Analysis of hierarchical organization in gene expression networks reveals underlying principles of collective tumor cell dissemination and metastatic aggressiveness of inflammatory breast cancer

Abstract: Clusters of circulating tumor cells (CTCs), although rare, may account for more than 95% of metastases. Inflammatory breast cancer (IBC) is a highly aggressive subtype that chiefly metastasizes via CTC clusters. Theory suggests that physical systems with hierarchical organization tend to be more adaptable due to their ability to efficiently span the set of available states. We used the cophenetic correlation coefficient (CCC) to quantify the hierarchical organization in the expression of collective dissemination associated and IBC associated genes, and found that the CCC of both gene sets was higher in (a) epithelial cell lines as compared to mesenchymal cell lines and (b) IBC tumor samples as compared to non-IBC breast cancer samples. A higher CCC of both networks was also correlated with a higher rate of metastatic relapse in breast cancer patients. Gene set enrichment analysis could not provide similar insights, indicating that the CCC provides additional information regarding the organizational complexity of gene expression. These results suggest that retention of epithelial traits in disseminating tumor cells as IBC progresses promotes successful metastasis and the CCC may be a prognostic factor for IBC.