Stem cell technology in breast cancer: current status and potential applications

Figures & data

Table 1 Markers for BCSC characterization

Markers	Localization	Isolation	References
ALDH1	Cytoplasm	+	^Citation13
CD24	Cell surface	+	^Citation2
CD44	Cell surface	+	^Citation2
EpCAM	Cell surface	+	^Citation42
MUC1	Cell surface	+	^Citation76
P-cadherin	Cell surface		^Citation70, ^Citation71
N-cadherin	Cell surface		^Citation74
CD49f	Cell surface		^Citation42
CD29	Cell surface		^Citation42
CD47	Cell surface		^Citation42
CD133	Cell surface		^Citation42, ^Citation74
CD338	Cell surface		^Citation77
MET	Cell surface		^Citation42, ^Citation35
HER2	Cell surface		^Citation42
Keratins	Cytoplasm		^Citation79
Vimentin	Cytoplasm/cell surface	+	^Citation58, ^Citation72, ^Citation93
Sox2	Nucleus/cytoplasm		^Citation42
Bmi1	Nucleus/cytoplasm		^Citation42
p53	Nucleus/cytoplasm		^Citation42
GLI1	Nucleus/cytoplasm		^Citation78
Twist1	Nucleus/cytoplasm		^Citation73, ^Citation75
Akt2	Nucleus/cytoplasm		^Citation75, ^Citation76
Snail	Nucleus/cytoplasm		^Citation73
Zeb1	Nucleus/cytoplasm		^Citation76
Tg2	Nucleus/cytoplasm		^Citation76

Note: The localization of proteins expressed in BCSCs and used for their isolation is shown.

Abbreviations: ALDH1, aldehyde dehydrogenase 1; BCSC, breast cancer stem cell; EpCAM, epithelial cell adhesion molecule; HER2, human epidermal growth factor receptor 2.

Figure 1 Methods for the isolation and molecular characterization of BCTCs.

Abbreviations: Ab, antibody; BCTC, breast cancer circulating tumor cell; CTC, circulating tumor cell; EPISPOT, epithelial immuno SPOT; FACS, fluorescence activated cell sorting; IF, immunofluorescence; ISET, isolation by size of epithelial tumor cells, FISH, fluorescence in situ hybridization; PBMC, peripheral blood mononuclear cell; PCR, polymerase chain reaction.

Table 2 Molecular and functional heterogeneity of BCSCs

Molecular signature	Significance/properties	References
ALDH1^+	High tumorigenic potential	^Citation101
	Epithelial-like, proliferative
	Expression of MET genes
	Located in tumor interior
EpCAM^+/ALDH1^+/HER2^+/EGFR^+/HPSE^+/Notch1^+	Brain metastasis	^Citation104
	High expression levels of vimentin and keratins 8 and 18
	No detectable levels of keratins 19 and 20
	Expression of the stem cell phenotype CD44^+/CD24^low
ALDH1^+/CD44^+/CD24^−	Very high tumorigenic potential, rare	^Citation13, ^Citation101
CD44^+/CD24^−	High tumorigenic potential	^Citation101, ^Citation102
	Mesenchymal-like, quiescent
	Expression of EMT genes
	Located in tumor periphery
CD44^+/CD24^low	High tumorigenic potential	^Citation102
	Epithelial-like
	Expression of keratins 5/6
	Low expression of vimentin, keratin 17, and E-cadherin
CD44^−/CD24^+	Bone tropism	^Citation105
	Expression of low molecular weight keratins, EMA, and vimentin
	Bone tropism signature (88 upregulated and 22 downregulated genes)
ER^−/CD44^+/CD49f^hi/CD133	High tumorigenic potential	^Citation103
	High levels of keratins 18 and 14
EpCAM^+CD44^+CD47^+MET^+	Escaping immune response	^Citation35
	Critical in bone, lung, and liver metastases
	Associated with disease progression

Abbreviations: ALDH1, aldehyde dehydrogenase 1; BCSC, breast cancer stem cell; EMA, epithelial membrane antigen; EGFR, epidermal growth factor receptor; EMT, epithelial-to-mesenchymal transition; EpCAM, epithelial cell adhesion molecule; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HPSE, heparanase MET, mesenchymal-to-epithelial transition.

Table 3 Applications of stem cell technology in breast cancer therapy

Targeting breast cancer stem cells	References	Normal stem cell-mediated therapy	References
Antibiotics Signal pathways	113–116	Umbilical cord	^Citation123^–^Citation125
Differentiation Metabolism	Reviewed in^Citation42	Adipose tissue	^Citation126^–^Citation129
microRNA Immunotherapy		Amniotic fluid	^Citation130^–^Citation131
Nanodrugs		Neural	^Citation132^–^Citation135

GinestierCHurMHCharafe-JauffretEALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcomeCell Stem Cell20071555556718371393

 PubMed Web of Science ®Google Scholar

Al-HajjMWichaMSBenito-HernandezAMorrisonSJClarkeMFProspective identification of tumorigenic breast cancer cellsProc Natl Acad Sci U S A200310073983398812629218

 PubMed Web of Science ®Google Scholar

ChiotakiRPolioudakiHTheodoropoulosPACancer stem cells in solid and liquid tissues of breast cancer patients: characterization and therapeutic perspectivesCurr Cancer Drug Targets201515325626925669721

 PubMed Web of Science ®Google Scholar

KrawczykNMeier-StiegenFBanysMNeubauerHRuckhaeberleEFehmTExpression of stem cell and epithelial-mesenchymal transition markers in circulating tumor cells of breast cancer patientsBio Med Res Int20142014415721

 Google Scholar

VieiraAFRicardoSAblettMPP-cadherin is coexpressed with CD44 and CD49f and mediates stem cell properties in basal-like breast cancerStem Cells201230585486422389315

