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Review
. 2011 Jun 10;13(3):211.
doi: 10.1186/bcr2876.

Breast cancer growth and metastasis: interplay between cancer stem cells, embryonic signaling pathways and epithelial-to-mesenchymal transition

Naoko Takebe  1 , Ronald Q Warren, S Percy Ivy
Affiliations
Review

Breast cancer growth and metastasis: interplay between cancer stem cells, embryonic signaling pathways and epithelial-to-mesenchymal transition

Naoko Takebe et al. Breast Cancer Res. .

Abstract

Induction of epithelial-to-mesenchymal transition (EMT) in cancer stem cells (CSCs) can occur as the result of embryonic pathway signaling. Activation of Hedgehog (Hh), Wnt, Notch, or transforming growth factor-β leads to the upregulation of a group of transcriptional factors that drive EMT. This process leads to the transformation of adhesive, non-mobile, epithelial-like tumor cells into cells with a mobile, invasive phenotype. CSCs and the EMT process are currently being investigated for the role they play in driving metastatic tumor formation in breast cancer. Both are very closely associated with embryonic signaling pathways that stimulate self-renewal properties of CSCs and EMT-inducing transcription factors. Understanding these mechanisms and embryonic signaling pathways may lead to new opportunities for developing therapeutic agents to help prevent metastasis in breast cancer. In this review, we examine embryonic signaling pathways, CSCs, and factors affecting EMT.

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Figures

Figure 1
Figure 1
Epithelial-to-mesenchymal transition, mesenchymal-to-epithelial transition, and the migration of cancer stem cells. In the presence of stimulatory signaling (that is, Hedgehog (Hh), Notch, Wnt, transforming growth factor (TGF)-β) primary tumor cells may undergo epithelial-to-mesenchymal transition (EMT), a process where cells suppress E-cadherin expression and lose their tight membrane junctions. Cells can acquire a mobile phenotype and migrate into the circulatory system by entering capillary beds. Exiting the circulatory system at a distant anatomical site, cells undergo the reverse process of mesenchymal-to-epithelial transition (MET), reacquiring their original non-mobile epithelial-like phenotype.
Figure 2
Figure 2
Cross-talk among embryonic signaling pathways and experimental inhibitors. Potential cross-talk among embryonic signaling pathways (transforming growth factor (TGF)-β, Hedgehog (Hh), Notch, Wnt, and ErbB) is shown. The expansive potential for signaling cross-talk suggests that signaling pathways do not function in isolation, but instead are parts of a complex signaling network. Cross-talk can lead to both enhancing and inhibitory interactions between pathways. The actions of experimental pathway inhibitors are shown in yellow. Positive interactions are shown in green, while negative interactions are shown in red.
Figure 3
Figure 3
Embryonic pathway signaling leads to induction of epithelial-to-mesenchymal transition. Hedgehog (Hh), Notch, Wnt, and transforming growth factor (TGF)-β signaling can activate epithelial-to-mesenchymal transition (EMT) regulators to induce phenotypic changes through a variety of signaling intermediates. EMT-inducing signals by Snail, Slug, KLF8, Twist, Goosecoid, Foxc1 and -2, or Zeb1 and -2 drive non-mobile epithelial-like cells to acquire more invasive phenotypes. By migrating into the circulatory system, cancer stem cells can translocate to new locations and initiate new metastatic growths. EGF, epidermal growth factor; Fzd, Frizzled; Hh, Hedgehog; HIF, hypoxia-inducible factor; NICD, Notch intracellular domain; Smo, Smoothened; TGF, transforming growth factor.
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