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IGF-1 increases invasive potential of MCF 7 breast cancer cells and induces activation of latent TGF-β1 resulting in epithelial to mesenchymal transition.

Walsh LA, Damjanovski S - Cell Commun. Signal (2011)

Bottom Line: Furthermore, most studies describing the biological effects of TGF-β have been performed using high concentrations of active, soluble TGF-β, despite the fact that TGF-β is produced and secreted as a latent complex.The effects of IGF-1 appear to be mediated through signals transduced via the PI3K and MAPK pathways.In addition, increased IGF-1, together with latent TGF-β1 and active MMPs result in EMT.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, University of Western Ontario, London, Ontario, N6A 5B7, Canada. sdamjano@uwo.ca.

ABSTRACT

Introduction: TGF-β signaling has been extensively studied in many developmental contexts, amongst which is its ability to induce epithelial to mesenchymal transitions (EMT). EMTs play crucial roles during embryonic development and have also come under intense scrutiny as a mechanism through which breast cancers progress to become metastatic. Interestingly, while the molecular hallmarks of EMT progression (loss of cell adhesion, nuclear localization of β-catenin) are straightforward, the cellular signaling cascades that result in an EMT are numerous and diverse. Furthermore, most studies describing the biological effects of TGF-β have been performed using high concentrations of active, soluble TGF-β, despite the fact that TGF-β is produced and secreted as a latent complex.

Methods: MCF-7 breast cancer cells treated with recombinant IGF-1 were assayed for metalloproteinase activity and invasiveness through a matrigel coated transwell invasion chamber. IGF-1 treatments were then followed by the addition of latent-TGF-β1 to determine if elevated levels of IGF-1 together with latent-TGF-β1 could cause EMT.

Results: Results showed that IGF-1 - a molecule known to be elevated in breast cancer is a regulator of matrix metalloproteinase activity (MMP) and the invasive potential of MCF-7 breast cancer cells. The effects of IGF-1 appear to be mediated through signals transduced via the PI3K and MAPK pathways. In addition, increased IGF-1, together with latent TGF-β1 and active MMPs result in EMT.

Conclusions: Taken together our data suggest a novel a link between IGF-1 levels, MMP activity, TGF-β signaling, and EMT in breast cancer cells.

No MeSH data available.


Related in: MedlinePlus

IGF-1 and latent TGF-β1 resulted in nuclear localization of β-catenin in MCF-7 cells. Nuclei are stained with DAPI (blue) while β-catenin is localized with a specific antibody (green). Treatment of MCF-7 cells with 100 nM recombinant IGF-1 + 10 nM TGF-β1 resulted in nuclear (blue) localization of β-catenin (green) (green blue overlap g-h). Treatment with vehicle control (a-b), IGF-1 (c-d) or TGF-β1 alone (e-f) showed β-catenin primarily localized at the plasma membrane. Images are representative of 3 independent experiments with consistent results.
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Figure 5: IGF-1 and latent TGF-β1 resulted in nuclear localization of β-catenin in MCF-7 cells. Nuclei are stained with DAPI (blue) while β-catenin is localized with a specific antibody (green). Treatment of MCF-7 cells with 100 nM recombinant IGF-1 + 10 nM TGF-β1 resulted in nuclear (blue) localization of β-catenin (green) (green blue overlap g-h). Treatment with vehicle control (a-b), IGF-1 (c-d) or TGF-β1 alone (e-f) showed β-catenin primarily localized at the plasma membrane. Images are representative of 3 independent experiments with consistent results.

Mentions: There have been many contradictory studies regarding the induction of the β-catenin/TCF pathway by IGF [18]. Playford et al., reported that IGF alone could not induce β-catenin/TCF-dependent transcriptional activation whereas other researchers have reported it can. Since activation of this pathway and the subsequent nuclear localization of β-catenin is a hallmark of EMT, we chose to look at the nuclear localization of β-catenin after IGF-1 and latent TGF-β1 treatment of MCF-7 breast cancer cells. IGF-1 + latent TGF-β1 treatment of MCF-7 cells resulted in nuclear localization of β-catenin (Figure 5g, h). Vehicle (control), IGF-1 or TGF-β1 alone did not cause nuclear localization of β-catenin as the β-catenin signal was still prevalent at the plasma membrane (Figure 5a-f).


IGF-1 increases invasive potential of MCF 7 breast cancer cells and induces activation of latent TGF-β1 resulting in epithelial to mesenchymal transition.

Walsh LA, Damjanovski S - Cell Commun. Signal (2011)

IGF-1 and latent TGF-β1 resulted in nuclear localization of β-catenin in MCF-7 cells. Nuclei are stained with DAPI (blue) while β-catenin is localized with a specific antibody (green). Treatment of MCF-7 cells with 100 nM recombinant IGF-1 + 10 nM TGF-β1 resulted in nuclear (blue) localization of β-catenin (green) (green blue overlap g-h). Treatment with vehicle control (a-b), IGF-1 (c-d) or TGF-β1 alone (e-f) showed β-catenin primarily localized at the plasma membrane. Images are representative of 3 independent experiments with consistent results.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3104381&req=5

Figure 5: IGF-1 and latent TGF-β1 resulted in nuclear localization of β-catenin in MCF-7 cells. Nuclei are stained with DAPI (blue) while β-catenin is localized with a specific antibody (green). Treatment of MCF-7 cells with 100 nM recombinant IGF-1 + 10 nM TGF-β1 resulted in nuclear (blue) localization of β-catenin (green) (green blue overlap g-h). Treatment with vehicle control (a-b), IGF-1 (c-d) or TGF-β1 alone (e-f) showed β-catenin primarily localized at the plasma membrane. Images are representative of 3 independent experiments with consistent results.
Mentions: There have been many contradictory studies regarding the induction of the β-catenin/TCF pathway by IGF [18]. Playford et al., reported that IGF alone could not induce β-catenin/TCF-dependent transcriptional activation whereas other researchers have reported it can. Since activation of this pathway and the subsequent nuclear localization of β-catenin is a hallmark of EMT, we chose to look at the nuclear localization of β-catenin after IGF-1 and latent TGF-β1 treatment of MCF-7 breast cancer cells. IGF-1 + latent TGF-β1 treatment of MCF-7 cells resulted in nuclear localization of β-catenin (Figure 5g, h). Vehicle (control), IGF-1 or TGF-β1 alone did not cause nuclear localization of β-catenin as the β-catenin signal was still prevalent at the plasma membrane (Figure 5a-f).

Bottom Line: Furthermore, most studies describing the biological effects of TGF-β have been performed using high concentrations of active, soluble TGF-β, despite the fact that TGF-β is produced and secreted as a latent complex.The effects of IGF-1 appear to be mediated through signals transduced via the PI3K and MAPK pathways.In addition, increased IGF-1, together with latent TGF-β1 and active MMPs result in EMT.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, University of Western Ontario, London, Ontario, N6A 5B7, Canada. sdamjano@uwo.ca.

ABSTRACT

Introduction: TGF-β signaling has been extensively studied in many developmental contexts, amongst which is its ability to induce epithelial to mesenchymal transitions (EMT). EMTs play crucial roles during embryonic development and have also come under intense scrutiny as a mechanism through which breast cancers progress to become metastatic. Interestingly, while the molecular hallmarks of EMT progression (loss of cell adhesion, nuclear localization of β-catenin) are straightforward, the cellular signaling cascades that result in an EMT are numerous and diverse. Furthermore, most studies describing the biological effects of TGF-β have been performed using high concentrations of active, soluble TGF-β, despite the fact that TGF-β is produced and secreted as a latent complex.

Methods: MCF-7 breast cancer cells treated with recombinant IGF-1 were assayed for metalloproteinase activity and invasiveness through a matrigel coated transwell invasion chamber. IGF-1 treatments were then followed by the addition of latent-TGF-β1 to determine if elevated levels of IGF-1 together with latent-TGF-β1 could cause EMT.

Results: Results showed that IGF-1 - a molecule known to be elevated in breast cancer is a regulator of matrix metalloproteinase activity (MMP) and the invasive potential of MCF-7 breast cancer cells. The effects of IGF-1 appear to be mediated through signals transduced via the PI3K and MAPK pathways. In addition, increased IGF-1, together with latent TGF-β1 and active MMPs result in EMT.

Conclusions: Taken together our data suggest a novel a link between IGF-1 levels, MMP activity, TGF-β signaling, and EMT in breast cancer cells.

No MeSH data available.


Related in: MedlinePlus