Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 156 (2), 211-26

Developmental Signaling Pathways Regulating Mammary Stem Cells and Contributing to the Etiology of Triple-Negative Breast Cancer


Developmental Signaling Pathways Regulating Mammary Stem Cells and Contributing to the Etiology of Triple-Negative Breast Cancer

Maria Cristina Rangel et al. Breast Cancer Res Treat.


Cancer has been considered as temporal and spatial aberrations of normal development in tissues. Similarities between mammary embryonic development and cell transformation suggest that the underlying processes required for mammary gland development are also those perturbed during various stages of mammary tumorigenesis and breast cancer (BC) development. The master regulators of embryonic development Cripto-1, Notch/CSL, and Wnt/β-catenin play key roles in modulating mammary gland morphogenesis and cell fate specification in the embryo through fetal mammary stem cells (fMaSC) and in the adult organism particularly within the adult mammary stem cells (aMaSC), which determine mammary progenitor cell lineages that generate the basal/myoepithelial and luminal compartments of the adult mammary gland. Together with recognized transcription factors and embryonic stem cell markers, these embryonic regulatory molecules can be inappropriately augmented during tumorigenesis to support the tumor-initiating cell (TIC)/cancer stem cell (CSC) compartment, and the effects of their deregulation may contribute for the etiology of BC, in particular the most aggressive subtype of BC, triple-negative breast cancer (TNBC). This in depth review will present evidence of the involvement of Cripto-1, Notch/CSL, and Wnt/β-catenin in the normal mammary gland morphogenesis and tumorigenesis, from fMaSC/aMaSC regulation to TIC generation and maintenance in TNBC. Specific therapies for treating TNBC by targeting these embryonic pathways in TICs will be further discussed, providing new opportunities to destroy not only the bulk tumor, but also TICs that initiate and promote the metastatic spread and recurrence of this aggressive subtype of BC.

Keywords: Cripto-1; Notch/CSL; TIC/CSC; TNBC; Wnt/β-catenin; fMaSC/aMaSC.


