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Regulator of Aggressive Breast Cancer

When the scientists suppressed the expression of PTPN23 in human mammary cells, they noted a cascade of effects that included the cells breaking away from their anchors; their scattering; and their invasion through extracellular matrix (essentially, cells' mooring in tissue). These are the hallmarks of metastasis, the primary cause of mortality in cancer.

PTPs are able to affect cell signaling as a consequence of their very specific biochemical function: they remove phosphate groups from other molecules. Another family of enzymes, called kinases, does precisely the opposite: its members add phosphate groups, and in so doing, work together with the PTPs to regulate cell signaling.

CSHL Professor Nicholas Tonks, who purified the first PTP over 20 years ago, is an authority on phosphatases. He teamed up with CSHL Associate Professor Senthil Muthuswamy, an expert on kinases and breast cancer biology, who is also affiliated with the University of Toronto. They and their colleagues methodically suppressed each of the 105 known PTPs, in a cell culture system constructed to simulate mammary epithelial tissue.

The cells were also modified so that the cancer-promoting receptor protein called HER2 (itself a kinase) could be activated selectively. Overabundant HER2 protein (also called ErbB2) is associated with aggressive disease and poor prognosis, and is found in about one-fourth of those who have breast cancer.

They discovered that PTPN23, under normal conditions, for example, when not suppressed, recognizes and removes phosphate groups from three molecules important in the signaling cascade in breast epithelial cells. These three molecules are called SRC, E-cadherin and β-catenin. Of the three, the key is SRC: it is a type of kinase that, like HER2, is well known to be a cancer-promoter. SRC-induced anomalies in cell signaling have been linked with breast and other cancer types.

"Considering the negative effect of PTPN23 on SRC activity, loss of PTPN23 may promote tumor growth and metastasis in breast tumors that are associated with activation of SRC," the team suggests.

MEDICA.de; Source: Cold Spring Harbor Laboratory

 
 
 

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