Affinage

ALCAM

CD166 antigen · UniProt Q13740

Length
583 aa
Mass
65.1 kDa
Annotated
2026-06-09
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALCAM (CD166) is a transmembrane immunoglobulin-superfamily cell adhesion molecule that engages in strong heterophilic binding to CD6 (KD ~0.4–1 µM) through its membrane-distal N-terminal Ig domain and weaker homophilic ALCAM–ALCAM interactions (KD ~29–48 µM) (PMID:7760007, PMID:15048703, PMID:26146185). Homophilic adhesion is biphasic: the N-terminal Ig domain mediates ligand binding, while membrane-proximal Ig domains drive clustering that controls avidity (PMID:11306570). Crystal structures of the CD6 SRCR domains bound to the two N-terminal ALCAM Ig domains define the interface, and native mass spectrometry shows that heterophilic CD6–ALCAM and homophilic ALCAM–ALCAM engagement compete (PMID:26146185). Intracellularly, ALCAM is recruited to cell-cell contacts by α-catenin and couples to the actin cortex; this linkage does not alter individual bond affinity but stiffens the cortex and strengthens overall adhesion to CD6 at the immunological synapse (PMID:10673383, PMID:24496453). ALCAM surface levels are dynamically controlled by clathrin-mediated endocytosis with recycling, an endophilin-A3/galectin-8-driven clathrin-independent pathway, and ADAM17-mediated ectodomain shedding that is induced by TGF-β and restrained by the tetraspanin CD9 (PMID:15769845, PMID:32193381, PMID:27130882, PMID:24385212, PMID:23052204). Through CD6–ALCAM engagement at the immunological synapse, ALCAM sustains DC-induced T-cell proliferation and is required for γδ T cell activation (PMID:16352806, PMID:16818742). In vivo, ALCAM is required for hematopoietic stem cell self-renewal and engraftment, lymphatic network formation and dendritic cell migration, blood-brain barrier tight-junction integrity and leukocyte transmigration, and intestinal stem cell niche maintenance via Wnt signaling (PMID:23280653, PMID:23169771, PMID:28069965, PMID:28462380). In cancer, ALCAM controls MMP-2 activation through MT1-MMP processing and promotes survival signaling through PI3K/AKT–YAP and AKT–FOXO axes (PMID:16204050, PMID:24482231, PMID:24891117). ALCAM additionally serves as a binding partner for ILT3 (LILRB4), galectin-8, and S100B, and its expression is regulated transcriptionally by NF-κB and HIF-1α and post-translationally by the E3 ligase CHIP and by PRMT1 (PMID:29263213, PMID:27130882, PMID:23729438, PMID:21572107, PMID:38956900, PMID:28279658, PMID:27175582).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1995 High

    Establishing ALCAM's first molecular partner: it was unknown what receptor ALCAM engaged, and reciprocal fusion-protein binding defined a direct heterophilic ALCAM–CD6 interaction, founding the entire CD6–ALCAM axis.

    Evidence COS cell transfection with reciprocal Ig-fusion-protein binding and antibody blocking

    PMID:7760007

    Open questions at the time
    • Did not map the binding site at residue resolution
    • Did not address homophilic binding or downstream signaling
  2. 1997 High

    Localizing the CD6-binding determinant: mutagenesis and truncation mapped CD6 binding to specific residues on the N-terminal Ig domain β-sheet and explained cross-species interaction.

    Evidence Truncation constructs, site-directed mutagenesis, and molecular modeling with soluble CD6

    PMID:9209500

    Open questions at the time
    • No atomic structure yet
    • Did not resolve how homophilic binding uses the same domain
  3. 1998 Medium

    Defining a second adhesion mode: whether ALCAM could act independently of CD6 was unknown, and transfection into CD6-negative melanoma showed ALCAM expression is sufficient for homophilic clustering.

    Evidence ALCAM transfection into ALCAM-negative melanoma with FACS aggregation assays

    PMID:9502422

    Open questions at the time
    • Affinity and structural basis of homophilic binding not measured
    • Single-lab gain-of-function
  4. 2000 High

    Quantifying the adhesion hierarchy and its modularity: biophysics revealed heterophilic CD6 binding is ~100-fold stronger than homophilic binding, and structure-function work showed ligand binding and avidity-controlling clustering are separable modules.

    Evidence SPR/biophysical KD measurements and deletion/dominant-negative adhesion assays

    PMID:11306570 PMID:15048703

    Open questions at the time
    • Did not define the clustering interface structurally
    • Intracellular coupling not addressed
  5. 2000 Medium

    Connecting ALCAM to the junctional cytoskeleton: α-catenin was shown to be required to recruit ALCAM to cell-cell contacts alongside E-cadherin.

    Evidence α-N-catenin rescue in α-catenin-null prostate cancer cells with immunofluorescence

    PMID:10673383

    Open questions at the time
    • Direct vs indirect coupling to actin not resolved
    • No biophysical adhesion measurement
  6. 2006 High

    Defining ALCAM's immune function: CD6–ALCAM engagement was shown not only to initiate but to sustain DC-induced T-cell proliferation and to be required for γδ T cell activation at the immunological synapse.

    Evidence Blocking antibodies, ALCAM-Fc, CD6/CD3 crosslinking, synapse imaging, and gain/loss-of-function in tumor lines

    PMID:16352806 PMID:16818742

    Open questions at the time
    • Downstream T-cell signaling from CD6 not dissected
    • Relative contribution of homophilic vs heterophilic binding unclear
  7. 2005 High

    Linking ALCAM to proteolytic invasion machinery: ALCAM was shown to control MMP-2 activation in a cell-density-dependent manner by regulating MT1-MMP transcription and processing.

    Evidence Dominant-negative truncation and RNAi with zymography, 3D collagen culture, and xenografts

    PMID:16204050

    Open questions at the time
    • Mechanism linking ALCAM adhesion to MT1-MMP regulation not defined
    • Direct ALCAM signaling intermediates unidentified
  8. 2005 High

    Establishing ALCAM surface dynamics: ligand engagement was shown to drive clathrin-mediated internalization with recycling back to the surface.

