Loss of N-Myc interactor promotes epithelial-mesenchymal transition by activation of TGF-ß/SMAD signaling.

Epithelial-mesenchymal transition is one of the critical cellular programs that facilitate the progression of breast cancer to an invasive disease. We have observed that the expression of N-myc interactor (NMI) decreases significantly during progression of breast cancer, specifically in invasive and metastatic stages. Recapitulation of this loss in breast cell lines with epithelial morphology (MCF10A (non-tumorigenic) and T47D (tumorigenic)) by silencing NMI expression causes mesenchymal-like morphological changes in 3D growth, accompanied by upregulation of SLUG and ZEB2 and increased invasive properties. Conversely, we found that restoring NMI expression attenuated the mesenchymal attributes of metastatic breast cancer cells, accompanied by distinctly circumscribed 3D growth with basement membrane deposition and decreased invasion. Further investigations into the downstream signaling modulated by NMI revealed that NMI expression negatively regulates SMAD signaling, which is a key regulator of cellular plasticity. We demonstrate that NMI blocks TGF-ß/SMAD signaling via upregulation of SMAD7, a negative feedback regulator of the pathway. We also provide evidence that NMI activates STAT signaling, which negatively modulates TGF-ß/SMAD signaling. Taken together, our findings suggest that loss of NMI during breast cancer progression could be one of the driving factors that enhance the invasive ability of breast cancer by aberrant activation of TGF-ß/SMAD signaling.

Lower extremity range of motion in the recreational sport runner.

The purposes of this study in the recreational runner were to describe and compare lower extremity sagittal range of motion and vertical body displacement for slow and fast paces during treadmill and overground running, and to compare timing of the running phases at the two paces. Vertical displacement of the body, and flexion and extension of the hip, knee, and ankle were measured with a motion analysis system at 200 hertz as the subjects self-selected the two paces. No statistically significant differences were seen when comparing sagittal motion on a treadmill with overground running. Statistically more vertical displacement during overground running was recorded when compared with treadmill running. Peak vertical force was near midstance when the ankle, knee, and hip approached maximum flexion. Results demonstrated that during a slow pace the approximate arcs of motion were: ankle, 50 degrees; knee, 95 degrees; and hip, 40 degrees. During running at a fast pace, the hip required more extension in early swing; the hip and knee required more flexion in middle and late swings. The fact that ankle motion did not change with the different speeds gave credence to the belief that push-off, or toe-off, is not the source of power in running.