasRESUMEN
Objective To mine and analyse the hub genes associated with the prognosis of basal-like breast cancer(BLBC)by bioinformatic methods.Methods We searched the GEO database to obtain an appropriate microarray dataset related to molecular subtyp-ing of breast cancer,and identified modules associated with BLBC by WGCNA.Then,the top 10％differential expressed genes in the module were screened as candidate genes using PPI and cytohubba.The candidate genes were subjected to survival analysis and expression analysis to obtain hub genes.Finally,we explored the correlation between the expressive level of hub genes and immune cell infiltration,chemokines,and immunomodulators by TIMER and TISIDB database.Furthermore,transcription factors(TFs)-hub gene network was constructed.Results A total of 891 genes in black modules related to BLBC were analyzed,and two hub genes,ESPL1 and CCNB2,were identified from the 80differential expressed genes.Two hub genes are associated with BLBC immune cell infiltration,mainly inclu-ding Th2 cells,CD8+T cells,endothelial cells,and tumor-associated fibroblasts.They were also related to chemokines,immunostimu-lators,immunosuppressive factors,and MHC molecules.The upstream transcriptional regulatory network of hub genes showed that 22 transcription factors simultaneously regulate two hub genes.Conclusion ESPL1 and CCNB2 are prognostic markers of BLBC and related to breast tumor immunity.
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Breast cancer is a heterogeneous disease highlighted by the presence of multiple tumor variants and the basal-like breast cancer (BLBC) is considered to be the most aggressive variant with limited therapeutics and a poor prognosis. Though the absence of detectable protein and hormonal receptors as biomarkers hinders early detection, the integration of genomic and transcriptomic profiling led to the identification of additional variants in BLBC. The high-throughput analysis of tissue-specific micro-ribonucleic acids (microRNAs/miRNAs) that are deemed to have a significant role in the development of breast cancer also displayed distinct expression profiles in each subtype of breast cancer and thus emerged to be a robust approach for the precise characterization of the BLBC subtypes. The classification schematic of breast cancer is still a fluid entity that continues to evolve alongside technological advancement, and the transcriptomic profiling of tissue-specific microRNAs is projected to aid in the substratification and diagnosis of the BLBC tumor subtype. In this review, we summarize the current knowledge on breast tumor classification, aim to collect comprehensive evidence based on the microRNA expression profiles, and explore their potential as prospective biomarkers of BLBC.
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BACKGROUND: About 20% of breast cancers in humans are basal-like, a subtype that is often triple-negative and difficult to treat. An effective translational model for basal-like breast cancer is currently lacking and urgently needed. To determine whether spontaneous mammary tumors in pet dogs could meet this need, we subtyped canine mammary tumors and evaluated the dog-human molecular homology at the subtype level. METHODS: We subtyped 236 canine mammary tumors from 3 studies by applying various subtyping strategies on their RNA-seq data. We then performed PAM50 classification with canine tumors alone, as well as with canine tumors combined with human breast tumors. We identified feature genes for human BLBC and luminal A subtypes via machine learning and used these genes to repeat canine-alone and cross-species tumor classifications. We investigated differential gene expression, signature gene set enrichment, expression association, mutational landscape, and other features for dog-human subtype comparison. RESULTS: Our independent genome-wide subtyping consistently identified two molecularly distinct subtypes among the canine tumors. One subtype is mostly basal-like and clusters with human BLBC in cross-species PAM50 and feature gene classifications, while the other subtype does not cluster with any human breast cancer subtype. Furthermore, the canine basal-like subtype recaptures key molecular features (e.g., cell cycle gene upregulation, TP53 mutation) and gene expression patterns that characterize human BLBC. It is enriched in histological subtypes that match human breast cancer, unlike the other canine subtype. However, about 33% of canine basal-like tumors are estrogen receptor negative (ER-) and progesterone receptor positive (PR+), which is rare in human breast cancer. Further analysis reveals that these ER-PR+ canine tumors harbor additional basal-like features, including upregulation of genes of interferon-γ response and of the Wnt-pluripotency pathway. Interestingly, we observed an association of PGR expression with gene silencing in all canine tumors and with the expression of T cell exhaustion markers (e.g., PDCD1) in ER-PR+ canine tumors. CONCLUSIONS: We identify a canine mammary tumor subtype that molecularly resembles human BLBC overall and thus could serve as a vital translational model of this devastating breast cancer subtype. Our study also sheds light on the dog-human difference in the mammary tumor histology and the hormonal cycle.