Fig. 1
Fig. 1
Hypothetical hierarchical organization of normal mammary epithelial cells and their potential relationship with defined human breast cancer molecular subtypes. Isolation of cells from mouse and human mammary tissues supports this schematic hierarchical organization of the mammary gland development. Multipotent fetal mammary stem cells (fMaSC) give rise to adult mammary stem cells (aMaSC). Long-lived aMaSCs in turn generate transitional common progenitor cells (CommProg) that can commit to either basal/myoepithelial (BasalProg) or luminal progenitor (LumProg) cells. BasalProg cells develop mature basal cells (MatureBasal), and LumProg cells produce either ductal progenitor (DuctalProg) or alveolar progenitor cells (AlveoProg), which in turn generate mature luminal cells (MatureLum) in the form of mature ductal or alveolar cells, respectively. Disruption in the homeostasis of any of these cells—from the most primitive/undifferentiated (fMaSC/aMaSC) to the most differentiated cells (ductal and alveolar cells)—may lead to the development of mammary/breast tumors. The more undifferentiated, greater the potential of proliferating and self-renewing for multiple generations, and therefore accumulating deleterious genetic and/or epigenetic alterations that can persist over the lifespan of an individual. These cells may possibly become putative cancer stem cells (CSC) or tumor-initiating cells (TIC), implicated in the etiology of the distinct molecular subtypes of breast cancer (BC). For mammary/breast tumor development, reactivation of embryonic stem cell (ES) markers (shown in purple), certain transcriptional factors (TF) (shown in red or green) and crucial developmental signaling pathways (shown in blue), such as Cripto-1, Notch/CSL and Wnt/β-catenin, result in increased proliferation and restoration of self-renewal capacity of mammary epithelial cells, as well as enable the initiation of a de-differentiation program. A schematic illustration of recognized regulatory cross-talk occurring between master regulators of mammary gland development and tumorigenesis discussed in this review is depicted in figure. Some examples of commonly mutated and/or amplified genes other than BRCA1/2 in the different subtypes of BC include TP53, PTEN, AKT, RB1, PIK3CA, TBX3, FOXA1, CDH1, CBFB, MAP3K1, NF1, KRAS, KIT, MET, FGFR1/2, BRAF, EGFR, RUNX1, MLL3, and MAP2K4 [40], but they are not represented in figure. TNBC triple-negative breast cancer; ER estrogen receptor; PR progesterone receptor; interm intermediary; hi high; lo low; mut mutation
Fig. 2
Fig. 2
Signaling cascades of Cripto-1, Notch/CSL, and Wnt/β-catenin. The transduction of Cripto-1 signaling (shown in blue) occurs through both the canonical signaling pathway mediated by Smad2/3 with Smad4 following Nodal/GDF-1, -3 activation of the Activin type I receptor (Alk4,7)/Activin type II (ActRII) receptor complex and the non-canonical pathway resulting in MAPK activation by GRP78 or Glypicans through Src. Therapeutic interventions (shown in red) for this pathway include antisense oligos to inhibit Cripto-1 expression, small molecule antagonists, and monoclonal antibodies (mAbs) against the EGF domain of Cripto-1 to inhibit the non-canonical pathway, Alantolactone, small molecule antagonists, mAbs against the CFC domain of Cripto-1 and the Cripto-1 ligand Nodal to inhibit the canonical Smad-mediated signaling, and a cytotoxin-conjugated non-neutralizing mAb against the amino terminus of Cripto-1 to directly kill target cells. Notch/CSL activation (shown in yellow) occurs when a Jagged (Jag) or Delta-like (Dll) ligand bound to an adjacent cell binds a Notch receptor on the target cell facilitating cleavage by ADAM proteases extracellularly followed by the gamma secretase complex intracellularly, releasing the Notch intracellular domain (NICD) which translocates to the nucleus to transactivate transcription through CSL. Therapeutic strategies against Notch include Notch antisense oligonucleotides, mAbs against Notch ligands, mAbs against Notch receptors, and gamma secretase inhibitors. The canonical Wnt/β-catenin pathway (in green) involves the binding of a Wnt ligand to a Frizzled receptor (Fzd) with the aid of a Lrp co-receptor. Stimulation of Fzd results in the activation of Disheveled (Dvl) which in turn inhibits the β-catenin destruction complex, glycogen synthase kinase 3 β (GSK-3β)/axin/casein kinase 1 a (Ck1a)/adenomatous polyposis coli (Apc), allowing β-catenin to translocate to the nucleus to initiate Tcf/Lef transactivation in the context of Pygo, BCL9, and CBP. The non-canonical Wnt pathway (in green) involves the activation of Fzd and Dvl leading to the subsequent activation of the c-Jun N-terminal kinase (JNK) and phospholipase C (PLC) triggering gene activation independently of β-catenin. The Wnt family can also activate the ROR family of receptor tyrosine kinases to potentiate JNK activation. Therapeutic strategies have involved mAbs against various members of the Frizzled family, a Frizzled 8-Fc-conjugated decoy receptor, a radiolabeled anti-Frizzled-10 mAb, and small molecule antagonists against Porcupine and β-catenin/CBP binding

Similar articles

See all similar articles

Cited by 26 PubMed Central articles

See all "Cited by" articles


    1. Fu N, Lindeman GJ, Visvader JE. The mammary stem cell hierarchy. Curr Top Dev Biol. 2014;107:133–160. - PubMed
    1. Sternlicht MD, Kouros-Mehr H, Lu P, Werb Z. Hormonal and local control of mammary branching morphogenesis. Differentiation. 2006;74(7):365–381. - PMC - PubMed
    1. Robinson GW. Cooperation of signalling pathways in embryonic mammary gland development. Nat Rev Genet. 2007;8(12):963–972. - PubMed
    1. Rangel MC, Karasawa H, Castro NP, Nagaoka T, Salomon DS, Bianco C. Role of Cripto-1 during epithelial-to-mesenchymal transition in development and cancer. Am J Pathol. 2012;180(6):2188–2200. - PMC - PubMed
    1. Howard B, Ashworth A. Signalling pathways implicated in early mammary gland morphogenesis and breast cancer. PLoS Genet. 2006;2(8):e112. - PMC - PubMed

MeSH terms


LinkOut - more resources