Project description:This SuperSeries is composed of the following subset Series: GSE41971: In vivo NCL-targeting affects breast cancer aggressiveness through miRNA regulation [NanoString] GSE41972: In vivo NCL-targeting affects breast cancer aggressiveness through miRNA regulation [Affymetrix] Refer to individual Series
Project description:MicroRNA (miRNA/miR) miR526b and miR655 overexpressed tumor cell-free secretions promote breast cancer phenotypes in the tumor microenvironment (TME). However, the mechanisms of miRNA regulating TME have never been investigated. With mass spectrometry analysis of MCF7-miRNA-overexpressed versus miRNA-low MCF7-Mock tumor cell secretomes, we identified 34 novel secretory proteins coded by eight genes YWHAB, TXNDC12, MYL6B, SFN, FN1, PSMB6, PRDX4, and PEA15 those are differentially regulated. We used bioinformatic tools and systems biology approaches to identify these markers’ role in breast cancer. Gene ontology analysis showed that the top functions are related to apoptosis, oxidative stress, membrane transport, and motility, supporting miRNA-induced phenotypes. These secretory markers expression is high in breast tumors, and a strong positive correlation exists between upregulated markers’ mRNA expressions with miRNA cluster expression in luminal A breast tumors. Gene expression of secretome markers is higher in tumor tissues compared to normal samples, and immunohistochemistry data supported gene expression data. Moreover, both up and downregulated marker expressions are associated with breast cancer patient survival. miRNA regulates these marker protein expressions by targeting transcription factors of these genes. Premature miRNA (pri-miR526b and pri-miR655) are established breast cancer blood biomarkers. Here we report novel secretory markers upregulated by miR526b and miR655 (YWHAB, MYL6B, PSMB6, and PEA15) are significantly upregulated in breast cancer patients’ plasma, and are potential breast cancer biomarkers.
Project description:Microtubule-associated serine/threonine-protein kinase-like (MASTL; a.k.a. Greatwall (Gwl) kinase) has an established role in the acceleration of cell cycle progression through inhibition of the PP2A-B55 phosphatase activity. Importantly, MASTL has emerged as a putative oncogene. Especially in breast cancer, high MASTL expression levels correlate with increased tumor growth and metastasis in vivo. We reported recently a kinase-independent role for MASTL as a regulator of cell adhesion, contractility and MRTF-A/SRF activity in breast cancer. This study also revealed that depletion of MASTL affects transcription and protein expression of multiple targets. Cell surface proteins are critical for characterization, isolation, and regulation of signaling. In order to reveal if MASTL affects breast cancer cells directly by regulation of surface proteins, we performed SILAC based surfaceome proteomics. Heavy and light isotope labelled endogenously produced surface proteins of MDA-MB-231 cells were purified by biotin enrichment and subjected to proteomics analysis.
Project description:This study introduces a predictive classifier for breast cancer-related proteins, utilising a combination of protein sequence descriptors and machine learning techniques. The best-performing classifier is a Multi Layer Perceptron (artificial neural network) with 300 features, achieving an average Area Under the Receiver Operating Characteristics (AUROC) score of 0.984 through 3-fold cross-validation. Notably, the model identified top-ranked cancer immunotherapy proteins associated with breast cancer that should be studied for further biomarker discovery and therapeutic targeting.
Please note that in this model, the output '0' means BC non-related protein and '1' means BC related protein. The original GitHub repository can be accessed at https://github.com/muntisa/neural-networks-for-breast-cancer-proteins
Project description:Numerous studies have described the altered expression and the causal role of miRNAs in human cancer. However, to date efforts to modulate miRNA levels for therapeutic purposes have been challenging to implement. Here, we find that Nucleolin (NCL), a major nucleolar protein, post-transcriptionally regulates the expression of a specific subset of miRNAs, including miR-21, miR-221, miR-222, and miR-103, causally involved in breast cancer initiation, progression and drug-resistance. We also show that NCL is commonly overexpressed in human breast tumors, and its expression correlates with that of NCL-dependent miRNAs. Finally, this study indicates that NCL-binding guanosine-rich aptamers affect the levels of NCL-dependent miRNAs and their target genes, reducing breast cancer cell aggressiveness, both in vitro and in vivo. These findings illuminate a path to novel therapeutic approaches based on NCL-targeting aptamers for the modulation of miRNA expression in the treatment of breast cancer. MCF7 cells were treated with the control drug or AS1411 aptamer. After 72hours total RNA was collected and analyzed by Affymetrix U133 plus.
Project description:Pre-operative progesterone intervention has been shown to confer a survival benefit to breast cancer patients independent of their progesterone receptor (PR) status, raising a question about how progesterone affects the outcome of PR-negative cells. Here, we identify up-regulation of a Serum- and glucocorticoid-regulated kinase gene, SGK1 and an N-Myc Downstream Regulated Gene 1, NDRG1, along with down-regulation of miR-29a and miR-101-1 targeting 3’UTR region of SGK1, to differential extents in a PR dependent manner in breast cancer cells. We further demonstrate a novel dual-phase transcriptional and post-transcriptional regulation of SGK1 in response to progesterone leading to up-regulation of a tumor metastasis suppressor gene, NDRG1, mediated by a set of AP-1 network genes. The NDRG1 further inactivates a set of kinases impeding the invasion and migration of breast cancer cells. In summary, we propose a model for the mode of action of progesterone in breast cancer deciphering the molecular basis of a randomized clinical trial studying the effect of progesterone in breast cancer with a potential to improve the prognosis of breast cancer patients for receiving pre-operative progesterone treatment.