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Neoplasias de la Mama , Neoplasias Mamarias Animales , Humanos , Perros , Animales , Femenino , Neoplasias de la Mama/patología , Biomarcadores de Tumor/genética , Receptor ErbB-2/metabolismo , Neoplasias Mamarias Animales/genética , Receptores de Progesterona/metabolismoRESUMEN
Basal-like breast cancer (BLBC) is highly aggressive, and often characterized by BRCA1 and p53 deficiency. Although conventional mouse models enabled the investigation of BLBC at malignant stages, its initiation and pre-malignant progression remain understudied. Here, we leveraged a mouse genetic system known as mosaic analysis with double markers (MADM) to study BLBC initiation by generating rare GFP+Brca1, p53-deficient mammary cells alongside RFP+ wild-type sibling cells. After confirming the close resemblance of mammary tumors arising in this model to human BLBC at both transcriptomic and genomic levels, we focused our studies on the pre-malignant progression of BLBC. Initiated GFP+ mutant cells showed a stepwise pre-malignant progression trajectory from focal expansion to hyper-alveolarization and then to micro-invasion. Furthermore, despite morphological similarities to alveoli, hyper-alveolarized structures actually originate from ductal cells based on twin-spot analysis of GFP-RFP sibling cells. Finally, luminal-to-basal transition occurred exclusively in cells that have progressed to micro-invasive lesions. Our MADM model provides excellent spatiotemporal resolution to illuminate the pre-malignant progression of BLBC, and should enable future studies on early detection and prevention for this cancer.
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Neoplasias de la Mama , Neoplasias Mamarias Animales , Ratones , Animales , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proteína p53 Supresora de Tumor/genética , Neoplasias Mamarias Animales/genética , Mama/patologíaRESUMEN
Basal-like breast cancer (BBC) and glioblastoma multiforme (GBM) are aggressive cancers associated with poor prognosis. BBC and GBM have stem cell-like gene expression signatures, which are in part driven by forkhead box O (FOXO) transcription factors. To gain further insight into the impact of FOXO1 in BBC, we treated BT549 cells with AS1842856 and performed RNA sequencing. AS1842856 binds to unphosphorylated FOXO1 and inhibits its ability to directly bind to DNA. Gene Set Enrichment Analysis indicated that a set of WNT pathway target genes, including lymphoid enhancer-binding factor 1 (LEF1) and transcription factor 7 (TCF7), were robustly induced after AS1842856 treatment. These same genes were also induced in GBM cell lines U87MG, LN18, LN229, A172, and DBTRG upon AS1842856 treatment. By contrast, follow-up RNA interference (RNAi) targeting of FOXO1 led to reduced LEF1 and TCF7 gene expression in BT549 and U87MG cells. In agreement with RNAi experiments, CRISPR Cas9-mediated FOXO1 disruption reduced the expression of canonical WNT genes LEF1 and TCF7 in U87MG cells. The loss of TCF7 gene expression in FOXO1 disruption mutants was restored by exogenous expression of the DNA-binding-deficient FOXO1-H215R. Therefore, FOXO1 induces TCF7 in a DNA-binding-independent manner, similar to other published FOXO1-activated genes such as TCF4 and hes family bHLH transcription factor 1. Our work demonstrates that FOXO1 promotes canonical WNT gene expression in examined BBC and GBM cells, similar to results found in Drosophila melanogaster, T-cell development, and murine acute myeloid leukemia models.
