Mediator complex subunit 18: A novel breast cancer stem cell marker in tumor microenvironment

Table 1 Current evidence status for therapeutic strategies associated with breast cancer stem cell markers or pathways

	BCSC-related property	Representative agent	Mechanism/modality	Setting/stage	Current evidence status/Limitation	Ref.
ALDH1A1	High enzymatic activity enriches self-renewing, tumor-initiating, and drug-resistant populations	Quercetin	Downregulation of ALDH1A1 and other stem-cell-associated proteins	Preclinical breast cancer models	No validated clinical BCSC-selective efficacy or standardized treatment threshold	[8,22]
CD44	CD44+/CD24-/Low phenotype and hyaluronan binding can enrich BCSC-like populations	HA-based nanocarriers; P245	CD44/HA-mediated delivery or anti-CD44 antibody targeting	Preclinical nanoparticle and xenograft studies	CD44 is heterogeneous and is also expressed by non-BCSC and normal cell populations	[21,23,26,27]
CD44/DLL4-Notch4	Associated with treatment-resistant and endocrine-resistant BCSC programs	FKBPL; AD-01	Modulation of the CD44 pathway and downregulation of DLL4/Notch4	Preclinical	Not a clinically validated CD44-directed therapy; pathway effects may not be BCSC-specific	[24,25]
CD133	Enriches tumorigenic and drug-resistant cells in selected breast cancer models	CD133-paclitaxel nanoparticles; CD133 mRNA dendritic-cell vaccine	Targeted drug delivery or immunization	Preclinical	Model-dependent expression and no validated clinical companion assay	[28,29]
CXCR4	Chemokine receptor associated with migration, homing, and stem-like behavior	Balixafortide plus eribulin	CXCR4 antagonism combined with microtubule inhibition	Phase I, HER2-negative metastatic breast cancer	Clinical benefit was not shown to result specifically from BCSC elimination	[32]
CXCR1/2	Inflammatory chemokine signaling has been linked to BCSC survival	Reparixin plus paclitaxel	CXCR1/2 inhibition combined with chemotherapy	Phase Ib, HER2-negative metastatic breast cancer	Exploratory clinical evidence without a validated BCSC-specific endpoint	[33]
PD-1/immune checkpoint	Immune modulation; not a BCSC marker	Pembrolizumab plus eribulin	PD-1 blockade combined with chemotherapy	Phase II, HR-positive/HER2-negative metastatic breast cancer	Not a BCSC-directed regimen and should not be classified as HER2-targeted therapy	[34]
HER2	Subtype-defining receptor; association with stem-cell-enriched phenotypes is context-dependent	T-DM1; T-DXd; A166; lapatinib	HER2-directed antibody-drug conjugates or tyrosine kinase inhibition	Approved therapies or phase I development	Clinical efficacy has not been demonstrated to be mediated specifically through BCSC targeting	[35-38]
HER2/Akt program	Stem-like properties in selected HER2-positive models	Disulfiram	Suppression of HER2/Akt signaling and stem-like traits	Preclinical	Not validated clinically as a HER2-directed BCSC treatment	[39]
CD49f/integrin α6	Associated with adhesion, tumor initiation, and radioresistance	LY294002	Indirect PI3K pathway inhibition downstream of integrin α6/Akt/ERK	Preclinical	Indirect pathway inhibition with limited marker and cell-type specificity	[40]
GD2	Identifies a tumorigenic BCSC-like subset in selected breast cancers	Dinutuximab	Anti-GD2 monoclonal antibody	Preclinical, including triple-negative breast cancer models	Antigen heterogeneity and no breast cancer approval	[41-43]
OAcGD2	BCSC-associated ganglioside in experimental models	mAb8B6	Anti-O-acetyl-GD2 monoclonal antibody	Preclinical	Early experimental evidence without clinical validation	[44]
ABCG2	Drug-efflux phenotype associated with treatment resistance but not specific to BCSCs	Ko143	ABCG2 transporter inhibition	In vitro and preclinical	Broad transporter expression raises selectivity and toxicity concerns	[45,46]
Notch pathway	Contributes to self-renewal and treatment resistance	MK-0752	Gamma-secretase/Notch pathway inhibition	Clinical investigation and reviewed studies	On-target pathway toxicity and lack of BCSC specificity	[47]
Hedgehog pathway	Stemness-associated developmental signaling	Vismodegib	Smoothened inhibition	Approved in another indication; investigated in breast cancer contexts	Not MED18-directed and no established BCSC-selective clinical benefit	[48]
MED18	Associated with a prognostic risk signature, BCSC-like programs, and tumor-microenvironment features	None identified	No validated therapeutic modality	Hypothesis-generating bioinformatics, multi-omics, and spatial analyses	Early-stage evidence; functional, biomarker-performance, druggability, efficacy, and safety validation remain priorities	[3]

BCSC: Breast cancer stem cell; ALDH1A1: Aldehyde dehydrogenase 1 family member A1; HA: Hyaluronic acid; ADC: Antibody-drug conjugate; CXCR4: C-X-C chemokine receptor 4; HER2: Human epidermal growth factor receptor 2; PD-1: Programmed cell death protein 1; HR: Hormone receptor; Akt: Protein kinase B; PI3K: Phosphoinositide 3-kinases; ERK: Extracellular signal-regulated kinase; OAcGD2: O-acetylated disialoganglioside GD2; MED18: Mediator complex subunit 18.