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Background  Gene regulation is dynamic across cellular conditions and disease subtypes. From the aspect of regulation under modulation, regulation strength between a pair of genes can be modulated by (dependent on) expression abundance of another gene (modulator gene). Previous studies have demonstrated the involvement of genes modulated by single modulator genes in cancers, including breast cancer. However, analysis of multi-modulator co-modulation that can further delineate the landscape of complex gene regulation is, to our knowledge, unexplored previously. In the present study we aim to explore the joint effects of multiple modulator genes in modulating global gene regulation and dissect the biological functions in breast cancer.    Results  To carry out the analysis, we proposed the  Co variability-based  M ultiple  Re gression (CoMRe) method. The method is mainly built on a multiple regression model that takes expression levels of multiple modulators as inputs and regulation strength between genes as output. Pairs of genes were divided into groups based on their co-modulation patterns. Analyzing gene expression profiles from 286 breast cancer patients, CoMRe investigated ten candidate modulator genes that interacted and jointly determined global gene regulation. Among the candidate modulators,  ESR1, ERBB2 , and  ADAM12  were found modulating the most numbers of gene pairs. The largest group of gene pairs was composed of ones that were modulated by merely  ESR1 . Functional annotation revealed that the group was significantly related to tumorigenesis and estrogen signaling in breast cancer.  ESR1 − ERBB2  co-modulation was the largest group modulated by more than one modulators. Similarly, the group was functionally associated with hormone stimulus, suggesting that functions of the two modulators are performed, at least partially, through modulation. The findings were validated in majorities of patients (> 99%) of two independent breast cancer datasets.    Conclusions  We have showed CoMRe is a robust method to discover critical modulators in gene regulatory networks, and it is capable of achieving reproducible and biologically meaningful results. Our data reveal that gene regulatory networks modulated by single modulator or co-modulated by multiple modulators play important roles in breast cancer. Findings of this report illuminate complex and dynamic gene regulation under modulation and its involvement in breast cancer.

Co-modulation analysis of gene regulation in breast cancer reveals complex interplay between ESR1 and ERBB2 genes