    Evidence Antibody-induced internalization, clathrin/caveolin colocalization, surface biotinylation, and recycling assays

    PMID:15769845

    Open questions at the time
    • Adaptor proteins for clathrin uptake not identified
    • Did not address alternative endocytic routes
  9. 2012 High

    Connecting surface regulation to a tetraspanin: ALCAM was shown to associate with CD9 and ADAM17, with CD9 boosting ALCAM adhesion by promoting clustering and inhibiting sheddase activity.

    Evidence Co-IP, confocal colocalization, ADAM17 activity assays, and adhesion/migration functional readouts

    PMID:23052204

    Open questions at the time
    • Structural basis of the CD9–ALCAM–ADAM17 assembly unknown
    • How CD9 inhibits ADAM17 not resolved
  10. 2014 High

    Defining the biophysics of intracellular coupling: actin-cortex linkage of the ALCAM tail was shown to strengthen adhesion by stiffening the cortex rather than altering bond affinity.

    Evidence Single-cell force spectroscopy, TIRF microscopy, and cytoplasmic-tail deletion mutants

    PMID:24496453

    Open questions at the time
    • Identity of the actin-coupling adaptors not defined
    • Link to α-catinin-mediated recruitment unresolved
  11. 2014 High

    Establishing ALCAM as a sheddable driver of metastasis: ADAM17 was identified as the TGF-β-induced sheddase, and ALCAM shedding was shown required for prostate cancer bone metastasis.

    Evidence Biochemical shedding assays, ADAM17 inhibitor/siRNA, ALCAM shRNA, and in vivo intratibial bone metastasis model

    PMID:24385212

    Open questions at the time
    • Function of the shed ectodomain vs membrane stub not separated
    • Signaling triggered by shedding unclear
  12. 2014 Medium

    Placing ALCAM in cancer survival signaling: ALCAM/CD166 was shown to drive PI3K/AKT–YAP and AKT–FOXO axes and to stabilize partner proteins, with CD9 facilitating CD166 homophilic interaction.

    Evidence Knockdown/overexpression, AKT rescue epistasis, ubiquitination, fractionation, and reporter assays

    PMID:24385212 PMID:24482231 PMID:24891117

    Open questions at the time
    • Direct molecular link between surface ALCAM and AKT activation not defined
    • Single-lab dissection of these feedback loops
  13. 2015 High

    Achieving atomic resolution: crystal structures of CD6 SRCR and ALCAM Ig domains defined the binding interface and showed heterophilic and homophilic interactions compete.

    Evidence X-ray crystallography, native mass spectrometry, and SNP glycosylation analysis

    PMID:26146185

    Open questions at the time
    • Full-length complex in membrane context not resolved
    • Structural basis of avidity clustering not captured
  14. 2016 High

    Expanding the ALCAM ligand repertoire: SPR established glycosylation-dependent galectin-8 binding, and CRISPR work defined ILT3 (LILRB4) as a direct partner that inhibits tumor growth via p70S6K.

    Evidence SPR with recombinant and endogenous ALCAM, mass spectrometry, CRISPR-Cas9 KO, and p70S6K signaling assays

    PMID:27130882 PMID:29263213

    Open questions at the time
    • Physiological context of ILT3–ALCAM signaling beyond tumors unclear
    • Whether galectin-8 binding competes with CD6 not tested
  15. 2013 High

    Establishing ALCAM's stem-cell-niche and vascular-barrier roles: knockout mice revealed requirements for HSC self-renewal, lymphatic network formation, and DC migration.

    Evidence Alcam knockout mice with serial transplantation, LEC adhesion/tube assays, and in vivo DC migration

    PMID:23169771 PMID:23280653

    Open questions at the time
    • Whether niche function is homophilic or heterophilic not resolved
    • Molecular signaling downstream of niche adhesion unidentified
  16. 2017 High

    Defining ALCAM in barrier and epithelial niches: knockouts showed ALCAM is required for BBB tight-junction integrity and Th1/monocyte transmigration, and for intestinal stem cell maintenance via Wnt3/β-catenin.

    Evidence ALCAM KO mice, EAE and passive-transfer models, BBB permeability and transmigration assays, and enteroid/ISC analysis

    PMID:28069965 PMID:28273717 PMID:28462380

    Open questions at the time
    • How ALCAM mechanistically promotes tight-junction assembly unknown
    • Link between ALCAM adhesion and Wnt ligand expression not defined
  17. 2020 High

    Identifying a selective clathrin-independent endocytic route: endophilin-A3 and galectin-8 were shown to drive ALCAM internalization that tunes surface abundance and migration.

    Evidence Isoform-specific endophilin knockdown, galectin-8 perturbation, live-cell carrier imaging, and co-IP

    PMID:32193381

    Open questions at the time
    • How cells choose between clathrin-dependent and -independent routes unknown
    • Fate of internalized ALCAM not fully tracked
  18. 2022 Medium

    Linking the CD6–ALCAM axis to disease and exhaustion: antibody blockade implicated ALCAM in lupus nephritis, and HIF-1α-driven ALCAMhigh macrophages were shown to promote CD8 T cell exhaustion.

    Evidence Anti-CD6 blockade in lupus models, patient uALCAM ELISA, and spatial/single-cell transcriptomics with HIF-1α ChIP and inhibition

    PMID:34981775 PMID:38956900

    Open questions at the time
    • Direct ALCAM ligand mediating exhaustion in this context not defined
    • Causality of macrophage ALCAM in human tumors not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the cytoplasmic adaptors that physically couple the ALCAM tail to the actin cortex, and the unified signaling output that links surface adhesion to AKT/YAP/FOXO regulation, remain undefined.
  • No direct ALCAM intracellular signaling effector identified
  • Mechanism converting adhesion into survival signaling unknown
  • Structure of full-length clustered ALCAM in membranes unsolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 4 GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005856 cytoskeleton 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-5653656 Vesicle-mediated transport 2
Partners
ADAM17CD6CD9CTNNA1LGALS8LILRB4S100BSOSTDC1
Complex memberships
immunological synapse

