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Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
Published on: February 21, 2014
Integrated analysis reveals microRNA networks coordinately expressed with key proteins in breast cancer
Miriam Ragle Aure1, Sandra Jernström1, Marit Krohn1
1Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, 0310 Norway ; K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, 0316 Norway.
Background:
The role played by microRNAs in the deregulation of protein expression in breast cancer is only partly understood. To gain insight, the combined effect of microRNA and mRNA expression on protein expression was investigated in three independent data sets.
Methods:
Protein expression was modeled as a multilinear function of powers of mRNA and microRNA expression. The model was first applied to mRNA and protein expression for 105 selected cancer-associated genes and to genome-wide microRNA expression from 283 breast tumors. The model considered both the effect of one microRNA at a time and all microRNAs combined. In the latter case the Lasso penalized regression method was applied to detect the simultaneous effect of multiple microRNAs.
Results:
An interactome map for breast cancer representing all direct and indirect associations between the expression of microRNAs and proteins was derived. A pattern of extensive coordination between microRNA and protein expression in breast cancer emerges, with multiple clusters of microRNAs being associated with multiple clusters of proteins. Results were subsequently validated in two independent breast cancer data sets. A number of the microRNA-protein associations were functionally validated in a breast cancer cell line.
Conclusions:
A comprehensive map is derived for the co-expression in breast cancer of microRNAs and 105 proteins with known roles in cancer, after filtering out the in-cis effect of mRNA expression. The analysis suggests that group action by several microRNAs to deregulate the expression of proteins is a common modus operandi in breast cancer.
Insights
MicroRNAs significantly coordinate protein expression in breast cancer, revealing a complex regulatory network. This study maps these interactions, highlighting group action by microRNAs in cancer deregulation.
Area of Science:
- Genomics
- Molecular Biology
- Cancer Research
Background:
- The precise role of microRNAs in breast cancer protein deregulation remains unclear.
- Investigating the combined influence of microRNA and mRNA expression on protein levels is crucial for understanding cancer mechanisms.
Purpose of the Study:
- To elucidate the regulatory relationships between microRNA and protein expression in breast cancer.
- To construct a comprehensive interactome map of microRNA-protein associations.
Main Methods:
- Developed a multilinear model to assess microRNA and mRNA effects on protein expression.
- Applied Lasso penalized regression to identify simultaneous microRNA influences on protein levels.
- Utilized three independent breast cancer datasets for robust analysis.
Main Results:
- Generated a breast cancer interactome map detailing microRNA-protein associations.
- Observed extensive coordination between microRNA and protein expression, with clustered interactions.
- Validated findings in independent datasets and functionally confirmed specific microRNA-protein links in cell lines.
Conclusions:
- A detailed map of microRNA and 105 cancer-associated protein co-expression in breast cancer was established.
- Group action by multiple microRNAs is a prevalent mechanism for protein deregulation in breast cancer.
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