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Drosophila melanogaster , Glioblastoma , Animales , Ratones , Diferenciación Celular , ADN , Glioblastoma/genética , Células Madre , HumanosRESUMEN
BACKGROUND: Basal-like breast cancer (BLBC) takes up about 10-20% of all breast cancer(BC), what's more, BLBC has the lowest survival rate among all BC subtypes because of lacks of efficient treatment methods. We aimed to explore the molecules that can be used as diagnostic maker for BLBC at early stage and provide optimized treatment strategies for BLBC patients in this study. METHODS: Apply weighted gene co-expression network analysis (WGCNA) to identify gene modules related to BLBC;The functional enrichment of candidate genes related to BLBC in the red module of Go data package and KEGG analysis;Overlapping cross analysis of URGs and WGCNA to identify candidate genes in each BC subtype;Divide BCBL patients into high-risk and low-risk groups, and analyze the two groups of overall survival (OS) and relapse free survival (RFS);Screening of GEMIN4 dependent cell lines; QRT PCR was used to verify the expression of GEMIN4 transfected with siRNA; CCK8 was used to determine the effect of GEMIN4 on cell viability; Positive cell count detected by BrdU staining;GO and KEGG enrichment analysis of GEMIN4. RESULTS: The "red module" has the highest correlation with BLBC, with 913 promising candidate genes identified from the red module;913 red module candidate genes related to BLBC participated in multiple GO terms, and KEGG enrichment analysis results mainly enriched in estrogen signaling pathways and pathways in cancer;There are 386 overlapping candidate genes among the 913 "red module" genes identified by 1893 common URG and WGCNA;In BLBC patients, 9 highly expressed genes are associated with OS. Five highly expressed genes are associated with RFS. Kaplan Meier survival analysis suggests that high GEMIN4 expression levels are associated with poor prognosis in BLBC patients;The GEMIN4 gene dependency score in HCC1143 and CAL120 cell lines is negative and low; Si-GEMIN4-1 can significantly reduce the mRNA expression of GEMIN4; Si-GEMIN4 can inhibit cell viability; Si-GEMIN4 can reduce the number of positive cells;GO enrichment analysis showed that GEMIN4 is associated with DNA metabolism processes and adenylate binding; KEGG pathway enrichment analysis shows that GEMIN4 is related to ribosome biogenesis in eukaryotes. CONCLUSION: We hypothesized that GEMIN4 may be the potential target for the treatment of BLBC.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Recurrencia Local de Neoplasia , Perfilación de la Expresión Génica/métodos , Transducción de Señal , Antígenos de Histocompatibilidad Menor/uso terapéutico , Ribonucleoproteínas Nucleares Pequeñas/genética , Ribonucleoproteínas Nucleares Pequeñas/metabolismoRESUMEN
Liver X receptors (LXRs) are nuclear transcription factors important in the regulation of cholesterol transport, and glucose and fatty acid metabolism. The antiproliferative role of LXRs has been studied in a variety of malignancies and may represent a therapeutic opportunity in cancers lacking targeted therapies, such as triple-negative breast cancer. In this study, we investigated the impact of LXR agonists alone and in combination with carboplatin in preclinical models of breast cancer. In vitro experiments revealed a dose-dependent decrease in tumor cell proliferation in estrogen receptor-positive breast cancer cells, whereas LXR activation in vivo resulted in an increased growth inhibitory effect in a basal-like breast cancer model (in combination with carboplatin). Functional proteomic analysis identified differences in protein expression between responding and nonresponding models related to Akt activity, cell-cycle progression, and DNA repair. Furthermore, pathway analysis suggested that the LXR agonist in combination with carboplatin inhibits the activity of targets of E2F transcription factors and affects cholesterol homeostasis in basal-like breast cancer.
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Neoplasias de la Mama , Receptores Nucleares Huérfanos , Humanos , Femenino , Receptores X del Hígado/metabolismo , Receptores Nucleares Huérfanos/metabolismo , Neoplasias de la Mama/patología , Carboplatino/metabolismo , Proteómica , Colesterol/metabolismo , Hígado/patologíaRESUMEN
Breast cancer biology varies markedly among patients. Basal-like breast cancer is one of the most challenging subtypes to treat because it lacks effective therapeutic targets. Despite numerous studies on potential targetable molecules in this subtype, few targets have shown promise. However, the present study revealed that FOXD1, a transcription factor that functions in both normal development and malignancy, is associated with poor prognosis in basal-like breast cancer. We analyzed publicly available RNA sequencing data and conducted FOXD1-knockdown experiments, finding that FOXD1 maintains gene expression programs that contribute to tumor progression. We first conducted survival analysis of patients grouped via a Gaussian mixture model based on gene expression in basal-like tumors, finding that FOXD1 is a prognostic factor specific to this subtype. Then, our RNA sequencing and chromatin immunoprecipitation sequencing experiments using the basal-like breast cancer cell lines BT549 and Hs578T with FOXD1 knockdown revealed that FOXD1 regulates enhancer-gene programs related to tumor progression. These findings suggest that FOXD1 plays an important role in basal-like breast cancer progression and may represent a promising therapeutic target.
