The chemokine receptor CXCR7 interacts with EGFR to promote breast cancer cell proliferation

Salazar, Nicole; Muñoz, Daniel; Kallifatidis, Georgios; Singh, Rajendra K.; Jordà, Mercè; Lokeshwar, Balakrishna L.

doi:10.1186/1476-4598-13-198

Cited by 90 publications

(74 citation statements)

References 46 publications

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“…We have previously shown that CXCR7 mediates EGFR phosphorylation/transactivation in a CXCR7-ligand independent fashion(6, 14). Rajagopal et al,(7) observed recruitment of β-AR2 by CXCR7 in human embryonic kidney-29 (HEK29) cells that are overexpressing CXCR7.…”

Section: Resultsmentioning

confidence: 99%

“…PLA was performed using a kit and the contained instructions (Duolink In Situ, Olink Bioscience-Sigma) as described previously(14). Combination of a primary rabbit anti-CXCR7 antibody and a nonspecific mouse isotype antibody was used as a negative control.…”

Section: Methodsmentioning

confidence: 99%

“…Further, alteration in CXCR7 expression levels directly affects phosphorylation of EGFR at Tyrosine 1110 . In addition, we have reported direct coupling of EGFR and CXCR7 in PCa and breast cancer cells both in vitro and in tumors in vivo(6, 14). Although CXCR7 is an atypical GPCR, the mechanism of transactivation of EGFR by unstimulated-CXCR7 is unknown.…”

Section: Introductionmentioning

confidence: 99%

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β-Arrestin-2 Counters CXCR7-Mediated EGFR Transactivation and Proliferation

Kallifatidis

Muñoz

Singh

et al. 2016

Molecular Cancer Research

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The atypical 7-transmembrane chemokine receptor, CXCR7, transactivates the EGFR leading to increased tumor growth in several tumor types. However, the molecular mechanism of CXCR7 ligand-independent EGFR transactivation is unknown. We used cDNA knock-in, RNAi and analysis of mitogenic signaling components in both normal prostate epithelial cells and prostate cancer cells to decipher the proliferation-inducing mechanism of the CXCR7-EGFR interaction. The data demonstrate that CXCR7-induced EGFR transactivation is independent of both the release of cryptic EGFR ligands (e.g., AREG/ amphiregulin) and G-protein-coupled receptor signaling. An alternate signaling mechanism involving b-arrestin-2 (ARRB2/ b-AR2) was examined by manipulating the levels of b-AR2 and analyzing changes in LNCaP cell growth and phosphorylation of EGFR, ERK1/2, Src, and Akt. Depletion of b-AR2 in LNCaP cells increased proliferation/colony formation and significantly increased activation of Src, phosphorylation of EGFR at Tyr-1110, and phosphorylation/activation of ERK1/2 compared with that with control shRNA. Moreover, b-AR2 depletion downregulated the proliferation suppressor p21. Stimulation of b-AR2-expressing cells with EGF resulted in rapid nuclear translocation of phosphorylated/activated EGFR. Downregulation of b-AR2 enhanced this nuclear translocation. These results demonstrate that b-AR2 is a negative regulator of CXCR7/Src/ EGFR-mediated mitogenic signaling.Implications: This study reveals that b-AR2 functions as a tumor suppressor, underscoring its clinical importance in regulating CXCR7/EGFR-mediated tumor cell proliferation.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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β-Arrestin-2 Counters CXCR7-Mediated EGFR Transactivation and Proliferation

Kallifatidis

Muñoz

Singh

et al. 2016

Molecular Cancer Research

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“…While CXCR7 may play a role in transendothelial migration (53), Hernandez et al demonstrated that CXCR7 overexpression enhanced tumor growth and vascularization, but reduced invasiveness and metastases (54). Specifically designed to selectively target CXCR4, POL5551 showed no effect on SDF-1 binding to overexpressed CXCR7 by Gaussia luciferase complementation assay in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

CXCR4 Protein Epitope Mimetic Antagonist POL5551 Disrupts Metastasis and Enhances Chemotherapy Effect in Triple-Negative Breast Cancer

Xiang

Hurchla

Fontana³

et al. 2015

Molecular Cancer Therapeutics

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The SDF-1-receptor CXCR4 has been associated with early metastasis and poorer prognosis in breast cancers, especially the most aggressive triple negative subtype. In line with previous reports, we found that tumoral CXCR4 expression in patients with locally advanced breast cancer was associated with increased metastases and rapid tumor progression. Moreover, high CXCR4 expression identified a group of bone marrow disseminated tumor cells (DTC) negative patients at high risk for metastasis and death. The Protein Epitope Mimetic (PEM) POL5551, a novel CXCR4 antagonist, inhibited binding of SDF-1 to CXCR4, had no direct effects on tumor cell viability, but reduced migration of breast cancer cells in vitro. In two orthotopic models of triple negative breast cancer, POL5551 had little inhibitory effect on primary tumor growth but significantly reduced distant metastasis. When combined with eribulin, a chemotherapeutic microtubule inhibitor, POL5551 additively reduced metastasis and prolonged survival in mice after resection of the primary tumor compared to single-agent eribulin. Hypothesizing that POL5551 may mobilize tumor cells from their microenvironment and sensitize them to chemotherapy, we utilized a “chemotherapy framing” dosing strategy. When administered shortly before and after eribulin treatment, 3 doses of POL5551 with eribulin reduced bone and liver tumor burden more effectively than chemotherapy alone. These data suggest that sequenced administration of CXCR4 antagonists with cytotoxic chemotherapy synergize to reduce distant metastases.

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“…Cell preparation and measurements were carried out as previously reported 13, 35 . Primary antibodies used for this assay are listed in Supplementary Table S2.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival

Hoy

Kallifatidis

Smith

et al. 2017

Sci Rep

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The atypical C-X-C chemokine receptor 7 (CXCR7) has been implicated in supporting aggressive cancer phenotypes in several cancers including prostate cancer. However, the mechanisms driving overexpression of this receptor in cancer are poorly understood. This study investigates the role of androgen receptor (AR) in regulating CXCR7. Androgen deprivation or AR inhibition significantly increased CXCR7 expression in androgen-responsive prostate cancer cell lines, which was accompanied by enhanced epidermal growth factor receptor (EGFR)-mediated mitogenic signaling, promoting tumor cell survival through an androgen-independent signaling program. Using multiple approaches we demonstrate that AR directly binds to the CXCR7 promoter, suppressing transcription. Clustered regularly interspaced short palindromic repeats (CRISPR) directed Cas9 nuclease-mediated gene editing of CXCR7 revealed that prostate cancer cells depend on CXCR7 for proliferation, survival and clonogenic potential. Loss of CXCR7 expression by CRISPR-Cas9 gene editing resulted in a halt of cell proliferation, severely impaired EGFR signaling and the onset of cellular senescence. Characterization of a mutated CXCR7-expressing LNCaP cell clone showed altered intracellular signaling and reduced spheroid formation potential. Our results demonstrate that CXCR7 is a potential target for adjuvant therapy in combination with androgen deprivation therapy (ADT) to prevent androgen-independent tumor cell survival.

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The chemokine receptor CXCR7 interacts with EGFR to promote breast cancer cell proliferation

Cited by 90 publications

References 46 publications

β-Arrestin-2 Counters CXCR7-Mediated EGFR Transactivation and Proliferation

β-Arrestin-2 Counters CXCR7-Mediated EGFR Transactivation and Proliferation

CXCR4 Protein Epitope Mimetic Antagonist POL5551 Disrupts Metastasis and Enhances Chemotherapy Effect in Triple-Negative Breast Cancer

Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival

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