CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts

Ginestier, Christophe; Liu, Suling; Diebel, Mark E.; Korkaya, Hasan; Luo, Ming; Brown, Marty; Wicinski, Julien; Cabaud, Olivier; Charafe-Jauffret, Emmanuelle; Birnbaum, Daniel; Guan, Jun; Dontu, Gabriela; Wicha, Max S.

doi:10.1172/jci39397

Cited by 674 publications

(653 citation statements)

References 39 publications

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“…Primers and probes for the Taqman system were selected from the Applied Biosystems, Carlsbad, CA, www.appliedbiosystems.com Web site (Hs00926054_m1), Hs00932159_m1), MVK (Hs0017 6077_m1), MVD (Hs00159403_m1), IDI1 (Hs01057440_m1), FDPS (Hs00266635_m1), SQLE (Hs01123768_m1), Hs00158 906_m1), Hs00940273_m1), Hs00999007_m1). The relative expression mRNA level of genes from the mevalonate pathway was computed with respect to internal standards GAPDH and GUSB genes to normalize for variations in the quality of RNA and the amount of input cDNA, as described previously [8].…”

Section: Rq-pcrmentioning

confidence: 99%

“…We established a gene expression signature that allowed the identification of CXCR1/IL-8 signaling as a key regulatory pathway of breast CSCs. Utilizing a small molecule inhibitor of CXCR1, repertaxin, we were able to specifically target the CSC population in human breast cancer xenografts, delaying tumor growth and reducing metastasis [8].…”

Section: Introductionmentioning

confidence: 99%

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Mevalonate Metabolism Regulates Basal Breast Cancer Stem Cells and Is a Potential Therapeutic Target

et al. 2012

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There is increasing evidence that breast tumors are organized in a hierarchy, with a subpopulation of tumorigenic cancer cells, the cancer stem cells (CSCs), which sustain tumor growth. The characterization of protein networks that govern CSC behavior is paramount to design new therapeutic strategies targeting this subpopulation of cells. We have sought to identify specific molecular pathways of CSCs isolated from 13 different breast cancer cell lines of luminal or basal/mesenchymal subtypes. We compared the gene expression profiling of cancer cells grown in adherent conditions to those of matched tumorsphere cultures. No specific pathway was identified to be commonly regulated in luminal tumorspheres, resulting from a minor CSC enrichment in tumorsphere passages from luminal cell lines. However, in basal/mesenchymal tumorspheres, the enzymes of the mevalonate metabolic pathway were overexpressed compared to those in cognate adherent cells. Inhibition of this pathway with hydroxy-3-methylglutaryl CoA reductase blockers resulted in a reduction of breast CSC independent of inhibition of cholesterol biosynthesis and of protein farnesylation. Further modulation of this metabolic pathway demonstrated that protein geranylgeranylation (GG) is critical to breast CSC maintenance. A small molecule inhibitor of the geranylgeranyl transferase I (GGTI) enzyme reduced the breast CSC subpopulation both in vitro and in primary breast cancer xenografts. We found that the GGTI effect on the CSC subpopulation is mediated by inactivation of Ras homolog family member A (RHOA) and increased accumulation of P27 kip1 in the nucleus. The identification of protein GG as a major contributor to CSC maintenance opens promising perspectives for CSC targeted therapy in basal breast cancer. STEM

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Section: Rq-pcrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mevalonate Metabolism Regulates Basal Breast Cancer Stem Cells and Is a Potential Therapeutic Target

et al. 2012

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“…The recent use of the terminology 'emergence of CSC properties' (Singh and Settleman, 2010) also implies this conclusion. The existence of a 'CSC-TPC' population in cancer cell lines cultured, that is, competing, over many generations (Ginestier et al, 2010) bears against the hypothesis of a perpetual coexistence of qualitatively, irreversibly determined populations. One possibility of maintaining over time a fractional population of CSC-TPC would be the existence of control feedback mechanisms as those operating to maintain the somatic stem cells (SSC) population (Lander, 2009).…”

