A differential role for CXCR4 in the regulation of normal versus malignant breast stem cell activity.
AffiliationBreast Biology Group, Institute of Cancer Sciences, Paterson Building, University of Manchester, Wilmslow Road, Manchester,M20 4BX,UK.
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AbstractC-X-C chemokine receptor type 4 (CXCR4) is known to regulate lung, pancreatic and prostate cancer stem cells. In breast cancer, CXCR4 signalling has been reported to be a mediator of metastasis, and is linked to poor prognosis. However its role in normal and malignant breast stem cell function has not been investigated. Anoikis resistant (AR) cells were collected from immortalised (MCF10A, 226L) and malignant (MCF7, T47D, SKBR3) breast cell lines and assessed for stem cell enrichment versus unsorted cells. AR cells had significantly higher mammosphere forming efficiency (MFE) than unsorted cells. The AR normal cells demonstrated increased formation of 3D structures in Matrigel compared to unsorted cells. In vivo, SKBR3 and T47D AR cells had 7- and 130-fold enrichments for tumour formationrespectively, compared with unsorted cells. AR cells contained significantly elevated CXCR4 transcript and protein levels compared to unsorted cells. Importantly, CXCR4 mRNA was higher in stem cell-enriched CD44+/CD24- patient-derived breast cancer cells compared to non-enriched cells. CXCR4 stimulation by its ligand SDF-1 reduced MFE of the normal breast cells lines but increased the MFE in T47D and patient-derived breast cancer cells. CXCR4 inhibition by AMD3100 increased stem cell activity but reduced the self-renewal capacity of the malignant breast cell line T47D. CXCR4+ FACS sorted MCF7 cells demonstrated a significantly increased MFE compared with CXCR4- cells. This significant increase in MFE was further demonstrated in CXCR4 over-expressing MCF7 cells which also had an increase in self-renewal compared to parental cells. A greater reduction in self-renewal following CXCR4 inhibition in the CXCR4 over-expressing cells compared with parental cells was also observed. Our data establish for the first time that CXCR4 signalling has contrasting effects on normal and malignant breast stem cell activity. Here, we demonstrate that CXCR4 signalling specifically regulates breast cancer stem cell activities and may therefore be important in tumour formation at the sites of metastases.
CitationA differential role for CXCR4 in the regulation of normal versus malignant breast stem cell activity. 2014, 5 (3):599-612 Oncotarget
- Effect of fibroblasts on breast cancer cell mammosphere formation and regulation of stem cell-related gene expression.
- Authors: Zhang F, Song C, Ma Y, Tang L, Xu Y, Wang H
- Issue date: 2011 Sep
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- Authors: Liu BQ, Zhang S, Li S, An MX, Li C, Yan J, Wang JM, Wang HQ
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- Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells.
- Authors: Jung MJ, Rho JK, Kim YM, Jung JE, Jin YB, Ko YG, Lee JS, Lee SJ, Lee JC, Park MJ
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- Effects of human mesenchymal stem cells on ER-positive human breast carcinoma cells mediated through ER-SDF-1/CXCR4 crosstalk.
- Authors: Rhodes LV, Antoon JW, Muir SE, Elliott S, Beckman BS, Burow ME
- Issue date: 2010 Nov 18
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- Authors: DeCastro AJ, Cherukuri P, Balboni A, DiRenzo J
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