Similar Datasets
Project description:Individual cancers are composed of heterogeneous tumor cells with distinct phenotypes and genotypes, with triple negative breast cancers (TNBC) demonstrating the most heterogeneity among breast cancer types. Variability in transcriptional phenotypes could meaningfully limit the efficacy of monotherapies and fuel drug resistance, although to an unknown extent. To determine if transcriptional differences between tumor cells lead to differential drug responses we performed single cell RNA-seq on cell line and PDX models of breast cancer revealing cell subpopulations in states associated with resistance to standard-of-care therapies. We found that TNBC models contained a subpopulation in an inflamed cellular state, often also present in human breast cancer samples. Inflamed cells display evidence of heightened cGAS/STING signaling which we demonstrate is sufficient to cause tumor cell resistance to chemotherapy. Accordingly, inflamed cells were enriched in human tumors taken after neoadjuvant chemotherapy and associated with early recurrence, highlighting the potential for diverse tumor cell states to promote drug resistance.
2023-12-18 | GSE250157 | GEO
Project description:Individual cancers are composed of heterogeneous tumor cells with distinct phenotypes and genotypes, with triple negative breast cancers (TNBC) demonstrating the most heterogeneity among breast cancer types. Variability in transcriptional phenotypes could meaningfully limit the efficacy of monotherapies and fuel drug resistance, although to an unknown extent. To determine if transcriptional differences between tumor cells lead to differential drug responses we performed single cell RNA-seq on cell line and PDX models of breast cancer revealing cell subpopulations in states associated with resistance to standard-of-care therapies. We found that TNBC models contained a subpopulation in an inflamed cellular state, often also present in human breast cancer samples. Inflamed cells display evidence of heightened cGAS/STING signaling which we demonstrate is sufficient to cause tumor cell resistance to chemotherapy. Accordingly, inflamed cells were enriched in human tumors taken after neoadjuvant chemotherapy and associated with early recurrence, highlighting the potential for diverse tumor cell states to promote drug resistance.
2023-12-18 | GSE250156 | GEO
Project description:BACKGROUND:Chemotherapy resistance is a great obstacle in effective treatment for metastatic triple negative breast cancer (TNBC). The ability to predict chemotherapy response would allow chemotherapy administration to be directed toward only those patients who would benefit, thus maximizing treatment efficiency. Differentially expressed plasma proteins may serve as putative biomarkers for predicting chemotherapy outcomes. PATIENTS AND METHODS:In this study, 26 plasma samples (10 samples with partial response (S) and 16 samples with progression disease (R)) from patients with metastatic TNBC were measured by Tandem Mass Tag (TMT)-based proteomics analysis to identify differentially expressed proteins between the S and R group. Potential proteinswere validated with enzyme-linked immunosorbent assay (ELISA) in another 67 plasma samples. RESULTS:A total of 320 plasma proteins were identified, and statistical analysis showed that 108 proteins were significantly dysregulated between R and S groups in the screening stage. Bioinformatics revealed relevant pathways and regulatory networks of the differentially expressed proteins. Three differentially expressed proteins were validated by ELISA with 67 samples from TNBC patients. The R group had significantly higher plasma CAMK2A level than the S group (P=0.0074). The ROC curve analysis showed an AUC of 0.708, with sensitivity 48.4% and specificity 86.1%. In multivariate logistic regression analysis, the level of plasma CAMK2A was also significant for chemotherapeutic response (P=0.009, OR=0.152). Furthermore, the patients with higher CAMK2A level had shorter OS than those with lower CAMK2A level, which amounted to 13.9 and 28.9 months, respectively (P=0.034). In the multivariate Cox regression analysis, CAMK2A level still had significant effect on OS (P=0.031, HR=1.865). CONCLUSION:TMT-based proteomic analysis was able to identify potential biomarkers in plasma that predicted chemotherapy resistance in the metastatic TNBC. The plasma of CAMK2A level may serve as apotential predictive and prognostic biomarker for chemotherapy in metastatic TNBC.