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 ALCAM (CD166) was identified as a ligand for CD6: COS cells transfected with ALCAM cDNA bound a CD6 immunoglobulin fusion protein (CD6-Rg), and an ALCAM-Rg fusion protein bound COS cell transfectants expressing CD6, establishing a direct heterophilic ALCAM–CD6 receptor–ligand interaction. COS cell transfection, immunoglobulin fusion protein binding assay, antibody-blocking studies The Journal of experimental medicine High 7760007
1997 The CD6-binding site of ALCAM maps to the N-terminal Ig-like domain, and mutagenesis of hALCAM identified residues critical for CD6 binding on the predicted A'GFCC'C" β-sheet of this domain; all critical residues are conserved in mouse ALCAM, explaining cross-species CD6/ALCAM interaction. Truncation constructs of ALCAM extracellular region, binding assays with soluble CD6, site-directed mutagenesis, molecular modeling European journal of immunology High 9209500
1998 ALCAM (MEMD) mediates homophilic (ALCAM–ALCAM) cell-cell clustering in CD6-negative melanoma cells; transfection of ALCAM into ALCAM-negative melanoma cells restored cell-cell interaction, demonstrating that ALCAM expression is sufficient for homophilic adhesion in this context. Transfection experiments, FACS-based aggregation assays The American journal of pathology Medium 9502422
2000 CD6–CD166 heterophilic interaction has a KD of ~0.4–1.0 µM with fast off-rate (Koff ≥0.4 s⁻¹); homophilic ALCAM–ALCAM interaction is ~100-fold weaker (KD ~29–48 µM, Koff ≥5.3 s⁻¹), demonstrating that heterophilic binding is substantially stronger than homophilic binding. In vitro binding assays with soluble recombinant proteins (surface plasmon resonance / biophysical characterization) European journal of immunology High 15048703
2000 α-catenin is required to recruit ALCAM to cell–cell contacts; prostate cancer cell lines lacking α-catenin show cytoplasmic ALCAM staining, whereas transfection of α-N-catenin restores ALCAM localization to cell-cell junctions alongside E-cadherin. α-catenin transfection into α-catenin-null cell lines, immunofluorescence localization Biochemical and biophysical research communications Medium 10673383
2001 Homophilic ALCAM–ALCAM cell adhesion requires two structurally and functionally distinct modules: (1) ligand binding mediated by the membrane-distal N-terminal Ig domain, and (2) avidity control through ALCAM clustering involving membrane-proximal Ig domains. A transmembrane deletion mutant lacking the ligand-binding domain inhibited cell-cell adhesion by interfering with ALCAM avidity without affecting soluble homophilic ligand binding. Amino-terminally deleted ALCAM constructs, monoclonal antibody blocking, co-expression of dominant-negative mutant, cell adhesion assays The Journal of biological chemistry High 11306570
2001 ALCAM expression on yolk sac endothelium supports hematopoietic progenitor cell development; ALCAM-transfected adult endothelial cells (EOMA) supported hematopoietic progenitor development compared to vector controls, and ALCAM was found to be involved in capillary tube formation and hemangioblast differentiation. ALCAM transfection into EOMA endothelial cells, hematopoietic progenitor co-culture assay, immunohistochemistry Blood Medium 11568000
2004 CD6–ALCAM interactions are required not only for establishing initial DC–T-cell contact but also for sustaining T-cell proliferation; ALCAM-blocking antibodies and recombinant ALCAM-Fc proteins strongly and sustainably inhibited DC-induced T-cell proliferation, and simultaneous crosslinking of CD6 and CD3 induced proliferation comparable to CD3+CD28 co-stimulation. Antibody-blocking assays, ALCAM-Fc recombinant protein inhibition, CD6/CD3 co-crosslinking, T-cell proliferation assays Blood High 16352806
2005 ALCAM controls MMP-2 activation in melanoma: truncation of ALCAM (dominant-negative) severely impaired pro-MMP-2 activation by reducing MT1-MMP transcript levels and impairing MT1-MMP processing. ALCAM depletion by RNAi recapitulated this failure of the proteolytic cascade mainly through incomplete MT1-MMP processing. Extensive cell–cell contacts, wild-type ALCAM, and cell–matrix interactions were all required for efficient MMP-2 activation. Dominant-negative ALCAM truncation mutant, RNA interference (RNAi), nude mouse xenograft model, 2D and 3D collagen-gel cultures, zymography/MMP-2 activation assay Cancer research High 16204050
2005 ALCAM undergoes ligand engagement-induced internalization via a clathrin-mediated pathway (colocalizing with clathrin but not caveolin) and recycles back to the cell surface, as shown by surface biotinylation and recycling assays. This endocytic pathway enables intracellular delivery of ALCAM-targeted immunotoxins. Phage display antibody-induced internalization, immunofluorescence colocalization with clathrin/caveolin, surface biotinylation, recycling assay, immunotoxin kill assay Journal of cell science High 15769845
2006 CD6 and CD166 are recruited together to the center of the immunological synapse between γδ T cells and antigen-loaded tumor cells, colocalizing with γδ TCR/CD3. CD166 transfection into a CD166-negative tumor line markedly enhanced γδ T cell activation, while shRNA-mediated CD166 knockdown reduced it, demonstrating that CD6–CD166 engagement at the synapse is required for γδ T cell activation by nonpeptide antigen-presenting tumor cells. CD166 cDNA transfection, shRNA knockdown, immunofluorescence of immunological synapse, T-cell activation assay Journal of immunology High 16818742
2006 ALCAM gene silencing in breast cancer cells (MCF-7) reduced BCL-2 protein levels and triggered apoptosis (caspase-7 activation, PARP cleavage) and autophagy (MAP1LC3, Beclin1 upregulation), indicating ALCAM supports cell survival downstream of BCL-2. ALCAM gene silencing (siRNA), laser scanning cytometry, Western blotting for apoptosis/autophagy markers Medical science monitor Medium 16865058
2007 NDRG2 expressed in dendritic cells prevents down-regulation of ALCAM during monocyte-to-DC differentiation; NDRG2 siRNA knockdown specifically reduced ALCAM expression in differentiating DCs and diminished their ability to induce T cell proliferation, while NDRG2 overexpression in U937 cells conferred resistance to GM-CSF/IL-4-induced ALCAM reduction. RNA interference of NDRG2, NDRG2 overexpression in U937, flow cytometry for ALCAM, T-cell proliferation assay Journal of leukocyte biology Medium 17911180
2008 DM-GRASP/ALCAM/CD166 is required for cardiac morphogenesis in Xenopus laevis; loss-of-function reduced expression of first-heart-field markers (Tbx20, TnIc) but not second-heart-field markers (Isl-1, BMP-4), caused defective cell adhesion and cardiac morphogenesis, and DM-GRASP expression rescued the phenotype caused by loss of non-canonical Wnt11-R signaling, demonstrating functional coupling between ALCAM and Wnt11-R during cardiac development. Xenopus laevis loss-of-function (morpholino knockdown), rescue experiments with DM-GRASP expression, in situ hybridization for cardiac marker genes Developmental biology High 18598690
