CXCL-12/Stromal Cell–Derived Factor-1α Transactivates HER2-neu in Breast Cancer Cells by a Novel Pathway Involving Src Kinase Activation

Cabıoğlu, Neslihan; Summy, Justin M.; Miller, Claudia P.; Parikh, Nila U.; Şahin, Ayşegül; Tuzlali, Sıtkı; Pumiglia, Kevin; Gallick, Gary E.; Price, Janet E.

doi:10.1158/0008-5472.can-04-1303

Cited by 155 publications

(140 citation statements)

References 22 publications

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“…Possible explanations of this finding include a CXCL12-induced general re-programming of cells rendering them more imatinib sensitive, or more direct crosstalk between CXCR4 signaling and PDGF receptors. Concerning the latter possibility, it is noteworthy that CXCR4 transactivation of EGF receptors has recently been described (Cabioglu et al, 2005;Porcile et al, 2005). Obviously, these topics merit further investigations.…”

Section: Discussionmentioning

confidence: 93%

Characterization of an imatinib-sensitive subset of high-grade human glioma cultures

et al. 2006

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High-grade gliomas, including glioblastomas, are malignant brain tumors for which improved treatment is urgently needed. Genetic studies have demonstrated the existence of biologically distinct subsets. Preliminary studies have indicated that platelet-derived growth factor (PDGF) receptor signaling contributes to the growth of some of these tumors. In this study, human high-grade glioma primary cultures were analysed for sensitivity to treatment with the PDGF receptor inhibitor imatinib/ Glivec/Gleevec/STI571. Six out of 15 cultures displayed more than 40% growth inhibition after imatinib treatment, whereas seven cultures showed less than 20% growth inhibition. In the sensitive cultures, apoptosis contributed to growth inhibition. Platelet-derived growth factor receptor status correlated with imatinib sensitivity. Supervised analyses of gene expression profiles and real-time PCR analyses identified expression of the chemokine CXCL12/SDF-1 (stromal cell-derived factor 1) as a predictor of imatinib sensitivity. Exogenous addition of CXCL12 to imatinib-insensitive cultures conferred some imatinib sensitivity. Finally, coregulation of CXCL12 and PDGF a-receptor was observed in glioblastoma biopsies. We have thus defined the characteristics of a novel imatinib-sensitive subset of glioma cultures, and provided evidence for a functional relationship between imatinib sensitivity and chemokine signaling. These findings will assist in the design and evaluation of clinical trials exploring therapeutic effects of imatinib on malignant brain tumors.

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Section: Discussionmentioning

confidence: 93%

Characterization of an imatinib-sensitive subset of high-grade human glioma cultures

et al. 2006

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“…However, our analysis shows that the reduction in the number of α-SMA/ RARβ-positive myofibroblasts and the lower expression of Cxcl12 by these cells sharply reduces CXCL12/SDF-1 levels in RARβ-null stroma. The decrease in stromal CXCL12/SDF-1 production is accompanied by a reduction in the activity of the Src/ErbB2/Akt signaling pathway in the RARβ-null tumors, a pathway that previously had been shown to contribute to the survival, invasion, and growth of breast cancer cells (24). The physiological relevance of the involvement of the CXCL12/SDF-1 in this process was demonstrated further by the observation that addition of the chemokine to conditioned medium obtained from Rarb −/− mammary fibroblasts restored the growth rate of mammary tumor cells to that generated with conditioned medium obtained from wild-type mammary fibroblasts.…”

Section: Discussionmentioning

confidence: 96%

“…Among those diffusible molecules, chemokine (C-X-C motif) ligands 12 (CXCL12, stromal derived factor-1, SDF-1) and 14 (CXCL14) appear to play major roles in this process, because the two chemokines have been implicated as regulators of cell proliferation, differentiation, migration, and invasion as well as supporting tumor angiogenesis (20)(21)(22). CXCL12 expression also has been shown to be under estrogenic control (23) and to transactivate the oncogenic protein tyrosine kinase ERBB2 via a pathway involving the chemokine C-X-C receptor 4 (CXCR4) and Src kinase activation (24). It thus is believed that CXCL12 secreted by stromal myofibroblasts exerts a considerable influence on the growth of breast cancer cells expressing CXCR4.…”

