Integrating transcription factor networks with chromatin accessibility as markers of survival outcome and drug response in triple-negative breast cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE323120 | GEO | 2026/06/24
REPOSITORIES: GEO
Similar Datasets
Project description:Neoadjuvant chemotherapy (NAC) is the major pre-treatment for breast cancer before surgery. Patients who achieve pathologic complete response (pCR) have a higher chance to receive lumpectomy and a better quality of life after neoadjuvant treatment. Luminal subtype breast cancer has poor NAC response compared with triple-negative breast cancer (TNBC) subtype. The molecular and cellular mechanisms underlying this chemoresistance are not fully understood. Here we report that the 17 featured transcriptional factors (TFs) in luminal and TNBC were identified. The association between 17 TFs and NAC pCR were analysis and exogenous luminal featured TF GATA3 overexpression promotes chemotherapy resistance in TNBC cell lines whereas its knockdown promotes sensitivity. In mechanism, we found that anthracycline based chemotherapy induces robust cellular ROS and Fe2+ overload in sensitivity cells; GATA3 mediates cell survival through repress CYB5R2 expression and Fenton reducing in DOX recycle which reduce cellular ROS and Fe2+ level during chemotherapy procedure. These founding altogether indicate that luminal featured transcription factor GATA3 enhance NAC resistance thorough repress ROS production and Fenton reducing. Breast cancer patient with GATA3 high expression might not suit for anthracycline based NAC regimen.
2023-01-01 | GSE216413 | GEO
Project description:Triple-Negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is associated with poor prognosis due to its propensity to form metastases. Unfortunately, the current treatment options are limited to chemotherapy such that identification of actionable targets are needed. The receptor tyrosine kinase AXL plays a role in the tumor cell dissemination and its expression in TNBC correlates with poor patients? survival. Here, we explored whether exploiting an AXL knockdown gene signature in TNBC cells may offer an opportunity for drug repurposing. To this end, we queried the PharmacoGx pharmacogenomics platform with an AXL gene signature which revealed Phenothiazines, a class of Dopamine Receptors antagonists (Thioridazine, Fluphenazine and Trifluoperazine) typically used as anti-psychotics. We next tested if drugs may be active to limit growth and metastatic progression of TNBC cells, similarly to AXL depletion. We found that the Phenothiazines were able to reduce cel l invasion, proliferation and viability, and also increased apoptosis of TNBC cells in vitro. Mechanistically, these drugs did not affect AXL activity but instead reduced PI3K/AKT/mTOR and ERK signaling. When administered to mice bearing TNBC xenografts, these drugs showed were able to reduce tumor growth and metastatic burden. Collectively, these results suggest that these antipsychotics are novel anti-tumor and anti-metastatic agents that could potentially be repurposed, in combination with standard chemotherapy, for use in TNBC.
2019-04-01 | GSE120268 | GEO
Project description:Evidence suggests that BRCA1 mutation associated tumors have increased sensitivity to DNA damaging agents like cisplatin. Sporadic triple negative breast cancers (TNBC) have many phenotypic similarities to BRCA1 tumors and may have a similar sensitivity to cisplatin. We tested the efficacy of cisplatin monotherapy in 28 TNBC patients in a single arm neoadjuvant trial with outcome measured by pathologic treatment response quantified using the Miller-Payne scale. We used microarrays gene expression profiles to determine tumor subtype of each trial tumor sample and to test various expression signatures for association with pathologic response to cisplatin. Pretreatment tumor samples from the clinical trial (N=24 with adequate tissue) were used for RNA extraction, linear amplification, biotin labeling and hybridization to Affymetrix U133 plus 2.0 arrays. A reference set of 51 primary breast tumors representing all subtypes of breast cancer were processed in a similar manner to include linear amplification, and hybridized to Affymetrix arrays.