2011 NF-κB P50/P65 heterodimer activates both CD166/ALCAM and miR-9-1 transcription after serum deprivation. miR-9, induced with a delay, represses ALCAM protein translation via its 3'-UTR, creating a negative auto-regulatory loop. miR-9 also promotes cell migration partly via inhibition of CD166. Luciferase reporter assay, NF-κB inhibition/knockdown, miRNA overexpression and inhibitor experiments, Western blotting, qRT-PCR Nucleic acids research Medium 21572107
2012 ALCAM directly associates with the tetraspanin CD9 and ADAM17/TACE on the leukocyte surface; CD9 upregulates both homophilic and heterophilic ALCAM-mediated adhesion by (1) promoting ALCAM clustering and (2) inhibiting ADAM17 sheddase activity to increase ALCAM surface expression. Confocal microscopy colocalization, co-immunoprecipitation, cell adhesion and migration/proliferation functional assays, ADAM17 activity assays Cellular and molecular life sciences High 23052204
2012 ALCAM regulates motility, invasiveness, and adherens junction formation in uveal melanoma; shRNA knockdown of ALCAM reduced cell motility and invasion and disrupted adherens junction formation, while ALCAM overexpression enhanced recruitment of β-catenin and N-cadherin to adherens junctions. ALCAM is necessary but not sufficient to promote metastasis-associated behaviors. shRNA stable knockdown, stable overexpression, gap-closure motility assay, transwell invasion assay, immunostaining for adherens junction components PloS one Medium 22745734
2012 ALCAM mRNA is locally translated in retinal ganglion cell axonal growth cones, regulated by the 3'-UTR and dependent on ERK and TOR kinase activity. Local growth cone translation of ALCAM is required for enhanced axon elongation on ALCAM substrate, rapid compensation for experimentally induced ALCAM internalization, and axonal preference for ALCAM-containing lanes. Isolated growth cone translation assay, 3'-UTR reporter constructs, kinase inhibitors (ERK, TOR), ALCAM internalization assay, axon choice assay Journal of cell science High 22421359
2013 ALCAM regulates long-term hematopoietic stem cell (HSC) self-renewal and engraftment; Alcam-/- mice show reduced long-term repopulating capacity and engraftment efficiency, age-associated expansion of CD150hi LT-HSCs with myeloid-biased output, and premature elevation of age-associated genes (Selp, Clu, Cdc42, Foxo3). Alcam knockout mouse model, serial transplantation assays, in vitro replating, gene expression analysis Stem cells High 23280653
2013 ALCAM mediates adhesion, migration, and tube formation in lymphatic endothelial cells (LECs) and supports dendritic cell adhesion to lymphatic endothelium. ALCAM knockout mice have reduced LEC numbers, defects in organized lymphatic vessel network formation, and compromised DC migration from lung to draining lymph nodes. ALCAM knockout mouse, in vitro LEC adhesion/migration/tube formation assays, DC migration assay in vivo and in vitro FASEB journal High 23169771
2013 S100B binds CD166/ALCAM and induces dose- and time-dependent NF-κB activation in endothelial cells. siRNA knockdown of CD166/ALCAM completely inhibited S100B-induced NF-κB activation in RAGE-/- cells. In vivo, ALCAM siRNA attenuated delayed-type hypersensitivity (DTH) by ~40–50%; ALCAM-/- mice showed compensatory RAGE upregulation. siRNA knockdown, NF-κB reporter/activation assay, ALCAM-/- and RAGE-/- mouse DTH model Journal of immunology High 23729438
2014 ALCAM is shed from metastatic prostate cancer cells by the sheddase ADAM17 in response to TGF-β signaling, and this ectodomain shedding is required for effective bone metastasis; shRNA knockdown of ALCAM in bone-metastatic PC3 cells greatly diminished skeletal dissemination and tumor growth in bone, associated with increased apoptosis and decreased proliferation. Biochemical shedding assays, ADAM17 identification by inhibitor and siRNA, ALCAM shRNA knockdown, in vivo bone metastasis model (intratibial engraftment), IHC for caspase-3 and Ki67 Cancer research High 24385212
2014 ALCAM intracellular domain coupling to the actin cortex does not affect the affinity of individual ALCAM–CD6 bonds, but does control ALCAM recruitment to adhesion sites and membrane tether formation. Linking ALCAM to the actin cortex stiffens the cortex and strengthens overall cell adhesion to CD6 at the immunological synapse. Single-cell force spectroscopy (SCFS), TIRF microscopy, ALCAM cytoplasmic tail deletion mutants, actin cytoskeleton perturbation Journal of cell science High 24496453
2014 CD166 promotes anti-apoptotic signaling in liver cancer via PI3K/AKT: AKT upregulates CD166 expression post-transcriptionally, and CD166 in turn promotes AKT expression and activity (positive feedback). CD166 also activates YAP through transcriptional regulation via CREB and post-transcriptional stabilization via AMOT130 inhibition. CD9 enhances CD166-mediated YAP regulation by facilitating CD166–CD166 homophilic interaction. CD166 siRNA knockdown, AKT overexpression rescue, subcellular fractionation, co-immunoprecipitation, luciferase reporter, tissue microarray The Journal of biological chemistry Medium 24482231
2014 CD166 regulates MCAM protein stability by suppressing the ubiquitin E3 ligases βTrCP and Smurf1 through PI3K/AKT and c-Raf/MEK/ERK signaling, thereby protecting MCAM from proteasomal degradation. CD166 knockdown/overexpression, ubiquitination assays, E3 ligase overexpression, pathway inhibitors (PI3K, MEK), co-immunoprecipitation, tissue microarray Cellular signalling Medium 26004137
2014 CD166 regulates FOXO protein stability and subcellular localization through AKT: CD166 overexpression accelerates FOXO ubiquitination and degradation and shifts FOXO from nucleus to cytoplasm, while CD166 knockdown reduces FOXO phosphorylation. AKT overexpression rescues CD166 knockdown-induced FOXO dephosphorylation and anti-carcinogenic effects, placing AKT between CD166 and FOXO. CD166 knockdown/overexpression, subcellular fractionation, ubiquitination assay, AKT overexpression rescue, in vitro and in vivo tumor assays Oncology reports Medium 24891117
2015 Crystal structures of the three SRCR domains of CD6 and the two N-terminal Ig domains of CD166 were solved by X-ray crystallography. Structural analysis revealed the CD6/CD166 binding interface, showed that a SNP in CD6 introduces glycosylation that sterically hinders the CD6/CD166 interaction, and native mass spectrometry demonstrated competition between heterophilic CD6-CD166 and homophilic CD166-CD166 interactions. X-ray crystallography, native mass spectrometry, SNP glycosylation analysis Structure High 26146185
2016 ILT3 (LILRB4) binds CD166/ALCAM directly; CRISPR-Cas9 knockout of CD166 abolished ILT3.Fc binding and its tumor-inhibitory effect. ILT3.Fc binding to CD166 inhibits tumor cell growth through inactivation of the p70 S6 kinase (p70S6K) signaling pathway. Flow cytometry, mass spectrometry, Biacore (SPR), CD166 knockdown by nucleofection and CRISPR-Cas9 KO, p70S6K signaling assay, in vitro and in vivo tumor growth assays Journal of immunology High 29263213
