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Review
. 2011 Jun;16(2):127-46.
doi: 10.1007/s10911-011-9207-3. Epub 2011 Mar 31.

Noncanonical TGF-β signaling during mammary tumorigenesis

Jenny G Parvani  1 , Molly A Taylor, William P Schiemann
Affiliations
Review

Noncanonical TGF-β signaling during mammary tumorigenesis

Jenny G Parvani et al. J Mammary Gland Biol Neoplasia. 2011 Jun.

Abstract

Breast cancer is a heterogeneous disease comprised of at least five major tumor subtypes that coalesce as the second leading cause of cancer death in women in the United States. Although metastasis clearly represents the most lethal characteristic of breast cancer, our understanding of the molecular mechanisms that govern this event remains inadequate. Clinically, ~30% of breast cancer patients diagnosed with early-stage disease undergo metastatic progression, an event that (a) severely limits treatment options, (b) typically results in chemoresistance and low response rates, and (c) greatly contributes to aggressive relapses and dismal survival rates. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that regulates all phases of postnatal mammary gland development, including branching morphogenesis, lactation, and involution. TGF-β also plays a prominent role in suppressing mammary tumorigenesis by preventing mammary epithelial cell (MEC) proliferation, or by inducing MEC apoptosis. Genetic and epigenetic events that transpire during mammary tumorigenesis conspire to circumvent the tumor suppressing activities of TGF-β, thereby permitting late-stage breast cancer cells to acquire invasive and metastatic phenotypes in response to TGF-β. Metastatic progression stimulated by TGF-β also relies on its ability to induce epithelial-mesenchymal transition (EMT) and the expansion of chemoresistant breast cancer stem cells. Precisely how this metamorphosis in TGF-β function comes about remains incompletely understood; however, recent findings indicate that the initiation of oncogenic TGF-β activity is contingent upon imbalances between its canonical and noncanonical signaling systems. Here we review the molecular and cellular contributions of noncanonical TGF-β effectors to mammary tumorigenesis and metastatic progression.

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Figures

Figure 1
Figure 1
Schematic depicting the canonical and noncanonical TGF-β signaling systems activated during mammary tumorigenesis. Transmembrane signaling by TGF-β is stimulated upon its binding and activation of the Ser/Thr protein kinase receptors, TβR-I and TβR-II. The physical interaction of TGF-β with either TβR-III or TβR-II facilitates the recruitment and transphosphorylation of TβR-I, resulting in its activation and subsequent phosphorylation of the receptor-activated Smads, Smad2 and Smad3. Once activated, Smad2/3 form heterocomplexes with Smad4 and translocate to the nucleus to regulate the expression of TGF-β-responsive genes in concert with an ever expanding list of transcriptional coactivators and repressors. This branch of the bifurcated TGF-β signaling system represents the “canonical” or “Smad2/3-dependent” TGF-β pathway, which is the predominant pathway coupled to cytostasis and activated by TGF-β in normal MECs (left panel). Alternatively, TGF-β also activates a variety of “noncanonical” or “Smad2/3-independent” effectors, including Par6, NF-κB, ILK, FAK, Src, Rho-family GTPases, MAP kinases, and the PI3K:AKT:mTOR signaling axis (right panel). During EMT and mammary tumorigenesis, the balance between canonical and noncanonical TGF-β signaling systems becomes distorted and favors coupling to noncanonical effector systems, an event that manifests the “TGF-β Paradox” and the initiation of EMT, invasion, and metastasis. These events are further exacerbated by elevated deposition and eventual cross-linking of ECM molecules within tumor microenvironments (LOX, right panel), an event that promotes tumor rigidity and the activation of mechanotransduction pathways operant in amplifying noncanonical TGF-β signaling and its oncogenic activities in mammary tumors. See text for additional details.
Figure 2
Figure 2
The exodus of invasive breast cancer cells from the primary tumor may require EMT and its induction of acquired stemness. A Normal mammary epithelium is comprised of CD24+ luminal cells and CD44+ basal cells (top panel). Tumor initiation in either cell type may confer a proliferative advantage and deregulated growth (middle panel). Disease progression ultimately results in the local invasion of breast cancer cells, followed by their dissemination into the circulation (bottom panel). B Metastatic progression stimulated by TGF-β is coupled to EMT and its ability to (i) induce the expression EMT- and developmentally-responsive transcription factors (left panel); (ii) promote the dissolution of adherens and tight junctional complexes, as well as the downregulation of epithelial phenotypic markers (middle panel); and (iii) stimulate the upregulation of mesenchymal and stem-like phenotypic markers, including CD44.
Figure 3
Figure 3
Cooperation between distinct subpopulations of breast cancer cells may underlie local invasion and metastasis. A Carcinoma cell heterogeneity is a hallmark of primary mammary tumors and represented as “gray” and “black” breast cancer cells. B TGF-β signaling within the primary tumor microenvironment induces a subpopulation of breast cancer cells to undergo EMT and local invasion (gray cells), doing so via the activation of αvβ3 integrin, FAK, p38 MAPK, and Rho GTPases and their coupling to the production of MMPs and uPA. The efficiency of these events may be enhanced and bolstered by the cooperation of nonmetastatic cells (black cells) to produce “prometastatic” microenvironments. C Once liberated from the primary tumor, metastatic breast cancer cells intravasate the endothelium to gain access to the vascular for systemic dissemination. Surviving transport through the circulatory system is essential for the metastatic cascade and may be linked to upregulated expression of αvβ3 integrin, which is also essential for disseminated breast cancer cells to extravasate the vasculature. D) Colonization and eventual outgrowth of the metastatic lesion is associated with β1 integrin expression.
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