Heterogeneity of Breast Cancer Vasculature
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Francois Pepin
PROVIDER: E-GEOD-15363 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Background: Epithelial-stromal crosstalk plays a critical role in invasive breast cancer (IBC) pathogenesis; however, little is known on a systems level about how epithelial-stromal interactions evolve during carcinogenesis. Results: We develop a framework for building genome-wide epithelial-stromal co-expression networks composed of pairwise co-expression relationships between mRNA levels of genes expressed in the epithelium and stroma across a population of patients. We apply this method to laser capture micro-dissection expression profiling datasets in the setting of breast carcinogenesis. Our analysis shows that epithelial-stromal co-expression networks undergo extensive re-wiring during carcinogenesis, with the emergence of distinct network hubs in normal breast, ER-positive IBC, and ER-negative IBC, and the emergence of distinct patterns of functional network enrichment. In contrast to normal breast, the strongest epithelial-stromal co-expression relationships in IBC mostly represent self-loops, in which the same gene is co-expressed in epithelial and stromal regions. We validate this observation using an independent laser capture micro-dissection dataset and confirm that self-loop interactions are significantly increased in cancer by performing computational image analysis of epithelial and stromal protein expression using images from the Human Protein Atlas. Conclusions: Epithelial-stromal co-expression network analysis represents a new approach for systems-level analyses of spatially-localized transcriptomic data. The analysis provides new biological insights into the re-wiring of epithelial-stromal co-expression networks and the emergence of epithelial-stromal co-expression self-loops in breast cancer. The approach may facilitate the development of new diagnostics and therapeutics targeting epithelial-stromal interactions in cancer. 36 flash-frozen human primary breast cancer samples were subjected to laser capture microdissection to separately isolate matched tumor epithelial and tumor-associated stromal components. RNA was isolated, subjected to 2 rounds of amplification, and hybridized on Agilent 4x44K microarrays along with a common reference (single round-amplified commercially obtained Universal Human Reference RNA) in a dyeswap design. For two samples of tumor-associated stroma, a second technical replicate was performed. Samples were labelled as ER-positive based on ESR1 gene expression levels in the tumor epithelium, using univariate Gaussian mixture model-based clustering via the mclust package in R.
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Project description:Tumor-associated breast stroma was laser-capture microdissected from IDC breast cancer cases. The goal of the study was to characterize the heterogeneity of breast tumor-assocaited stroma and identify gene expression signatures predictive of clinical outcome. Experiment Overall Design: Common reference design, 53 samples, with dye-swap replicates. Some samples replicated three or four times, a total of 111 arrays.
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Project description:Bone is the primary site of breast cancer metastasis and complications associated with bone metastases can lead to a significantly decreased quality of life in these patients. Thus, it is essential to gain a better understanding of the molecular mechanisms that underlie the emergence and growth of breast cancer skeletal metastases. Methods: To search for novel molecular mediators that influence breast cancer bone metastasis, we generated gene expression profiles from laser capture micro-dissected trephine biopsies of both breast cancer bone metastases and primary breast tumors that metastasized to bone. Bioinformatics analysis identified genes that are differentially expressed in breast cancer bone metastases compared to primary mammary tumors. Results: ABCC5, an ATP-dependent transporter, was found to be overexpressed in breast cancer osseous metastases relative to primary mammary tumors. In addition, ABCC5 was significantly up-regulated in human and mouse breast cancer cell lines with high bone-metastatic potential. Stable knockdown of ABCC5 significant reduced bone metastatic burden and osteolytic bone destruction in mice. The decrease in osteolysis was further associated with diminished osteoclast numbers. Conclusions: Our data, for the first time, suggests that ABCC5 functions as a mediator of breast cancer skeletal metastasis. ABCC5 expression in breast cancer cells is important for the efficient bone resorption mediated by osteoclasts. Hence, ABCC5 may be a potential therapeutic target for breast cancer bone metastasis. primary breast tumors vs. bone trephine biopsies
2012-11-09 | E-GEOD-39494 | biostudies-arrayexpress
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Project description:Novel insights on proteins involved in Alzheimer disease (AD) are needed. Since multiple cell types and matrix components are altered in AD, bulk analysis of brain tissue may be difficult to interpret. In the current study, we isolated pyramidal cells from the CA1 region of the hippocampus from five AD and five neurologically healthy donors using laser capture microdissection. The samples were analysed by proteomics using 18O labeled internal standard and nano-HPLC MS/MS for relative quantification. Fold change between AD and control was calculated for the proteins that were identified in at least two individual proteomes from each group. From the ten cases analyzed, sixty-two proteins were identified in at least two AD cases and two control cases. Creatine Kinase B-type (CKB), 14-3-3-g and Heat Shock Cognate 71 (Hsc71) which have not been extensively studied in the context of human AD brain previously, were selected for further studies by immunohistochemistry (IHC). In hippocampus, semi-quantitative measures of IHC staining of the three proteins confirmed the findings from our proteomic analysis. Studies of the same proteins in frontal cortex revealed that the alterations remained for CKB and 14-3-3-g but not for Hsc71. Protein upregulation in CA1 neurons of final stage AD is either a result from detrimental, pathological effects, or from cell specific protective response mechanisms in surviving neurons. Based on previous findings from experimental studies, CKB and Hsc71 likely exhibit protective effects, whereas 14-3-3-g represents a detrimental path. These new players could represent pathways of importance for development of new therapeutic strategies.
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