Section: Csc-tpc Quiescent or Proliferative?mentioning

confidence: 99%

Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating–cancer stem cells: distinct, overlapping or same populations

Floor¹,

Staveren²,

et al. 2011

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“…IL8 signaling has been shown to play a role in BCSC self-renewal (29,30). Because the expression of IL8 is regulated by NF-κB activity (31), we investigated whether HRG induces the expression of IL8.…”

Section: Nf-κb Is Required To Maintain Mammosphere-forming Ability Andmentioning

confidence: 99%

ErbB receptor tyrosine kinase/NF-κB signaling controls mammosphere formation in human breast cancer

Hinohara

Kobayashi

Kanauchi

et al. 2012

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

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Breast cancer is one of the most common cancers in humans. However, our understanding of the cellular and molecular mechanisms underlying tumorigenesis in breast tissues is limited. Here, we identified a molecular mechanism that controls the ability of breast cancer cells to form multicellular spheroids (mammospheres). We found that heregulin (HRG), a ligand for ErbB3, induced mammosphere formation of a breast cancer stem cell (BCSC)-enriched population as well as in breast cancer cell lines. HRG-induced mammosphere formation was reduced by treatment with inhibitors for phosphatidyl inositol 3-kinase (PI3K) or NF-κB and by expression of IκBα-Super Repressor (IκBαSR), a dominant-negative inhibitor for NF-κB. Moreover, the overexpression of IκBαSR in breast cancer cells inhibited tumorigenesis in NOD/SCID mice. Furthermore, we found that the expression of IL8, a regulator of self-renewal in BCSCenriched populations, was induced by HRG through the activation of the PI3K/NF-κB pathway. These findings illustrate that HRG/ ErbB3 signaling appears to maintain mammosphere formation through a PI3K/NF-κB pathway in human breast cancer.EGF | HER | tumor sphere | cancer stem cells | inflammation C ancer stem cells (CSCs), which make up only a small proportion of heterogeneous tumor cells, may possess a greater ability to maintain tumorigenesis than other tumor cell types (1, 2). CSCs can self-renew and simultaneously produce differentiated daughter cells; thus they can strongly proliferate until they reach their final differentiated state. With improvements in the isolation of CSCs, there is now a growing body of evidence that, in some cases of hematologic and solid tumors, a cancer stem cell population can be enriched based on phenotype (3-10). In human breast cancers, breast cancer stem cells (BCSCs) are enriched in the CD44 high /CD24 low cell population, whereas the CD44 low / CD24 high cells represent a more differentiated phenotype with limited stem cell-like potential (3). Because BCSCs withstand anoikis in culture, they expand under anchorage-independent conditions, giving rise to clonal spheroids (mammospheres), which can be serially passaged in vitro (11,12). These processes can in part recapitulate the breast tumorigenesis process (13-16). To develop more effective cancer therapies, it would be reasonable to target molecules that have a critical role in the maintenance of mammospheres. However, the molecular mechanism by which mammospheres are maintained is still largely obscure.NF-κB is a transcription factor complex that is typically a heterodimer of p50, p52, p65 (RelA), RelB, and c-Rel. It is usually inactive and bound to IκB, an inhibitory protein, in the cytoplasm. The primary mechanism of regulation of NF-κB activity is through activation of the IKK complex, including heterodimers of IKKα and IKKβ, as a result of various signaling pathways. The serine-threonine kinase Akt is one of the activators of IKKβ (17), and the activated IKK complex phosphorylates the IκBα protein, resulting in its ubiquitination, p...

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CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts

Cited by 674 publications

References 39 publications

Mevalonate Metabolism Regulates Basal Breast Cancer Stem Cells and Is a Potential Therapeutic Target

Mevalonate Metabolism Regulates Basal Breast Cancer Stem Cells and Is a Potential Therapeutic Target

Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating–cancer stem cells: distinct, overlapping or same populations

ErbB receptor tyrosine kinase/NF-κB signaling controls mammosphere formation in human breast cancer

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