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Apr 25, 2014

Metastatic Breast Cancer Co-Opts Brain Development Mechanism

  • Cancer is most dangerous when it is at its most perverse, warping otherwise wholesome cellular mechanisms, turning them to dangerous ends. For example, cancer cells become metastatic by twisting behaviors healthy cells use to change shape and move. To prevent these depredations, it will be necessary to interrupt them at the molecular level, which is the ultimate ground for all cellular behaviors, good or ill.

    Molecular mechanisms capable of being led astray include those responsible for keeping voltage-gated sodium channels (VGSCs) in good working order. VGSCs are found in the membranes of excitable cells, such as neurons, where they are involved in transmission of electrical impulses. VGSCs, however, are also expressed in cells from a number of different cancers, where they are proposed to play a role in potentiating metastasis.

    The details of exactly how VGSCs go wrong are poorly understood, but important clues have emerged. For example, a study led by researchers at the University of York has shown that a sodium channel protein called β1 is present at high levels in breast cancer samples compared with normal tissue.

    In an article published April 12 in the International Journal of Cancer, the researchers described how they discovered that the increase in beta-one protein levels make tumors grow faster. The researchers also learned that β1 proteins play a significant role in enabling the cells to change shape and move, and consequently metastasize.

    In their article (“The sodium channel β1 subunit mediates outgrowth of neurite-like processes on breast cancer cells and promotes tumour growth and metastasis”), the researchers noted that VGSCs are unique among ion channels in that their β subunits not only modulate channel activity, but are also cell adhesion molecules (CAMs) that regulate neurite outgrowth and migration during development.

    “Expression of β subunits has been reported in breast, bone, cervical, colorectal, lung, and prostate cancer cell lines, and β1 is the dominant isoform in breast, cervical, lung, and prostate cancer cell lines,” the authors wrote. “However, in vivo evidence for β subunit expression in cancer is limited.”

    To address this shortcoming, the researchers used clinical breast cancer specimens from the Breast Cancer Campaign Tissue Bank and preclinical laboratory modeling. Ultimately, the researchers found that “β1-mediated process outgrowth in BCa cells required the presence and activity of fyn kinase, and Na+ current, thus replicating the mechanism by which β1 regulates neurite outgrowth in CNS neurons.” The authors concluded that when present in breast tumors, β1 enhances pathological growth and cellular dissemination.

    Study leader Will Brackenbury, Ph.D., a Medical Research Council Fellow in the Department of Biology at York, said: “While there is no cure for metastasis, blocking the sodium channels inhibits migration and invasiveness and it may therefore be a viable therapeutic target. What is most exciting is that the mechanism by which β1 regulates migration appears to replicate what it does in the central nervous system.”

    “As well as regulating electrical activity in neurons, β1 also regulates the migration of neurons during brain development and the breast cancer signaling mechanism seems to be the same,” Dr. Brankenbury added. “A process that is important in the development of the nervous system is being co-opted to play an insidious role in tumor development.”



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