Scientists from Cold Spring Harbor Laboratory (CSHL) have identified an enzyme, which is significant regulator of breast cancer development and metastasis. PTPN23 is intracellular protein, which plays key role in cell signaling and can promote metastases.

The primary cause of mortality in cancer is metastasis. Scientists from Cold Spring Harbor Laboratory (CSHL) have identified an enzyme, which belong to protein tyrosine phosphatases (PTP) family. PTPN23 can regulate development of aggressive breast cancer and ability to invasion and metastasis. Cascade of effects such like the cells breaking away from their anchors, scattering and invasion is characteristic for metastasis.

PTPN23 is intracellular phosphatase and remove phosphate groups from other proteins. The other process – adding phosphate groups is controlled by kinases. These two kinds of enzymes play important role in regulation of cell signaling and when they are disturbed can promote cancer development. The researchers suppressed known PTP’s in human mammary cells. The cells were also modified – the cancer-promoting receptor protein called HER2 was activated selectively. Overexpression of HER2 is observed in about 25% of breast cancers. It is associated with aggressive disease and poor prognosis.

To determine possible function of PTP’s in cancer development in cells expressing activated HER2 the team used RNA’s, which had the ability to inactivate the genes expressing activated PTP’s, one by one. They found three of them, when suppressed were associated with increased motility, or the ability of cells to move freely of one another. The suppression of PTPN23 was also observed to caused the cells become invasive. Under the normal conditions recognizes and remove phosphate groups from molecules like SRC, E-cadherin and β-catenin. The key is SRC. This protein like HER2 is known as a cancer-promotor. PTPN23 acts directly on SRC and inhibits its phosphate-adding activity. When PTPN23 is suppressed SRC is free to add phosphates to other proteins in cell, including E-cadherin and β-catenin. These molecules are important in cell adhesion. When their function is impaired cells are able to break free from the anchors and become invasive. Interesting is fact, that gene whoch encodes PTPN23 is located on human chromosome 3, that is mutated in breast and other cancers.The scientists tried to inhibit activity of SRC by candidate drug molecule SU6656. They reversed metastatic effects.

Next step is to check theory that PTPN23 regulates the activity of SRC and the phosphorylation status of the cadherin-E and β-catenin in living mice, which have been genetically engineered to lack PTPN23. They expect formation of aggressive breast cancer in such animals. They want to check effect of inhibitors of SRC too.

Author: Piotr Łażewski-Banaszak


Source:
1. Guang Ling, Victoria Aranda, Senthil K. Muthuswamy and Nicholas K. Tonks. Identification of PTPN23 as a novel regulator of cell invasion in mammary epithelial cells from a loss-of-function screen on the ‘PTP-ome’. Genes & Development, 2011; DOI: 10.1101/gad.201891
2. Cold Spring Harbor Laboratory. “Enzyme is important regulator of aggressive breast cancer development”. ScienceDaily, 30 Jun. 2011. Web. 7 Jul. 2011