Project description:Triple-negative breast cancer (TNBC), characterized by the lack of hormone receptors and HER2 expression, remains a challenging subtype due to the absence of effective targeted therapies. Tumor budding (TB), a histopathological feature reflecting invasive potential, has recently emerged as a valuable prognostic marker across various cancers, including TNBC. Identifying transcriptomic alterations associated with high TB is critical for understanding mechanisms of tumor progression and immune evasion. In this study, we employed TempO-Seq, a high-throughput targeted RNA sequencing technology, to profile gene expression in immune cell-enriched regions of breast cancer tissues. Our objective was to uncover immune-related biomarkers and gene signatures specific to high TB cases, with the ultimate goal of informing prognostic stratification and potential therapeutic targets in aggressive breast cancer subtypes.
Project description:Triple negative breast cancers lack targeted therapies with little side effects and contain higher percentage of cancer stem cells than the other breast cancer subtypes. Genes capturing the features of cancer stem cells of such diseases may serve as potential subtyping marker or therapeutic targets for triple negative breast cancer management. This data descriptor presents a set of transcriptome data from 3 cohorts of cancer stem cells as represented as CD44+/CD24-/low and 2 cohorts of non-cancer stem cells isolated from triple negative breast cancer cells, each having 3 replicates.
Project description:Triple negative breast cancer is a heterogeneous disease with distinct molecular subtypes that differentially respond to chemotherapy and targeted agents. The purpose of this study was to explore the clinical relevance of Lehmann triple negative breast cancer subtypes by identifying any differences in response to neoadjuvant chemotherapy among them.
Project description:Using an H3K4ox-specific antibody, we determined that the H3K4ox modification is enriched in triple-negative breast cancer (TNBC) cells compared with luminal breast cancer subtypes—correlating with high LOXL2 levels— and, importantly, is found primarily in heterochromatin.
Project description:Triple negative breast cancer (TNBC) lacks targeted therapy options. TNBC is enriched in breast cancer stem cells (BCSCs), which play a key role in metastasis, chemoresistance, relapse and mortality. γδ T cells hold great potential in immunotherapy against cancer, and might be an alternative to target TNBC. γδ T cells are commonly observed to infiltrate solid tumors and have an extensive repertoire of tumor sensing, recognizing stress-induced molecules and phosphoantigens (pAgs) on transformed cells. We show that patient derived triple negative BCSCs are efficiently recognized and killed by ex vivo expanded γδ T cells from healthy donors. Orthotopically xenografted BCSCs, however, were refractory to γδ T cell immunotherapy. Mechanistically, we unraveled concerted differentiation and immune escape: xenografted BCSCs lost stemness, expression of γδ T cell ligands, adhesion molecules and pAgs, thereby evading immune recognition by γδ T cells. Indeed, neither pro-migratory engineered γδ T cells, nor anti-PD 1 checkpoint blockade significantly prolonged overall survival of tumor-bearing mice. BCSC immune escape was independent of the immune pressure exerted by the γδ T cells, and could be pharmacologically reverted by Zoledronate or IFN-α treatment. These results pave the way for novel combinatorial immunotherapies for TNBC.
Project description:When triple-negative breast cancer (TNBC) patients have residual disease after neoadjuvant chemotherapy (NACT), they have a high risk of metastatic relapse. With immune infiltrate in TNBC being prognostic and predictive of response to treatment, our aim was to develop an immunologic transcriptomic signature using post NACT samples to predict relapse.
Project description:Breast tumors are highly heterogeneous and for many molecular subtypes no targeted therapies are available. These include breast cancers that display hallmarks of epithelial to mesenchymal transition (EMT), a process related to metastasis and enriched in triple negative breast cancers (TNBCs). To determine whether this EMT cellular state could be therapeutically exploited, we performed a large-scale chemical genetic screen. We identified a group of structurally related compounds, including the clinically advanced drug PKC412 (midostaurin), that targeted post-EMT breast cancer cells. PKC412 induced apoptosis specifically in basal-like TNBC cells and inhibited tumor growth in vivo. Structure activity relationship (SAR) studies, chemical proteomics, and computational modeling identified the kinase SYK as a critical PKC412 target. Specific SYK inhibitors and PKC412 displayed a similar profile across a large panel of breast cancer cell lines, indicating a shared mode of action. Phosphoproteomics analysis revealed that SYK activates STAT3, and chemical or genetic inhibition of STAT3 resulted in cell death in basal-like breast cancer cells. This non-oncogene addiction of basal-like breast cancer cells to SYK suggests that chemical SYK inhibition may be beneficial for a specific subset of triple negative breast cancer patients.
Project description:Systems modelling of the EGFR-PYK2-c-Met interaction network predicted and prioritized synergistic drug combinations for Triple-negative breast cancer
Project description:Breast cancers enriched for the triple negative breast cancer phenotype with extensive clinico-pathological features were profiled to establish their comprehensive transcriptional profiles
Project description:The objective is to identify splicing and expression changes that occur after spliceosome inhibition in triple-negative breast cancer using immune competent GEMM tumors.