2016 CD166 in multiple myeloma cells inhibits osteoblastogenesis by suppressing Runx2 gene expression in osteoblast progenitors, and promotes osteoclastogenesis by activating TRAF6-dependent signaling in osteoclast progenitors; CD166 silencing reduced skeletal dissemination and osteolytic lesion formation in vivo. CD166 siRNA/shRNA knockdown in MM cell lines, intratibial engraftment model, ex vivo bone organ culture, osteoblast/osteoclast differentiation assays, Runx2 and TRAF6 signaling analysis Cancer research High 27634757
2017 ALCAM knockout mice develop more severe EAE (experimental autoimmune encephalomyelitis) with increased CNS-infiltrating leukocytes; passive transfer experiments linked this to absence of ALCAM on blood-brain barrier endothelial cells. ALCAM KO mice also show reduced expression of BBB tight junction proteins and increased CNS blood vessel permeability, establishing ALCAM as a component required for tight junction assembly and BBB integrity. ALCAM knockout mouse, active and passive EAE model, phenotypic characterization, tight junction protein expression, in vitro BBB permeability assay Proceedings of the National Academy of Sciences of the United States of America High 28069965
2016 ALCAM mediates preferential diapedesis of CD4+ Th1 cells (but not Th17 cells) across the human BBB in vitro; antibody-mediated ALCAM inhibition reduced Th1 but not Th17 diapedesis under static conditions. ALCAM also contributes to rolling, adhesion, and diapedesis of CD14+ monocytes across the human BBB under flow and static conditions. Anti-ALCAM antibody blocking, ALCAM-/- in vitro BBB model, leukocyte transmigration assays under static and flow conditions Journal of cerebral blood flow and metabolism Medium 28273717
2017 CD166 loss in intestinal crypts reduces active-cycling Lgr5+ ISC numbers; homeostasis is maintained by transit-amplifying compartment expansion (not slow-cycling Bmi1+ ISC stimulation). Loss of active-cycling ISCs is coupled to defective Paneth cell terminal differentiation linked to reduced Wnt3 ligand expression and depleted nuclear β-catenin in CD166-/- Paneth cells. CD166-/- mouse, immunohistochemistry, flow cytometry, gene expression analysis, enteroid culture Cellular and molecular gastroenterology and hepatology High 28462380
2017 ALCAM mediates DC migration through afferent lymphatics and promotes allospecific immune reactions; anti-murine ALCAM blocking antibody reduced DC transmigration across lymphatic endothelial monolayers, DC emigration from human skin explants, lymphangiogenic processes in vitro, and prevented corneal allograft rejection by retaining DCs in the cornea. Blocking monoclonal antibody, in vitro DC transmigration assay, human skin explant emigration, in vivo corneal allograft model, developmental lymphangiogenesis assay Frontiers in immunology High 31031759
2017 E3 ubiquitin ligase CHIP directly regulates ALCAM protein stability through the ubiquitin proteasome system; CHIP negatively correlates with CD166 in head and neck cancer samples, and CHIP expression represses cancer stem-like cell characteristics via targeting CD166 for degradation. Co-immunoprecipitation, ubiquitin proteasome inhibitor assay, CHIP overexpression/knockdown, Western blotting, tissue microarray Experimental cell research Medium 28279658
2019 PRMT1 interacts with ALCAM directly (confirmed by co-immunoprecipitation and LC-MS); PRMT1 silencing reduced ALCAM protein levels and suppressed melanoma tumor growth and metastasis, while re-expression of ALCAM in PRMT1-silenced cells restored colony formation and metastatic ability, placing ALCAM downstream of PRMT1. LC-MS/MS, co-immunoprecipitation, PRMT1 shRNA knockdown, ALCAM rescue overexpression, colony formation and migration assays Molecular medicine reports Medium 27175582
2020 CD166/ALCAM is internalized via a clathrin-independent endocytic pathway driven by endophilin-A3 (not A1 or A2 isoforms) and extracellular galectin-8. Endophilin-A3 physically interacts with CD166-containing early endocytic carriers. This endocytic modality modulates CD166 surface abundance and regulates adhesive and migratory properties of cancer cells. Endophilin-A isoform-specific knockdown, galectin-8 perturbation, live-cell endocytic carrier imaging, co-immunoprecipitation, cell adhesion and migration assays Nature communications High 32193381
2020 SOSTDC1 interacts with ALCAM/CD166 (identified by immunoprecipitation and mass spectrometry, confirmed by confocal microscopy and competition ELISA); this interaction involves the N-terminal region of SOSTDC1, which contains a sequence similar to the CD6-binding motif for ALCAM. ALCAM also interacts with α2β1 and α1β1 integrins. Knockdown of either SOSTDC1 or ALCAM, or antibody blockade, reduces invasion by inhibiting Src and PI3K/AKT signaling. Co-immunoprecipitation, mass spectrometry, confocal microscopy, competition ELISA, SOSTDC1/ALCAM knockdown, invasion assay, Src/PI3K-AKT signaling readout, in vivo liver metastasis model Oncogene High 32801337
2016 Galectin-8 interacts with ALCAM/CD166 in a glycosylation-dependent manner (demonstrated by surface plasmon resonance with recombinant glycosylated ALCAM ectodomain and endogenous ALCAM from breast cancer cells); ALCAM-silenced cells showed reduced binding to Gal-8. Exogenous Gal-8 caused ALCAM surface segregation/trapping at the cell surface. Surface plasmon resonance (SPR) binding assay, ALCAM siRNA knockdown, SPR binding of ALCAM-silenced cells, internalization/surface localization assay Biochimica et biophysica acta High 27130882
2022 ALCAM/CD166 is involved in binding and uptake of cancer-derived extracellular vesicles (EVs) by recipient cancer cells; ALCAM participates in EV docking and subsequent uptake, demonstrated in colorectal and ovarian cancer cell systems. ALCAM expression manipulation, EV binding and uptake assays, flow cytometry International journal of molecular sciences Medium 35628559
2022 The CD6/ALCAM pathway promotes lupus nephritis (LN) via T cell-mediated responses; ALCAM is expressed by renal structural cells while CD6 is exclusive to T cells in the LN kidney. Antibody blockade of CD6 in murine lupus and immune-complex glomerulonephritis models significantly decreased immune cell infiltration, inflammatory markers, and disease measures. Immunophenotyping of LN kidney cells, anti-CD6 antibody blockade in spontaneous lupus and immune-complex glomerulonephritis mouse models, uALCAM ELISA in patient cohorts The Journal of clinical investigation High 34981775
2024 Hypoxia promotes ALCAM expression in macrophages via HIF-1α binding to the ALCAM promoter; ALCAMhigh macrophages co-localize with exhausted CD8+ T cells in the tumor spatial microenvironment and promote T cell exhaustion. HIF-1α inhibition reduces ALCAM expression in macrophages and potentiates T cell anti-tumor function. Bulk, single-cell, and spatial transcriptomics integration, HIF-1α ChIP on ALCAM promoter, HIF-1α inhibitor experiments, preclinical immunotherapy models Advanced science Medium 38956900

