Abstract
Breast cancer is a complex disease exhibiting extensive inter- and intra-tumor heterogeneity. Inflammation is a well-known driver of cancer progression, often attributed to immune cells infiltrating the tumor stroma. However, tumor cells themselves are capable to secrete a variety of inflammatory molecules, of which we understand very little about their role in intra-clonal communication. We recently reported the capacity of triple negative cell lines to induce a cancer stem cell (CSC)-like phenotype and invasion properties into luminal cells, a mechanism mediated by pro-inflammatory cytokines that up-regulated the CXCL12/CXCR4/CXCR7 chemokine signaling axis. We performed transcriptional array analyses of CSCs-associated genes and cancer-inflammatory cell crosstalk genes and built regulatory networks with the data collected. We found a specific molecular signature segregating with the induced-invasive/stemness phenotype. Regulatory network analysis pointed out to an NFκB transcriptional signature, active in aggressive triple negative cells and in induced-invasive/CSC-like luminal cells. In agreement, NFκB inhibition abolished the induction of the stemness/invasive features. These data support an NFκB dependent mechanism of intra-clonal communication responsible for tumor cell plasticity leading the acquisition of cancer aggressive features. Understanding the communication between different tumor clones would help to find better therapeutic and prophylactic targets to prevent BrC progression and relapse.
Highlights
Breast cancer (BrC) is the leading cause of cancer mortality in working age women
We recently reported the capacity of triple negative cell lines to induce a cancer stem cell (CSC)-like phenotype and invasion properties into luminal cells, a mechanism mediated by pro-inflammatory cytokines that up-regulated the C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4)/C-X-C chemokine receptor type 7 (CXCR7) chemokine signaling axis
We previously reported that highly aggressive triple negative cell lines (HA-BrC: HS578T and MDA-MB-231) produced high concentrations of pro-inflammatory cytokines Granulocyte-colony-stimulating factor (G-CSF), Granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8, and Monocyte chemoattractant protein-1 (MCP-1), and the conditioned media (CM) of these cells induced aggressive features in non-aggressive luminal cell lines (NA-BrC: MCF-7 and T47D)
Summary
Breast cancer (BrC) is the leading cause of cancer mortality in working age women. prevalence is higher in developed countries, mortality is greater in developing countries in which most cases are diagnosed at advanced stages [1, 2]. BrC is a highly heterogeneous disease from which we have identified different molecular subtypes that are used to predict the clinical outcome. Expression of estrogen receptor (ER), progesterone receptor www.oncotarget.com (PR) and the human epidermal growth factor receptor (HER2/ERBB2/CD340) is extensively used to classify BrC into luminal, HER2 positive and triple negative subtypes. We have recognized intra-tumor heterogeneity as an important factor contributing to disease aggression [6]. Intra-tumor heterogeneity is deeply influenced by the composition of the tumor stroma, which is formed by the extracellular matrix (ECM), multiple types of immune cells, connective tissue cells, blood, and lymph vessels [7]. Mounting evidence supports the capacity of tumor cells to harness immune cells to fulfill pro-tumoral functions, through secreted cytokines, chemokines, growth factors, and other bioactive compounds [7, 8, 10]
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