| S-EPMC6958019 | biostudies-literature
Project description:Humanin (HN) is a mitochondrial-derived peptide with cytoprotective effect in many tissues. Administration of HN analogs has been proposed as therapeutic approach for degenerative diseases. Although HN has been shown to protect normal tissues from chemotherapy, its role in tumor pathogenesis is poorly understood. Here, we evaluated the effect of HN on the progression of experimental triple negative breast cancer (TNBC). The meta-analysis of transcriptomic data from The Cancer Genome Atlas indicated that HN and its receptors are expressed in breast cancer specimens. By immunohistochemistry we observed up-regulation of HN in TNBC biopsies when compared to mammary gland sections from healthy donors. Addition of exogenous HN protected TNBC cells from apoptotic stimuli whereas shRNA-mediated HN silencing reduced their viability and enhanced their chemo-sensitivity. Systemic administration of HN in TNBC-bearing mice reduced tumor apoptotic rate, impaired the antitumor and anti-metastatic effect of chemotherapy and stimulated tumor progression, accelerating tumor growth and development of spontaneous lung metastases. These findings suggest that HN may exert pro-tumoral effects and thus, caution should be taken when using exogenous HN to treat degenerative diseases. In addition, our study suggests that HN blockade could constitute a therapeutic strategy to improve the efficacy of chemotherapy in breast cancer.
| S-EPMC7244539 | biostudies-literature
Project description:Chemoresistance is a major obstacle in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. Here we identify hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key inducer of chemoresistance by developing chemoresistant TNBC tumors in vivo and characterizing their transcriptomes by RNA-sequencing. Inhibiting LOX reduces collagen cross-linking and fibronectin assembly, increases drug penetration, and downregulates ITGA5/FN1 expression, resulting in inhibition of FAK/Src signaling, induction of apoptosis and re-sensitization to chemotherapy. Similarly, inhibiting FAK/Src results in chemosensitization. These effects are observed in 3D-cultured cell lines, tumor organoids, chemoresistant xenografts, syngeneic tumors and PDX models. Re-expressing the hypoxia-repressed miR-142-3p, which targets HIF1A, LOX and ITGA5, causes further suppression of the HIF-1α/LOX/ITGA5/FN1 axis. Notably, higher LOX, ITGA5, or FN1, or lower miR-142-3p levels are associated with shorter survival in chemotherapy-treated TNBC patients. These results provide strong pre-clinical rationale for developing and testing LOX inhibitors to overcome chemoresistance in TNBC patients.
| S-EPMC7229173 | biostudies-literature
Project description:Breast cancer (BC) is a leading cause of cancer-related death in women. Adjuvant systemic chemotherapies are effective in reducing risks of recurrence and have contributed to reduced BC mortality. Although targeted adjuvant treatments determined by biomarkers for endocrine and HER2-directed therapies are largely successful, predicting clinical benefit from chemotherapy is more challenging. Drug resistance is a major reason for treatment failures. Efforts are ongoing to find biomarkers to select patients most likely to benefit from chemotherapy. Importantly, cell surface biomarkers CD44+/CD24- are linked to drug resistance in some reports, yet underlying mechanisms are largely unknown. This study focused on the potential role of CD24 expression in resistance to either docetaxel or doxorubicin in part by the use of triple-negative BC (TNBC) tissue microarrays. In vitro assays were also done to assess changes in CD24 expression and differential drug susceptibility after chemotherapy. Further, mouse tumor xenograft studies were done to confirm in vitro findings. Overall, the results show that patients with CD24-positive TNBC had significantly worse overall survival and disease-free survival after taxane-based treatment. Also, in vitro cell studies show that CD44+/CD24+/high cells are more resistant to docetaxel, while CD44+/CD24-/low cells are resistant to doxorubicin. Both in vitro and in vivo studies show that cells with CD24-knockdown are more sensitive to docetaxel, while CD24-overexpressing cells are more sensitive to doxorubicin. Further, mechanistic studies indicate that Bcl-2 and TGF-βR1 signaling via ATM-NDRG2 pathways regulate CD24. Hence, CD24 may be a biomarker to select chemotherapeutics and a target to overcome TNBC drug resistance.
| S-EPMC5503533 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) represents a heterogeneous breast cancer subtype with a poor prognosis. The optimal adjuvant chemotherapy regimen is still unknown. Although numerous large randomized trials have established the benefit of adjuvant anthracyclines and/or taxanes in TNBC, there is no preferred regimen for these patients. There is currently no guideline. Moreover, without knowing the optimal treatment backbone, it will not be possible to evaluate whether adding agents such as platinum or other novel therapies is beneficial for TNBC patients. Furthermore, the best duration of adjuvant treatment in TNBC is still unknown. This review will focus on results of clinical trials that analyzed the benefits of extending the duration of adjuvant treatment in TNBCs with maintenance treatments. We will further discuss promising results in favor of other new agents including capecitabine, metronomic treatment, and biological drugs.
