The TGFα-EGFR-Akt signaling axis plays a role in enhancing proinflammatory chemokines in triple-negative breast cancer cells

Abstract

Triple-negative breast cancer (TNBC) is aggressive and typically has a poor prognosis. Chemokines have chemoattractant potential for cancer metastasis. Here, we investigated the chemokine signatures in BC subtypes and the underlying mechanisms that enhance proinflammatory chemokines in TNBC. Analysis from microarray dataset revealed that basal-like BC subtype including TNBC expressed dominantly proinflammatory chemokines, such as CXCL1 and 8, compared to non-TNBC. Chemokine PCR array confirmed the dominant chemokines in TNBC cells. To identify a driving factor for proinflammatory chemokines in TNBC cells, we determined the expression and signaling profiles of epidermal growth factor receptor (EGFR) family members. TNBC cells expressed higher levels of EGFR and phosphorylated Akt/Erk than non-TNBC cells. In addition, EGF further enhanced the proinflammatory chemokines in TNBC cells, including CXCL2. Knockdown of Akt reduced the CXCL2 promoter activity, while overexpression of Akt enhanced it. MK2206, an Akt inhibitor, reduced the CXCL2 promoter activity, while inhibition and knockdown of Erk did not reduce its activity. We found that transforming growth factor alpha (TGFα) could serve as a main ligand for EGFR to drive EGFR-mediated Akt activation in TNBC cells. MK2206 decreased TGFα promoter activity, while overexpression of Akt increased it. MK2206 also reduced TGFα release from TNBC cells. Moreover, MK2206 downregulated CXCL2 mRNA expression, while TGFα upregulated it. Taken together, the TGFα-EGFR-Akt signaling axis can play a role in enhancing proinflammatory chemokine expression in TNBC, subsequently contributing to the inflammatory burden that ultimately lead to cancer progression and a higher mortality rate among TNBC patients.

Expression of the BAD pathway is a marker of triple-negative status and poor outcome

“…It is well known that AKT phosphorylation of BAD protein is a negative regulator of the proapoptotic function of BAD protein 56 . Consistent with our data, other groups have shown that activated AKT signalling is increased in TNBC 57–60 and that inhibition of AKT signalling can increase the sensitivity of TNBC cells to nonspecific chemotherapies 61 . Others have shown that targeting the pro-survival BCL2 proteins of the BAD pathway, using the BH3 mimetic ABT-737, sensitized basal-like breast cancers to chemotherapy 62 .…”

Coupled Genome-Wide DNA Methylation and Transcription Analysis Identified Rich Biomarkers and Drug Targets in Triple-Negative Breast Cancer

“…The significantly enriched categories included cell proliferation, immune response, cell differentiation, extracellular space, sequence-specific DNA binding, and transcriptional mis-regulation in cancer (Figure S4). The GO terms “cell proliferation” and “cell differentiation” were significantly enriched by several TNBC-associated genes, including CXCL1 , ELF5 , LIPG , and UCHL1 , which are known to play crucial roles in the initiation and metastasis of breast cancer and as potential TNBC diagnostic markers and therapeutic targets [31,32,33,34]. Genes involved in immune response were also common in DMEGs, implying that some immune-related DMEGs can be potential therapeutic targets for TNBC [35].…”

The EGFR Signaling Modulates in Mesenchymal Stem Cells the Expression of miRNAs Involved in the Interaction with Breast Cancer Cells

“…Therefore, it might be possible that miR-23c acts as tumor suppressor in TNBC cell lines and that EGFR activation in MSCs contributes to breast cancer progression through the downregulation of such miRNA in the microenvironment. In addition, as MDA-MB-468 and MDA-MB-231 cells express EGF-related ligands [ 29 , 30 ], we can hypothesize that breast cancer cells, through the secretion of TGFα, educate MSCs to promote breast cancer progression by repressing miRNAs that act as tumor suppressors, such as miR-23c. The fact that the same miRNAs might act as tumor suppressors or as oncogenes might depend on the context.…”