Project description:This microarray dataset contains 51 triple-negative breast cancers with clinical and recurrence information for at least 3 years of follow-up and 106 luminal breast cancers (reanalyzed data from Series GSE24124, GSE9309, and GSE17040). A novel set of 45-gene signature that was statistically predictive of distant metastasis recurrence for triple-negative breast cancer was identified in this study.
Project description:Tumor-initiating cells with reprogramming plasticity and/or de-differentiation attributes have been thought to initiate primary tumor development as well as to regenerate secondary tumors in metastatic organs; however, the molecular mechanisms are not fully understood. We previously found that breast tumor-initiating cell marker, CD44, directs multicellular aggregation and cluster formation of circulating tumor cells (CTCs), which further enhance stemness and survival of such cells, enabling metastatic colonization to the lungs. To further elucidate the molecular network underlying CTC cluster formation, we performed global proteomic profiling and discovered that the tetraspanin protein CD81, which is normally enriched in exosomes (small extracellular vesicles), is a new driver of cancer initiation and metastasis as a facilitator and target of CD44. Loss of CD81 compromises tumorigenicity and mammosphere formation of triple negative breast cancer (TNBC) cells. Assisted by machine learning-based algorithms and mutagenesis approach, we found that CD81 interacts with CD44 on the cellular membrane through their extracellular regions. Notably, genetic knockout of CD44 or CD81 results in loss of both CD81 and CD44 in secreted exosomes, a state which abolishes exosome-induced self-renewal of recipient cells, such as mammosphere formation. In addition, RNA sequencing analysis showed that CD81 knockdown up-regulates expression of a cell differentiation marker, SEMA7a, whose down-regulation partially rescues mammosphere formation inhibition by CD81 depletion. Clinically, CD81 expression was observed in >80% of CTCs and specifically enriched and co-expressed along with CD44 in clustered CTCs of breast cancer patients. Mimicing the phenotypes of CD44 deficiency, loss of CD81 also inhibited tumor cell aggregation and lung metastasis of TNBC in both human and mouse tumor models, supporting the clinical significance of CD81 in association with patient outcomes. Our study highlights a new driving role of CD81 in cancer exosome-induced stemness, clustered CTCs, and metastasis initiation of TNBC, reported for the first time to our knowledge.
Project description:We identified sensory nerves as more abundant in triple-negative human breast tumors. Human triple negative breast cancer (TNBC) cells (MDA-MB-231, SUM159) were co-cultured with mice primary sensory neurons from dorsal root ganglia (DRG). Breast can-cer cells were found to attach to neurons and have higher migration speed and prolifera-tion rate. Species-specific RNA sequencing highlighted cell migration and adhesion among the most upregulated pathways for cancer cells in coculture. We identified a novel mechanism where cancer’s PlexinB3 interacted with neuron’s Sema5A to regulate attachment and migration along nerve fibers. These findings demonstrate that sensory nerves induced a drastic shift in TNBC cells gene expression, and that dirupting the nerve-cancer is a viable strategy to impede metastasis
Project description:Aberrant SMAD3 activation has been implicated as a driving event in cancer metastasis. However, the drivers of SMAD3 activation are poorly defined. Here, we identify SMAD3 as a non-histone substrate of lysine acetyltransferase 6A (KAT6A). The acetylation of SMAD3 at K20 and K117 by KAT6A with promotes SMAD3 association with oncogenic H3K23ac reader TRIM24 and upregulation of immune response-related cytokines. This event in turn leads to enhanced myeloid-derived suppressor cell (MDSC) recruitment and triple-negative breast cancer (TNBC) metastasis. Inhibiting KAT6A in combination with anti-PD-L1 therapy in treating breast cancer xenograft-bearing animals markedly attenuates TNBC metastasis and provides a significant survival benefit. Thus, our work presents an KAT6A acetylation-dependent regulatory mechanism governing SMAD3 oncogenic function and provides insight into how targeting an epigenetic factor with immunotherapies enhances the anti-metastasis efficacy.
Project description:This microarray dataset contains 51 triple-negative breast cancers, 25 normal breast tissues, and 106 luminal breast cancers (reanalyzed data from Series GSE24124, GSE9309, and GSE17040). Keywords: Expression profiling by array Specimens of breast cancer tissue were collected and snap-frozen from breast cancer patients who had surgery between 1995 and 2008 at National Taiwan University Hospital (NTUH, Taipei, Taiwan). Clinicopathological information was obtained for all breast cancer patients along with informed consent. The AJCC/UICC TNM system was used for breast cancer staging classification.
Project description:Breast cancer is one of the most common cancers in women. Of the different subtypes of breast cancer, the triple negative breast cancer subtype of breast cancer is the most aggressive. A proteomic screen of nucleolar content across breast cancer subtypes found that triple negative breast cancer cell lines have a distinct nucleolar proteome signature in comparison to non-TNBC breast cancer cell lines.
Project description:We propose to definitively characterise the somatic genetics of triple negative breast cancer through generation of comprehensive catalogues of somatic mutations in breast cancer cases by high coverage genome sequencing coupled with integrated transcriptomic and methylation analyses.