| S-EPMC5527164 | biostudies-other
Project description:The optimal neoadjuvant chemotherapy (NACT) regimen in triple-negative breast cancer (TNBC) has not been clearly defined. Achieving a pathologic complete response (pCR) provides important prognostic information, and, especially in TNBC, is considered a surrogate endpoint for event-free survival. Thus, many neoadjuvant studies in TNBC focus on this as a primary endpoint, and such information may be used for accelerated US Food and Drug Administration approval. Current controversies in the field include: (1) the role of platinum-based compounds; (2) the optimal chemotherapy backbone; and (3) the benefits of additional therapy after surgery. Conflicting results of 2 major studies adding carboplatin to NACT have highlighted the need to balance potential benefits to disease outcomes against increased toxicity. While the PROGECT study suggests efficacy of a nonanthracycline-containing regimen, this is observational data, and evidence in the form of a clinical trial remains to be seen. Data surrounding optimal taxane use support the use of nab-paclitaxel in place of paclitaxel in limited clinical situations. Although bevacizumab may increase pCR rates, this has not translated into survival benefit. Capecitabine shows promise in patients who have not achieved pCR after NACT. The neoadjuvant setting remains an important model for drug development. This review will focus on the most important and most current neoadjuvant trials in women with TNBC.
| S-EPMC5865448 | biostudies-literature
Project description:Using gene-expression data from over 6,000 breast cancer patients, we report herein that high CD73 expression is associated with a poor prognosis in triple-negative breast cancers (TNBC). Because anthracycline-based chemotherapy regimens are standard treatment for TNBC, we investigated the relationship between CD73 and anthracycline efficacy. In TNBC patients treated with anthracycline-only preoperative chemotherapy, high CD73 gene expression was significantly associated with a lower rate of pathological complete response or the disappearance of invasive tumor at surgery. Using mouse models of breast cancer, we demonstrated that CD73 overexpression in tumor cells conferred chemoresistance to doxorubicin, a commonly used anthracycline, by suppressing adaptive antitumor immune responses via activation of A2A adenosine receptors. Targeted blockade of CD73 enhanced doxorubicin-mediated antitumor immune responses and significantly prolonged the survival of mice with established metastatic breast cancer. Taken together, our data suggest that CD73 constitutes a therapeutic target in TNBC.
| S-EPMC3704029 | biostudies-literature
Project description:Anurag M, Jaehnig EJ, Krug K, Lei JT, Bergstrom EJ, Kim BJ, Vashist TD, Huynh AMT, Dou Y, Gou X, Huang C, Shi Z, Wen B, Korchina V, Gibbs RA, Muzny DM, Doddapaneni H, Dobrolecki LE, Rodriguez H, Robles AI, Hiltke T, Lewis MT, Nangia J, Shafaee MN, Hagemann I, Hoog J, Lim B, Osborne CK, Mani DR, Gillette MA, Zhang B, Echeverria GV, Miles G, Rimawi MF, Carr SA, Ademuyiwa FO, Satpathy S, and Ellis MJ.
Microscaled proteogenomics was deployed to probe the molecular basis for differential response to neoadjuvant carboplatin & docetaxel combination chemotherapy for triple-negative breast cancer (TNBC). Proteomic analyses of pre-treatment biopsies uniquely revealed that metabolic pathways including oxidative phosphorylation, fatty acid metabolism and glycolysis were resistance-associated. Both proteomics and transcriptomics revealed that sensitivity was marked by elevation of DNA repair, E2F targets, G2M checkpoint, interferon-gamma response, and immune checkpoint components. Proteogenomic analyses of somatic copy number aberrations identified a resistance-associated 19q13.32-33 deletion where LIG1, POLD1 and XRCC1 are located. In orthogonal datasets, LIG1 (DNA ligase I involved in lagging strand synthesis) gene deletion and/or low mRNA expression were associated with lack of pathological complete response and poor prognosis in TNBC, as well as selective carboplatin-resistance in TNBC patient-derived xenograft models. Low expression or LIG1 loss was also associated with higher chromosomal instability index (CIN) and poor prognosis in other cancer types, demonstrating that deletion of lagging-strand synthesis components has broad clinical significance.
2022-06-29 | MSV000089758 | MassIVE