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Cloning, mapping, and characterization of activated leukocyte-cell adhesion molecule (ALCAM), a CD6 ligand. The Journal of experimental medicine 326 7760007
2004 ALCAM/CD166 is overexpressed in colorectal carcinoma and correlates with shortened patient survival. Journal of clinical pathology 214 15509676
2002 Activated leukocyte cell adhesion molecule (CD166/ALCAM): developmental and mechanistic aspects of cell clustering and cell migration. European journal of cell biology 210 12113472
2005 Long-term engagement of CD6 and ALCAM is essential for T-cell proliferation induced by dendritic cells. Blood 179 16352806
2000 Activated leukocyte cell adhesion molecule/CD166, a marker of tumor progression in primary malignant melanoma of the skin. The American journal of pathology 173 10702391
2010 Characterization of the intestinal cancer stem cell marker CD166 in the human and mouse gastrointestinal tract. Gastroenterology 157 20826154
2001 Molecular basis for the homophilic activated leukocyte cell adhesion molecule (ALCAM)-ALCAM interaction. The Journal of biological chemistry 140 11306570
2014 miR-483-5p promotes invasion and metastasis of lung adenocarcinoma by targeting RhoGDI1 and ALCAM. Cancer research 139 24710410
1998 MEMD, a new cell adhesion molecule in metastasizing human melanoma cell lines, is identical to ALCAM (activated leukocyte cell adhesion molecule). The American journal of pathology 124 9502422
2004 Frontline: Optimal T cell activation requires the engagement of CD6 and CD166. European journal of immunology 123 15048703
2003 ALCAM/CD166 is up-regulated in low-grade prostate cancer and progressively lost in high-grade lesions. The Prostate 123 12481253
2001 ALCAM (CD166): its role in hematopoietic and endothelial development. Blood 114 11568000
2010 ALCAM/CD166: cancer-related issues. Cancer genomics & proteomics 111 20952758
2005 Activated leukocyte cell adhesion molecule (ALCAM/CD166/MEMD), a novel actor in invasive growth, controls matrix metalloproteinase activity. Cancer research 96 16204050
2012 Identification of CD166 as a surface marker for enriching prostate stem/progenitor and cancer initiating cells. PloS one 91 22880034
2022 The CD6/ALCAM pathway promotes lupus nephritis via T cell-mediated responses. The Journal of clinical investigation 89 34981775
2005 Activated leukocyte cell adhesion molecule (ALCAM/CD166): signaling at the divide of melanoma cell clustering and cell migration? Cancer metastasis reviews 89 15986133
2017 Dual role of ALCAM in neuroinflammation and blood-brain barrier homeostasis. Proceedings of the National Academy of Sciences of the United States of America 88 28069965
2014 ALCAM/CD166 is a TGF-β-responsive marker and functional regulator of prostate cancer metastasis to bone. Cancer research 76 24385212
1997 Characterization of mouse ALCAM (CD166): the CD6-binding domain is conserved in different homologs and mediates cross-species binding. European journal of immunology 76 9209500
2013 Plasma membrane proteomics of tumor spheres identify CD166 as a novel marker for cancer stem-like cells in head and neck squamous cell carcinoma. Molecular & cellular proteomics : MCP 75 23903875
2006 ALCAM/CD166 protects breast cancer cells against apoptosis and autophagy. Medical science monitor : international medical journal of experimental and clinical research 69 16865058
2000 Cell surface receptors and their ligands: in vitro analysis of CD6-CD166 interactions. Proteins 69 10861932
2005 MEMD/ALCAM: a potential marker for tumor invasion and nodal metastasis in esophageal squamous cell carcinoma. Oncology 68 16024937
2020 Endophilin-A3 and Galectin-8 control the clathrin-independent endocytosis of CD166. Nature communications 67 32193381
2021 ALCAM/CD166: A pleiotropic mediator of cell adhesion, stemness and cancer progression. Cytokine & growth factor reviews 66 34272152
2019 Anti-CD166/4-1BB chimeric antigen receptor T cell therapy for the treatment of osteosarcoma. Journal of experimental & clinical cancer research : CR 63 30995926
2015 Structures of CD6 and Its Ligand CD166 Give Insight into Their Interaction. Structure (London, England : 1993) 63 26146185
2014 CD166 regulates human and murine hematopoietic stem cells and the hematopoietic niche. Blood 56 24740813
2008 Comparative study of SPR and ELISA methods based on analysis of CD166/ALCAM levels in cancer and control human sera. Biosensors & bioelectronics 56 19157844
2012 CD133+, CD166+CD44+, and CD24+CD44+ phenotypes fail to reliably identify cell populations with cancer stem cell functional features in established human colorectal cancer cell lines. Stem cells translational medicine 55 23197865
2008 Predictive impact of activated leukocyte cell adhesion molecule (ALCAM/CD166) in breast cancer. Breast cancer research and treatment 55 18172759
2016 ALCAM (CD166) is involved in extravasation of monocytes rather than T cells across the blood-brain barrier. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 54 28273717
2011 NF-kappaB P50/P65 hetero-dimer mediates differential regulation of CD166/ALCAM expression via interaction with micoRNA-9 after serum deprivation, providing evidence for a novel negative auto-regulatory loop. Nucleic acids research 54 21572107
