New signaling pathway discovered in HER2-positive breast cancer, and 2 powerful drug targets

One of the most promising ideas in cancer treatment is to apply a lesson learned in the fight against AIDS (Acquired Immune Deficiency Syndrome): simultaneously attacking a pathological process at different points of weakness can, in some cases, deal a knock-out blow. Just as the so-called AIDS "cocktail" directs multiple agents against multiple targets, so too might future anti-cancer cocktails be directed at multiple, highly specific targets in known cancer pathways. One key in cancer is knowing precisely which targets to hit, in which combinations, for the illness takes many different forms and works through a stunning variety of biological mechanisms.

A team at Cold Spring Harbor Laboratory (CSHL) has published in the Journal of Biological Chemistry results of experiments that lay bare a previously unknown pathway activated in a highly lethal form of breast cancer. The pathway, they discovered, contains at least two potentially powerful drug targets, according to the team leader, CSHL Professor Nicholas K. Tonks.

The breast cancer type is called HER2-positive. Affecting about one breast cancer patient in four, it is characterized by tumor cells overexpressing a signaling protein called HER2. The drug Herceptin, which targets HER2, is an effective first-line treatment for about one-third of women with HER2-positive breast cancer, but in most cases, resistance to the treatment develops within a year.

HER2-positive breast cancer, which is associated with poor prognosis, has been traced to an excess of signaling through receptors, or docking ports, called HER2 found on the surface of certain mammary epithelial cells. (Scientists also use the name ERBB2 to describe this surface receptor). When an activating protein docks at the receptor, a cascade of signals is sent inside breast cells. Ultimately, these signals change the expression of genes in the cell nucleus, causing the cell to grow abnormally. Herceptin, when it works, blocks the ability of HER2 receptors to send these aberrant, growth-inducing signals inside the cell.

Genes contain the recipes for the various proteins a cell needs to stay healthy and function normally. Some genes and the proteins they make can influence how a breast cancer behaves and how it might respond to a specific treatment. Cancer cells from a tissue sample can be tested to see which genes are normal and abnormal. The proteins they make can also be tested.

HER2 (human epidermal growth factor receptor 2) is one such gene that can play a role in the development of breast cancer. Your pathology report should include information about HER2 status, which tells you whether or not HER2 is playing a role in the cancer.

The HER2 gene makes HER2 proteins. HER2 proteins are receptors on breast cells. Normally, HER2 receptors help control how a healthy breast cell grows, divides, and repairs itself. But in about 25% of breast cancers, the HER2 gene doesn't work correctly and makes too many copies of itself (known as HER2 gene amplification). All these extra HER2 genes tell breast cells to make too many HER2 receptors (HER2 protein overexpression). This makes breast cells grow and divide in an uncontrolled way.