Pro-Inflammatory Control Of The Phenotype And Functional Properties Of Triple Negative Breast Cancer Cells

The triple negative subtype of breast cancer (TNBC) is a most aggressive disease type, demonstrating high relapse rate and poor survival. This subtype is defined by the lack of expression of three receptors: estrogen receptors, progesterone receptors and epidermal growth factor receptor 2 (HER2); thus, receptor-targeting therapies cannot be applied in this type of disease and chemotherapy is the only treatment option possible for TNBC patients.

Breast tumors include a complex tumor microenvironment (TME) that consists of different cell types and soluble factors, and has an important role in determining the aggressiveness and the progression of the disease. TNFα and IL-1β are enriched in the TME of TNBC tumors, where they promote cancer progression and are related to poor prognosis. In many patients, the tumor cells are exposed continuously to pro-inflammatory cytokines from the time of malignant transformation and on, throughout disease progression.

In our study we stimulated human TNBC cells with the pro-inflammatory cytokines TNFα and IL-1β for prolonged periods, and determined cytokine impacts on TNBC tumor-promoting characteristics via live cell imaging, XTT, chemotaxis and RNAseq. We found that in response to the cytokines, human TNBC cells acquired morphological changes that are connected to increased migration and higher motility. These traits were accompanied by extensive changes in gene expression and modified metabolic phenotypes. We observed increased expression of genes involved in oxidative phosphorylation in the mitochondria, and also detected those elevated abilities in functional assays. A screen assay that we have developed is now being used as a basis for the identification of inhibitors that will prevent the cytokine-induced changes in TNBC cells. Those molecules that will be able to interfere with the process may lead to development of new therapies, and also will allow us to track the molecular mechanisms that are related to long-term cytokine stimulation.

Overall, we identify in our studies inflammation-driven effects on the TNBC characteristics that may promote their aggressiveness and metastatic potential.