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Purpose: This study aims to compare the clinicopathological and immunohistochemical characteristics of centrally necrotizing carcinoma of the breast (CNC) and basal-like breast cancer (BLBC), as well as to analyze the characteristics of the molecular typing of the CNC. Methods: The clinicopathological features of 69 cases of CNC and 48 cases of BLBC were observed and compared. EnVision immunohistochemical staining was performed to detect the expressions of hypoxia-inducible factor 1α (HIF-1α), breast cancer susceptibility gene 1 (BRCA1), and vascular endothelial growth factor (VEGF) in CNC and BLBC. Results: The age of the 69 patients ranged from 32 to 80 years, with an average of 54.55 years. Gross examination showed that most tumors were well-defined single central nodules with a diameter of 1.2~5.0 cm. Microscopically, there is a large necrotic or acellular area in the center of the tumor, mainly composed of tumor coagulative necrosis with varying degrees of fibrosis or hyaline degeneration. A small amount of cancer tissue remained in the form of a ribbon or small nest around the necrotic focus. Among 69 cases of CNC, the proportion of basal cell type (56.5%) was significantly higher than that of lumen type A (18.84%), lumen type B (13.04%), HER2 overexpression (5.8%), and nonexpression (5.8%). A total of 31 cases were followed up for 8~50 months, with an average of 33.94 months. There have been nine cases of disease progression. When compared to BLBC, there were no significant differences in BRCA1 and VEGF protein expression in response to CNC (p > 0.05), but there were significant differences in protein expression in HIF-1α (p < 0.05). Conclusion: The molecular typing of CNC showed that over half of those were BLBC. No statistically significant difference in the expression of BRCA1 was observed between CNC and BLBC; thus, we predict that targeted therapy for BRCA1 in BLBC may also have considerable effects in CNC patients. The expression of HIF-1α is significantly different in CNC and BLBC, and perhaps HIF-1α can be used as a new entry point to distinguish between the two. There is a significant correlation between the expression of VEGF and HIF-1α in BLBC, and there was no significant correlation between the expression levels of the two proteins in CNC.
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Basal-like triple-negative breast cancer (TNBC) tumor cells are difficult to eliminate due to resistance mechanisms that promote survival. While this breast cancer subtype has low PIK3CA mutation rates when compared to estrogen receptor-positive (ER+) breast cancers, most basal-like TNBCs have an overactive PI3K pathway due to gene amplification or high gene expression. BYL-719 is a PIK3CA inhibitor that has been found to have low drug-drug interactions, which increases the likelihood that it could be useful for combinatorial therapy. Alpelisib (BYL-719) with fulvestrant was recently approved for treating ER+ breast cancer patients whose cancer had developed resistance to ER-targeting therapy. In these studies, a set of basal-like patient-derived xenograft (PDX) models was transcriptionally defined with bulk and single-cell RNA-sequencing and clinically actionable mutation profiles defined with Oncomine mutational profiling. This information was overlaid onto therapeutic drug screening results. BYL-719-based, synergistic two-drug combinations were identified with 20 different compounds, including everolimus, afatinib, and dronedarone, which were also found to be effective at minimizing tumor growth. These data support the use of these drug combinations towards cancers with activating PIK3CA mutations/gene amplifications or PTEN deficient/PI3K overactive pathways.
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Basal-like breast cancer (BBC) and glioblastoma multiforme (GBM) are poor-prognosis cancers that lack effective targeted therapies and harbor embryonic stem gene expression signatures. Recently, our group and others found that forkhead box transcription factor FOXO1 promotes stem gene expression in BBC and GBM cell lines. Given the critical role of cancer stem cells in promoting cancer progression, we examined the impact of FOXO1 inhibition with AS1842856 (a cell-permeable small molecule that directly binds to unphosphorylated FOXO1 protein to block transcriptional regulation) on BBC and GBM cell viability. We treated a set of BBC and GBM cancer cell lines with increasing concentrations of AS1842856 and found reduced colony formation. Treatment of BBC and GBM cancer cells with AS1842856 led to increases in FAS (FAS cell surface death receptor) and BIM (BCL2L11) gene expression, as well as increased positivity for markers for apoptosis such as annexin V and propidium iodide. Treatment with another FOXO1 inhibitor AS1708727 or FOXO1 RNAi also led to FAS induction. This work is the first to show that targeting BBC and GBM with FOXO1 inhibition leads to apoptosis. These novel findings may ultimately expand the repertoire of therapies for poor-prognosis cancers.