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confidence: 99%

Stromal retinoic acid receptor β promotes mammary gland tumorigenesis

Liu

Nugoli

Laferrière

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Retinoic acid is a potent differentiation and antiproliferative agent of breast cancer cells, and one of its receptors, retinoic acid receptor β (RARβ), has been proposed to act as a tumor suppressor. In contrast, we report herein that inactivation of Rarb in the mouse results in a protective effect against ErbB2-induced mammary gland tumorigenesis. Strikingly, tissue recombination experiments indicate that the presence of Rarb in the stromal compartment is essential for the growth of mammary carcinoma. Ablation of Rarb leads to a remodeling of the stroma during tumor progression that includes a decrease in angiogenesis, in the recruitment of inflammatory cells, and in the number myofibroblasts. In agreement with this finding, we observed that a markedly reduced expression of chemokine (C-X-C motif) ligand 12 ( Cxcl12 ) in the stroma of Rarb -null mice is accompanied by a decrease in the CXCL12/chemokine C-X-C receptor 4 (CXCR4)/ErbB2 signaling axis in the tumors. Relevance to the human disease is underlined by the finding that gene-expression profiling of the Rarb -deficient mammary stromal compartment identified an ortholog RARβ signature in human microdissected breast tissues that differentiates tumor from normal stroma. Our study thus implicates RARβ in promoting tumorigenesis and suggests that retinoid-based approaches for the prevention and treatment of breast cancer should be redesigned.

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“…In breast cancer cells, CXCL12/CXCR4 interaction activates HER2 in a Src kinasedependent mechanism (7). In ovarian cancer cells, CXCL12/ CXCR4 interaction also activates epidermal growth factor receptor (EGFR), which leads to both mitogen-activated protein kinase and Akt activation (8).…”

Section: Introductionmentioning

confidence: 99%

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

Chinni

Yamamoto

Dong

et al. 2008

Molecular Cancer Research

118

102

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Chemokines and their receptors function in migration and homing of cells to target tissues. Recent evidence suggests that cancer cells use a chemokine receptor axis for metastasis formation at secondary sites. Previously, we showed that binding of the chemokine CXCL12 to its receptor CXCR4 mediated signaling events resulting in matrix metalloproteinase-9 expression in prostate cancer bone metastasis. A variety of methods, including lipid raft isolation, stable overexpression of CXCR4, cellular adhesion, invasion assays, and the severe combined immunodeficient -human bone tumor growth model were used. We found that (a) CXCR4 and HER2 coexist in lipid rafts of prostate cancer cells; (b) the CXCL12/CXCR4 axis results in transactivation of the HER2 receptor in lipid rafts of prostate cancer cells; (c) Src kinase mediates CXCL12/CXCR4 transactivation of HER2 in prostate cancer cells; (d) a pan-HER inhibitor desensitizes CXCR4-induced transactivation and subsequent matrix metalloproteinase-9 secretion and invasion; (e) lipid raft -disrupting agents inhibited raft-associated CXCL12/CXCR4 transactivation of the HER2 and cellular invasion; (f) overexpression of CXCR4 in prostate cancer cells leads to increased HER2 phosphorylation and migratory properties of prostate cancer cells; and (g) CXCR4 overexpression enhances bone tumor growth and osteolysis. These data suggest that lipid rafts on the cell membrane are the key site for CXCL12/CXCR4 -induced HER2 receptor transactivation. This transactivation contributes to enhanced invasive signals and metastatic growth in the bone microenvironment.

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CXCL-12/Stromal Cell–Derived Factor-1α Transactivates HER2-neu in Breast Cancer Cells by a Novel Pathway Involving Src Kinase Activation

Cited by 155 publications

References 22 publications

Characterization of an imatinib-sensitive subset of high-grade human glioma cultures

Characterization of an imatinib-sensitive subset of high-grade human glioma cultures

Stromal retinoic acid receptor β promotes mammary gland tumorigenesis

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

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