2009-11-04 | E-GEOD-18864 | biostudies-arrayexpress
Project description:Breast cancer is the most common malignancy that develops in women, responsible for the highest cancer-associated death rates. Triple negative breast cancers (TNBC) represent an important subtype that have an aggressive clinical phenotype, are associated with a higher likelihood of metastasis and are not responsive to current targeted therapies. miRNAs have emerged as an attractive candidate for molecular biomarkers and treatment targets in breast cancer, but their role in the progression of TNBC remains largely unexplored. This study has investigated miRNA expression profiles in 31 primary TNBC cases and in 13 lymph node metastases compared with 23 matched normal breast tissues to determine miRNAs associated with the initiation of this disease subtype and those associated with its metastasis. 71 miRNAs were differentially expressed in TNBC, the majority of which have previously been associated with breast cancer, including members of the miR-200 family and the miR-17-92 oncogenic cluster, suggesting that miRNAs involved in the initiation of TNBC are not subtype specific. However, the repertoire of miRNAs expressed in lymph node negative and lymph node positive TNBCs were largely distinct from one another. In particular, miRNA profiles associated with lymph node negative disease tended to be up-regulated, while those associated with lymph node positive disease were down-regulated and largely overlapped with the profiles of their matched lymph node metastases. miRNA expression profiles were examined in 31 primary TNBC cases and in 13 lymph node metastases compared with 23 matched normal breast tissues
2014-11-24 | E-GEOD-38167 | biostudies-arrayexpress
Project description:Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the highest rates of recurrence, metastasis and patient mortality due to lack of effective targeted therapies. In this study, we demonstrate that ISG20 expression is induced by hypoxia and directly targeted by HIF-1 for transcription in TNBC cells. ISG20 functions as RNA exonuclease to target mRNAs for degradation, resulting in breast cancer stem cell specification and lung metastasis, and also cancer cell immune evasion. Mostly importantly, ISG20 silencing could markedly increase the sensitivity of TNBC to anti-PD1 immune checkpoint blockade (ICB) in a mouse model. Our data suggested that, in combination with immunotherapy, targeting ISG20 might be an effective strategy for TNBC treatment.
2025-11-25 | GSE287164 | GEO
Project description:Triple-negative breast cancer (TNBC) is the most heterogeneous and aggressive subtype of breast carcinoma, defined by the absence of clinical biomarkers and the lack of targeted therapies. Despite numerous clinical trials, patient stratification remains suboptimal, limiting the identification of effective treatment strategies. In this study, we aimed to identify biomarkers exclusively expressed in the basal mammary epithelial compartment to refine TNBC subclassification. Through computational analysis of single-cell RNA sequencing data, we defined a set of basal identity genes, which were subsequently validated by immunohistochemistry in two independent TNBC cohorts. This approach enabled the identification of a novel TNBC subgroup, termed true basal TNBC (tB-TNBC), associated with poorer prognosis and distinct molecular features. To uncover therapeutic vulnerabilities in this subgroup, we conducted a high-throughput screen of 3,200 FDA-approved compounds in breast cancer cell lines classified by basal marker expression. This analysis identified dasatinib as a promising candidate with selective activity against tB-TNBC models. Furthermore, TAGLN emerged as a strong predictive biomarker of dasatinib response, with functional studies confirming its role in modulating drug sensitivity. Altogether, these findings support the clinical utility of basal markers for TNBC stratification and highlight a targeted treatment opportunity for tB-TNBC patients.
2026-02-04 | GSE300385 | GEO
Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by a poor prognosis owing to the lack of therapeutic targets, including hormone receptors and HER2. Systemic chemotherapy remains the primary treatment option; however, its efficacy is frequently limited by chemotherapy resistance, a substantial challenge in clinical management. In the present study, we aimed to develop a novel anticancer drug that overcomes chemotherapy resistance in TNBC. First, chemotherapy-resistant MDA-MB-468 cells derived from TNBC were developed via long-term exposure to adriamycin or paclitaxel. Compared with wild-type cells, these resistant cells exhibited reduced sensitivity to paclitaxel, adriamycin, and eribulin in the viability assays. Various compounds were screened for their cell growth-inhibitory activity against these resistant cells to identify novel therapeutic agents; ZSTK3744 was a promising candidate and showed significant anti-tumor activity in vitro and in vivo. Mechanistically, ZSTK3744 upregulated CYP1A1, CYP1B1, and TIPARP expression in MDA-MB-468 cells but exhibited no cell growth-inhibitory activity in aryl hydrocarbon receptor (AhR) knockout cells, indicating that ZSTK3744 act as an AhR agonist. Notably, ZSTK3744 demonstrated superior tumor inhibition and lower pulmonary toxicity in ex vivo and in vivo models than other AhR agonists. These results suggest that ZSTK3744 combines robust cell growth-inhibitory activity with a favorable safety profile. In conclusion, ZSTK3744 is a promising candidate for overcoming chemotherapy resistance in TNBC, addressing the urgent need for more effective treatment options for this aggressive cancer subtype. This study represents the first demonstration of the anti-tumor activity of an AhR agonist on chemotherapy-resistant TNBC.
