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The TGF?-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 (TGF?) could serve as a main ligand for EGFR to drive EGFR-mediated Akt activation in TNBC cells. MK2206 decreased TGF? promoter activity, while overexpression of Akt increased it. MK2206 also reduced TGF? release from TNBC cells. Moreover, MK2206 downregulated CXCL2 mRNA expression, while TGF? upregulated it. Taken together, the TGF?-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.

SUBMITTER: Ignacio RMC

PROVIDER: S-EPMC6047672 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Ignacio Rosa Mistica C RMC Gibbs Carla R CR Lee Eun-Sook ES Son Deok-Soo DS

Oncotarget 20180629 50

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 t ...[more]

PMID: 30034618

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Project description:PurposeTriple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is associated with high invasiveness, high metastatic occurrence and poor prognosis. Protein tyrosine kinase 7 (PTK7) plays an important role in multiple cancers. However, the role of PTK7 in TNBC has not been well addressed. This study was performed to evaluate the role of PTK7 in the progression of TNBC.MethodsCorrelation of PTK7 expression with clinicopathological parameters was assessed using tissue microarray immunohistochemistry (IHC) staining in 280 patients with breast cancer. PTK7 expression in TNBC (MDA-MB-468, MDA-MB-436 and MDA-MB-231) and non-TNBC (MCF7 and SK-BR-3) breast cancer cell lines were examined using immunoblotting assay. PTK7 correlated genes in invasive breast carcinoma were analyzed using cBioPortal breast cancer datasets including 1,904 patients. PTK7 overexpressed or knockdown TNBC cell lines (MDA-MB-468 and MDA-MB-436) were used to analyze the potential roles of PTK7 in TNBC metastasis and tumor progression. A TNBC tumor bearing mouse model was established to further analyze the role of PTK7 in TNBC tumorigenicity in vivo.ResultsPTK7 is highly expressed in breast cancer and correlates with worse prognosis and associates with tumor metastasis and progression in TNBC. Co-expression analysis and gain- or loss-of-function of PTK7 in TNBC cell lines revealed that PTK7 participates in EGFR/Akt signaling regulation and associated with extracellular matrix organization and migration genes in breast cancer, including COL1A1, FN1, WNT5B, MMP11, MMP14 and SDC1. Gain- or loss-of-function experiments of PTK7 suggested that PTK7 promotes proliferation and migration in TNBC cell lines. PTK7 knockdown MDA-MB-468 cell bearing mouse model further demonstrated that PTK7-deficiency inhibits TNBC tumor progression in vivo.ConclusionThis study identified PTK7 as a potential marker of worse prognosis in TNBC and revealed PTK7 promotes TNBC metastasis and progression via EGFR/Akt signaling pathway.

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

Publications

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

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