Inflammation-Driven Plasticity of Stromal Cells in Luminal-A Breast Cancer

Luminal-A is the most common subtype of breast cancer, strongly affected by factors of the tumor microenvironment (TME). Between others, the TME of breast tumors is populated by stromal cells. In most research systems, stromal cells have been shown to promote angiogenesis, tumor growth and metastasis. In luminal-A breast cancer, the TME is also enriched with pro-inflammatory factors, including cytokines. The cytokines TNFα and IL-1β are continuously co-expressed in the majority of patient breast tumors and have causative roles in promoting the malignancy process, by acting on the tumor cells themselves and on cells of the TME.

Our hypothesis in this study is that exposure of stromal cells to pro-inflammatory mediators, such as TNFα and IL-1β, enhance breast cancer progression.

To determine the impact of the pro-inflammatory stimulation on stromal cells and on progression of luminal-A tumors thereafter, and to identify the mechanisms involved, we stimulated the cells with the pro-inflammatory cytokines TNFα + IL-1β. RNAseq profiling revealed extensive changes in gene expression in the stromal cells following prolonged TNFα + IL-1β stimulation, including genes that are related to dynamic changes in fibroblasts; moreover, cytokine-stimulated stromal cells have expressed higher levels of genes that may lead to their pro-tumorigenic effects on tumor cells.

Additional analyses indicated that factors secreted by the TNFα + IL-1β-stimulated stromal cells induced epithelial-to-mesenchymal transition (EMT)-related morphological changes in luminal-A breast tumor cells. Moreover, luminal-A tumor cells have acquired functions that are related to increased aggressiveness, such as scattering out of tumor spheroids, spontaneous migration and migration in response to serum factors.

Overall, our results suggest that the pro-inflammatory conditions in the TME induce a pro-metastatic phenotype in stromal cells, leading to elevated aggressiveness in luminal-A tumors. Determination of the molecular mechanisms involved in the process may enable the identification of potential targets that could be inhibited and used as potential therapies in luminal-A breast cancer.