Dataset Information

CX3CL1 promotes breast cancer via transactivation of the EGF pathway.

ABSTRACT: Chemokines are relevant molecules in shaping the tumor microenvironment, although their contributions to tumorigenesis are not fully understood. We studied the influence of the chemokine CX3CL1/fractalkine in de novo breast cancer formation using HER2/neu transgenic mice. CX3CL1 expression was downmodulated in HER2/neu tumors, yet, paradoxically, adenovirus-mediated CX3CL1 expression in the tumor milieu enhanced mammary tumor numbers in a dose-dependent manner. Increased tumor multiplicity was not a consequence of CX3CL1-induced metastatic dissemination of the primary tumor, although CX3CL1 induced epithelial-to-mesenchymal transition in breast cancer cells in vitro. Instead, CX3CL1 triggered cell proliferation by induction of ErbB receptors through the proteolytic shedding of an ErbB ligand. This effect was important insofar as mammary tumorigenesis was delayed and tumor multiplicity was reduced by genetic deletion of CX3CL1 in HER2/neu mice, but not in polyoma middle T-antigen oncomice. Our findings support the conclusion that CX3CL1 acts as a positive modifier of breast cancer in concert with ErbB receptors.

SUBMITTER: Tardaguila M

PROVIDER: S-EPMC4533861 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CX3CL1 promotes breast cancer via transactivation of the EGF pathway.

Tardáguila Manuel M Mira Emilia E García-Cabezas Miguel A MA Feijoo Anna M AM Quintela-Fandino Miguel M Azcoitia Iñigo I Lira Sergio A SA Mañes Santos S

Cancer research 20130529 14

Chemokines are relevant molecules in shaping the tumor microenvironment, although their contributions to tumorigenesis are not fully understood. We studied the influence of the chemokine CX3CL1/fractalkine in de novo breast cancer formation using HER2/neu transgenic mice. CX3CL1 expression was downmodulated in HER2/neu tumors, yet, paradoxically, adenovirus-mediated CX3CL1 expression in the tumor milieu enhanced mammary tumor numbers in a dose-dependent manner. Increased tumor multiplicity was n ...[more]

PMID: 23720051

Similar Datasets

Project description:Background: Chemotherapy resistance is a major problem in breast cancer treatment and a leading cause of mortality in breast cancer patients. Biomarkers for chemotherapy resistance is under investigation. Methods: Paclitaxel resistant cells were established and subjected to RNA sequencing. Analysis combined with two additional RNA-seq datasets was conducted. CapG expression in patients with adjuvant chemotherapy was studied in breast cancer resection specimens using IHC and related to pathological response and disease-free survival. Paclitaxel resistance was assessed by half-maximal inhibitory concentrations (IC50) and a mouse xenograft model. Results: Increased expression of actin-binding protein CapG strongly correlated with the resistance to paclitaxel chemotherapy and decreased probability to achieve pathological complete response in breast cancer patients. Overexpressing CapG significantly enhanced paclitaxel resistance in breast cancer cells and xenograft tumors. High CapG level also significantly correlated with shorter relapse-free survival as well as hyper-activation of PI3K/Akt signaling in breast cancer patients. Mechanistically, CapG enhanced PIK3R1 expression which led to increased PI3K/Akt activation. Unexpectedly, CapG was found to bind to the variant-specific promoter of PIK3R1/P50 and directly enhance its transcription. We also identified p300/CBP as a transcriptional coregulator of CapG, which is recruited to PIK3R1 promoter through interaction with CapG, thereby increasing PIK3R1/P50 transcription by enhancing histone H3K27 acetylation. Consistently, inhibiting p300/CBP substantially decreased CapG-dependent upregulation of PIK3R1/P50 and subsequent PI3K/Akt activation, resulting in increased sensitivity to paclitaxel treatment in breast cancer cells. Conclusion: High CapG levels may predict poor paclitaxel response in breast cancer patients. Targeting CapG-mediated hyperactivation of PI3K/Akt pathway may mitigate resistance to chemotherapy in breast cancer.

Dataset Information

CX3CL1 promotes breast cancer via transactivation of the EGF pathway.

Publications

CX3CL1 promotes breast cancer via transactivation of the EGF pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure