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Tugging on the 'malignant' switch
Date:6/16/2014

related genes, and activity of the PI3K pathway that is known to drive cell proliferation and invasion increased.

"The invasive structures we observed in our stiff matrices resemble the morphology of early-stage invasive ductal carcinoma. They also show increased expression of the estrogen receptor alpha [ER+] gene that drives cell division," says Koshy. "It is striking that these changes, found in many human cancers, can be induced in normal mammary epithelial cells simply by varying the stiffness or composition of the matrix surrounding them."

But while stiffness is a key part of the story, it is not the full story. Further experiments indicated that the cells would recover their normal behavior in high-stiffness gels if they were exposed to increasing concentrations of laminin, a protein naturally found in the basement membrane.

When the extracellular matrix is very flexible, or when a high concentration of laminin is readily available, proteins called α6β4 integrins within the cell membrane bind with laminin to form small structures called hemidesmosomes, which anchor the epithelial cells to the basement membrane. But fluorescence microscopy revealed that the cells in a stiff matrix were not forming hemidesmosomes at all, so Mooney's team hypothesized that a stiffer matrix and a shortage of laminin was leaving the α6β4 integrins with dangling, unbound tails.

The team's final experiments demonstrated that these unbound integrin tails, indeed, get up to no good: they participate in the activation of two key biochemical pathways (PI3K and Rac1) that are necessary and sufficient to induce malignant cell behaviors in the in vitro epithelial tissue.

"If further studies validate that these processes are critical in human breast cancers," Koshy notes, "the possibility exists that agents that favorably modify the biophysical properties of the extracellular matrix, or that target the receptors and signaling
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Contact: Caroline Perry
cperry@seas.harvard.edu
Harvard University
Source:Eurekalert  

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