2013 Embryonic stem cell-derived CD166+ precursors develop into fully functional sinoatrial-like cells. Circulation research 52 23753573
2012 ALCAM/CD166 adhesive function is regulated by the tetraspanin CD9. Cellular and molecular life sciences : CMLS 52 23052204
2014 Cluster of differentiation 166 (CD166) regulated by phosphatidylinositide 3-Kinase (PI3K)/AKT signaling to exert its anti-apoptotic role via yes-associated protein (YAP) in liver cancer. The Journal of biological chemistry 51 24482231
2017 MiR-148a and miR-152 reduce tamoxifen resistance in ER+ breast cancer via downregulating ALCAM. Biochemical and biophysical research communications 50 28063929
2005 Internalization and recycling of ALCAM/CD166 detected by a fully human single-chain recombinant antibody. Journal of cell science 50 15769845
2000 Coordinate recruitment of E-cadherin and ALCAM to cell-cell contacts by alpha-catenin. Biochemical and biophysical research communications 50 10673383
2006 Involvement of CD166 in the activation of human gamma delta T cells by tumor cells sensitized with nonpeptide antigens. Journal of immunology (Baltimore, Md. : 1950) 49 16818742
2020 ALCAM and VCAM-1 as urine biomarkers of activity and long-term renal outcome in systemic lupus erythematosus. Rheumatology (Oxford, England) 48 31722419
2003 Human blastocysts and endometrial epithelial cells express activated leukocyte cell adhesion molecule (ALCAM/CD166). The Journal of clinical endocrinology and metabolism 48 12843199
2017 Expression of ALCAM (CD166) and PD-L1 (CD274) independently predicts shorter survival in malignant pleural mesothelioma. Human pathology 47 28811252
2011 CD166/activated leukocyte cell adhesion molecule is expressed on glioblastoma progenitor cells and involved in the regulation of tumor cell invasion. Neuro-oncology 47 22166264
2014 miR126-5p repression of ALCAM and SetD5 in endothelial cells regulates leucocyte adhesion and transmigration. Cardiovascular research 46 24562769
2009 Cardiomyocyte enrichment from human embryonic stem cell cultures by selection of ALCAM surface expression. Regenerative medicine 44 19317642
1998 Cytokine-regulated expression of activated leukocyte cell adhesion molecule (CD166) on monocyte-lineage cells and in rheumatoid arthritis synovium. Arthritis and rheumatism 44 9870879
2017 ILT3.Fc-CD166 Interaction Induces Inactivation of p70 S6 Kinase and Inhibits Tumor Cell Growth. Journal of immunology (Baltimore, Md. : 1950) 42 29263213
2014 Dynamic coupling of ALCAM to the actin cortex strengthens cell adhesion to CD6. Journal of cell science 42 24496453
2014 CD166/ALCAM expression is characteristic of tumorigenicity and invasive and migratory activities of pancreatic cancer cells. PloS one 42 25221999
2019 Dual knockdown of Galectin-8 and its glycosylated ligand, the activated leukocyte cell adhesion molecule (ALCAM/CD166), synergistically delays in vivo breast cancer growth. Biochimica et biophysica acta. Molecular cell research 41 30905597
2012 Novel role for ALCAM in lymphatic network formation and function. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 41 23169771
2013 CD166/ALCAM mediates proinflammatory effects of S100B in delayed type hypersensitivity. Journal of immunology (Baltimore, Md. : 1950) 40 23729438
2019 Modulation of cell adhesion and migration through regulation of the immunoglobulin superfamily member ALCAM/CD166. Clinical & experimental metastasis 39 30778704
2014 Activated leukocyte cell adhesion molecule (CD166): an "inert" cancer stem cell marker for non-small cell lung cancer? Stem cells (Dayton, Ohio) 38 24501004
2011 Cell surface markers CD44 and CD166 localized specific populations of salivary acinar cells. Oral diseases 37 21973167
2013 Alcam regulates long-term hematopoietic stem cell engraftment and self-renewal. Stem cells (Dayton, Ohio) 36 23280653
2010 ALCAM is associated with chemoresistance and tumor cell adhesion in pancreatic cancer. Journal of surgical oncology 36 20461761
2015 CD166 positively regulates MCAM via inhibition to ubiquitin E3 ligases Smurf1 and βTrCP through PI3K/AKT and c-Raf/MEK/ERK signaling in Bel-7402 hepatocellular carcinoma cells. Cellular signalling 35 26004137
2022 Significant co-expression of putative cancer stem cell markers, EpCAM and CD166, correlates with tumor stage and invasive behavior in colorectal cancer. World journal of surgical oncology 34 35016698
2013 Hierarchical organization of osteoblasts reveals the significant role of CD166 in hematopoietic stem cell maintenance and function. Bone 34 23369988
2012 ALCAM (CD166) expression and serum levels in pancreatic cancer. PloS one 33 22745698
2008 DM-GRASP/ALCAM/CD166 is required for cardiac morphogenesis and maintenance of cardiac identity in first heart field derived cells. Developmental biology 33 18598690
2014 ALCAM and CD6--multiple sclerosis risk factors. Journal of neuroimmunology 31 25216742
2019 ALCAM Mediates DC Migration Through Afferent Lymphatics and Promotes Allospecific Immune Reactions. Frontiers in immunology 30 31031759