2025-12-31 | GSE305009 | GEO
Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by a poor prognosis owing to the lack of therapeutic targets, including hormone receptors and HER2. Systemic chemotherapy remains the primary treatment option; however, its efficacy is frequently limited by chemotherapy resistance, a substantial challenge in clinical management. In the present study, we aimed to develop a novel anticancer drug that overcomes chemotherapy resistance in TNBC. First, chemotherapy-resistant MDA-MB-468 cells derived from TNBC were developed via long-term exposure to adriamycin or paclitaxel. Compared with wild-type cells, these resistant cells exhibited reduced sensitivity to paclitaxel, adriamycin, and eribulin in the viability assays. Various compounds were screened for their cell growth-inhibitory activity against these resistant cells to identify novel therapeutic agents; ZSTK3744 was a promising candidate and showed significant anti-tumor activity in vitro and in vivo. Mechanistically, ZSTK3744 upregulated CYP1A1, CYP1B1, and TIPARP expression in MDA-MB-468 cells but exhibited no cell growth-inhibitory activity in aryl hydrocarbon receptor (AhR) knockout cells, indicating that ZSTK3744 act as an AhR agonist. Notably, ZSTK3744 demonstrated superior tumor inhibition and lower pulmonary toxicity in ex vivo and in vivo models than other AhR agonists. These results suggest that ZSTK3744 combines robust cell growth-inhibitory activity with a favorable safety profile. In conclusion, ZSTK3744 is a promising candidate for overcoming chemotherapy resistance in TNBC, addressing the urgent need for more effective treatment options for this aggressive cancer subtype. This study represents the first demonstration of the anti-tumor activity of an AhR agonist on chemotherapy-resistant TNBC.
2025-12-31 | GSE305008 | GEO
Project description:Estrogen receptor-positive breast cancer (ER+BC) represents nearly 75% of all breast tumors, with nearly 20-40% patients eventually developing metastases. Everolimus is an mTOR inhibitor which has been approved for use in combination with exemestane in patients with metastatic ER+BC. However, many patients eventually develop resistance to everolimus leading to poor survival outcomes. Systematic characterization of the molecular phenotypes underlying everolimus resistance could reveal new therapeutic targets for metastatic ER+BC. We analyzed transcriptomic profiles from multiple pairs of everolimus resistant or sensitive ER+BC cell lines, to identify signaling mechanisms that distinguish resistant cells both at baseline and under everolimus treatment. Using a linear mixed-effects model, we identified strong activation of the growth-factor signaling meta-phenotype in resistant cells at baseline, which persisted even under everolimus treatment. This meta phenotype included alternate growth signaling mechanisms including IGF1R/insulin, ESR1, RAS and MAPK signaling. To understand the regulatory mechanism behind alternate growth-factor signaling activation, we adopted a network reconstruction architecture to identify SMARCD3 regulons as key transcriptional regulatory networks in resistant cells. In a neo-adjuvant trial for ER+BC patients, the expression levels of SMARCD3 and its regulon’s activity were significantly elevated in tumors refractory to everolimus. To develop a therapeutic strategy against everolimus resistance, we used transcriptomic and drug sensitivity profiles of 926 cancer cell lines treated with 395 compounds. We found that the activation of SMARCD3 regulons was consistently associated with sensitivity to several known MEK1/2 inhibitors, including trametinib. To validate these findings, we evaluated the efficacy of everolimus in combination with trametinib and demonstrated that the combination treatment significantly reduced the growth of resistant cells compared to everolimus. Our results demonstrate that everolimus resistant ER+BC cells utilize alternate growth-factor signaling to escape therapeutic control. We found that this phenotype is strongly linked with activation of the SMARCD3 regulons and can be therapeutically targeted using MEK1/2 inhibitors.
2025-12-11 | GSE286174 | GEO
Project description:Breast cancer is genetically and clinically heterogeneous. Triple negative cancer (TNBC) is a subtype of breast cancer usually associated with poor outcome and lack of benefit from target therapy. A pathway analysis in a microarray study was performed using TNBC compared with non-triple negative breast cancer (non-TNBC). Overexpression of several Wnt pathway genes, such as frizzled homolog 7 (FZD7), Low density lipoprotein receptor-related protein 6 (LRP6) and transcription factor 7 (TCF7) has been observed in TNBC. Focus was given to the Wnt pathway receptor, FZD7. To validate its function, inhibition of FZD7 using FZD7shRNA was carried out. Notably decreased cell proliferation, suppressed invasiveness and colony formation in triple negative MDA-MB-231 and BT-20 cells were observed. Mechanism study indicated that these effects occurred through silencing the canonical Wnt signaling pathway, as evidenced by loss of nuclear accumulation of ï?¢-catenin and decreased transcriptional activity of TCF7. In vivo study revealed that FZD7shRNA significantly suppressed the tumor formation in xenotransplation mice due to decrease cell proliferation. Our finding suggests that FZD7 involved canonical Wnt signaling pathway is essential for tumorigenesis of TNBC. Thus, FZD7 may be a biomarker and a potential therapeutic target for triple negative breast cancer. 14 pretreatment non-triple negative breast tumors compare with 5 triple negative breast tumor.
2011-06-01 | E-GEOD-27447 | biostudies-arrayexpress