 PubMed Web of Science ®Google Scholar

RibeiroASParedesJP-Cadherin linking breast cancer stem cells and invasion: A promising marker to identify an “intermediate/metastable” EMT stateFront Oncol2014437125601904

 PubMed Web of Science ®Google Scholar

BockCRackBHuoberJAndergassenUJeschkeUDoisneau-SixouSDistinct expression of cytokeratin, N-cadherin and CD133 in circulating tumor cells of metastatic breast cancer patientsFuture Oncol201410101751176525303055

 PubMed Web of Science ®Google Scholar

LecciaFDel VecchioLMariottiEABCG2, a novel antigen to sort luminal progenitors of BRCA1-breast cancer cellsMol Cancer20141321325216750

 PubMed Web of Science ®Google Scholar

BaccelliISchneeweissARiethdorfSIdentification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assayNat Biotechnol201331653954423609047

 PubMed Web of Science ®Google Scholar

LianidouESMarkouACirculating tumor cells in breast cancer: detection systems, molecular characterization, and future challengesClin Chem20115791242125521784769

 PubMed Web of Science ®Google Scholar

YangJWeinbergRAEpithelial-mesenchymal transition: at the crossroads of development and tumor metastasisDev Cell200814681882918539112

 PubMed Web of Science ®Google Scholar

PolioudakiHAgelakiSChiotakiRVariable expression levels of keratin and vimentin reveal differential EMT status of circulating tumor cells and correlation with clinical characteristics and outcome of patients with metastatic breast cancerBMC Cancer20151539925962645

 PubMed Web of Science ®Google Scholar

SatelliABrownleeZMitraAMengQHLiSCirculating tumor cell enumeration with a combination of epithelial cell adhesion moleculeand cell-surface vimentin-based methods for monitoring breast cancer therapeutic responseClin Chem201561125926625336717

 PubMed Web of Science ®Google Scholar

Fernandez-ZapicoMEGLI1 finds a new role in cancer stem cell biologyEMBO Mol Med20135448348523505092

 PubMed Web of Science ®Google Scholar

PapadakiMAKallergiGZafeiriouZCo-expression of putative stemness and epithelial-to-mesenchymal transition markers on single circulating tumour cells from patients with early and metastatic breast cancerBMC Cancer20141465125182808

 PubMed Web of Science ®Google Scholar

BarriereGRiouallonARenaudieJTartaryMRigaudMMesenchymal and stemness circulating tumor cells in early breast cancer diagnosisBMC Cancer20121211422443102

 PubMed Web of Science ®Google Scholar

LiuSCongYWangDBreast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterpartsStem Cell Reports201421789124511467

 PubMed Web of Science ®Google Scholar

ZhangLRidgwayLDWetzelMDThe identification and characterization of breast cancer CTCs competent for brain metastasisSci Transl Med20135180180ra148

 Web of Science ®Google Scholar

Leth-LarsenRTerpMGChristensenAGFunctional heterogeneity within the CD44 high human breast cancer stem cell-like compartment reveals a gene signature predictive of distant metastasisMol Med2012181109112122692575

 PubMed Web of Science ®Google Scholar

D’AmicoLPataneSGrangeCPrimary breast cancer stem-like cells metastasise to bone, switch phenotype and acquire a bone tropism signatureBr J Cancer2013108122525253623801032

 PubMed Web of Science ®Google Scholar

MeyerMJFlemingJMLinAFHussnainSAGinsburgEVonderhaarBKCD44posCD49fhiCD133/2hi defines xenograft-initiating cells in estrogen receptor-negative breast cancerCancer Res201070114624463320484027

 PubMed Web of Science ®Google Scholar

OhtaNIshiguroSKawabataAHuman umbilical cord matrix mesenchymal stem cells suppress the growth of breast cancer by expression of tumor suppressor genesPloS One2015105e012375625942583

 PubMed Web of Science ®Google Scholar

MaYHaoXZhangSZhangJThe in vitro and in vivo effects of human umbilical cord mesenchymal stem cells on the growth of breast cancer cellsBreast Cancer Res Treat2012133247348521947651

 PubMed Web of Science ®Google Scholar

IllouzYGBreast cancer treatment by adipose-derived stem cells: an experimental studyJ Stem Cells20149421121725942336

 PubMedGoogle Scholar

OrecchioniSGregatoGMartin-PaduraIComplementary populations of human adipose CD34+ progenitor cells promote growth, angiogenesis, and metastasis of breast cancerCancer Res201373195880589123918796

 PubMed Web of Science ®Google Scholar

KangNHHwangKAYiBRHuman amniotic fluid-derived stem cells expressing cytosine deaminase and thymidine kinase inhibits the growth of breast cancer cells in cellular and xenograft mouse modelsCancer Gene Ther201219641241922498724

 PubMed Web of Science ®Google Scholar

KangNHYiBRLimSYHuman amniotic membrane-derived epithelial stem cells display anticancer activity in BALB/c female nude mice bearing disseminated breast cancer xenograftsInt J Oncol20124062022202822344679

 PubMed Web of Science ®Google Scholar

Bagci-OnderTDuWFigueiredoJLMartinez-QuintanillaJShahKTargeting breast to brain metastatic tumours with death receptor ligand expressing therapeutic stem cellsBrain2015138Pt 61710172125910782

 PubMed Web of Science ®Google Scholar

YiBRHwangKAAboodyKSJeungEBKimSUChoiKCSelective antitumor effect of neural stem cells expressing cytosine deaminase and interferon-beta against ductal breast cancer cells in cellular and xenograft modelsStem Cell Res2014121364824141111

 PubMed Web of Science ®Google Scholar