2017 Cell Adhesion Molecule CD166/ALCAM Functions Within the Crypt to Orchestrate Murine Intestinal Stem Cell Homeostasis. Cellular and molecular gastroenterology and hepatology 30 28462380
2007 Expression of human NDRG2 by myeloid dendritic cells inhibits down-regulation of activated leukocyte cell adhesion molecule (ALCAM) and contributes to maintenance of T cell stimulatory activity. Journal of leukocyte biology 30 17911180
2006 ALCAM (CD166) is a surface marker for early murine cardiomyocytes. Cells, tissues, organs 29 17409743
2016 Glycosylation-dependent binding of galectin-8 to activated leukocyte cell adhesion molecule (ALCAM/CD166) promotes its surface segregation on breast cancer cells. Biochimica et biophysica acta 28 27130882
2011 Effect of EpCAM, CD44, CD133 and CD166 expression on patient survival in tumours of the ampulla of Vater. Journal of clinical pathology 28 22130902
2012 Translation of the cell adhesion molecule ALCAM in axonal growth cones - regulation and functional importance. Journal of cell science 27 22421359
2012 ALCAM regulates motility, invasiveness, and adherens junction formation in uveal melanoma cells. PloS one 27 22745734
2016 Cell Adhesion Molecule CD166 Drives Malignant Progression and Osteolytic Disease in Multiple Myeloma. Cancer research 26 27634757
2014 P21 and CD166 as predictive markers of poor response and outcome after fluorouracil-based chemoradiotherapy for the patients with rectal cancer. BMC cancer 26 24708484
2022 Urine ALCAM, PF4 and VCAM-1 Surpass Conventional Metrics in Identifying Nephritis Disease Activity in Childhood-Onset Systemic Lupus Erythematosus. Frontiers in immunology 25 35720325
2021 Targeting CD166+ lung cancer stem cells: Molecular study using murine dendritic cell vaccine. Toxicology and applied pharmacology 25 34437932
2016 KRAS mutation associated with CD44/CD166 immunoexpression as predictors of worse outcome in metastatic colon cancer. Cancer biomarkers : section A of Disease markers 25 27062566
2022 CD166-specific CAR-T cells potently target colorectal cancer cells. Translational oncology 24 36327697
2020 SOSTDC1 promotes invasion and liver metastasis in colorectal cancer via interaction with ALCAM/CD166. Oncogene 24 32801337
2020 CD166 promotes the cancer stem-like properties of primary epithelial ovarian cancer cells. BMB reports 24 32843129
2017 Cancer stem-like cell related protein CD166 degrades through E3 ubiquitin ligase CHIP in head and neck cancer. Experimental cell research 23 28279658
2017 MiR-148b, MiR-152/ALCAM Axis Regulates the Proliferation and Invasion of Pituitary Adenomas Cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 23 29176323
2023 Increase of ALCAM and VCAM-1 in the plasma predicts the Alzheimer's disease. Frontiers in immunology 22 36685605
2011 Clinical implication of CD166 expression in gastric cancer. Journal of surgical oncology 22 20886585
2012 Activated leukocyte cell-adhesion molecule (ALCAM) promotes malignant phenotypes of malignant mesothelioma. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 21 22722789
2024 Identification of Hypoxia-ALCAMhigh Macrophage- Exhausted T Cell Axis in Tumor Microenvironment Remodeling for Immunotherapy Resistance. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20 38956900
2021 The Clinical and Theranostic Values of Activated Leukocyte Cell Adhesion Molecule (ALCAM)/CD166 in Human Solid Cancers. Cancers 19 34680335
2011 Functional polymorphisms in CD166/ALCAM gene associated with increased risk for breast cancer in a Chinese population. Breast cancer research and treatment 19 21293922
2022 Phenotypic and functional characterization of the CD6-ALCAM T-cell co-stimulatory pathway after allogeneic cell transplantation. Haematologica 18 35484649
2019 MiR-148b suppressed non-small cell lung cancer progression via inhibiting ALCAM through the NF-κB signaling pathway. Thoracic cancer 18 31883226
2014 CD133/CD166/Ki-67 triple immunofluorescence assessment for putative cancer stem cells in colon carcinoma. Journal of gastrointestinal and liver diseases : JGLD 18 24949608
2022 ALCAM/CD166 Is Involved in the Binding and Uptake of Cancer-Derived Extracellular Vesicles. International journal of molecular sciences 17 35628559
2016 PRMT1 regulates tumor growth and metastasis of human melanoma via targeting ALCAM. Molecular medicine reports 17 27175582
2014 CD166 plays a pro-carcinogenic role in liver cancer cells via inhibition of FOXO proteins through AKT. Oncology reports 17 24891117
2013 CD166 and regulation of hematopoiesis. Current opinion in hematology 16 23615053
2010 Different subcellular localization of ALCAM molecules in neuroblastoma: Association with relapse. Cellular oncology : the official journal of the International Society for Cellular Oncology 16 20208136
2007 Isolation of cardiac cells from E8.5 yolk sac by ALCAM (CD166) expression. Mechanisms of development 16 17964124
2018 Activated leucocyte cell adhesion molecule (ALCAM/CD166) regulates T cell responses in a murine model of food allergy. Clinical and experimental immunology 15 29363753
2014 Enhanced down-regulation of ALCAM/CD166 in African-American Breast Cancer. BMC cancer 15 25255861

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