Monday, May 23, 2011

HER2 Part 1: Know the Molecule

For about a fourth of breast cancers, a molecule called HER2 plays a key role in both the cause of the disease and its treatment. For the next few days, we'll cover what HER2 is, its involvement in breast cancer, how it's targeted by drugs, and how HER2-positive patients are identified.

The methods for identifying HER2-positive patients are under scrutiny. One often-cited study states that up to 20% of HER2 test results could be inaccurate. If these inaccuracies result in inappropriate use or non-use of Herceptin (trastuzumab) and other powerful HER2-targeted drugs, then the impact on patient survival and unwanted side effects could be significant. So we'll also look at some new tests that might be able to help better identify HER2-positive patients, including TargetPrint (Agendia), HERmark (Monogram Biosciences/LabCorp), and DNAarray HER2 Pro (CombiMatrix Diagnostics).

First, HER2... Let's step back to biology for a minute. You need to know just a couple things before we discuss treatments and tests.

We know that cancer is a disease in which cells grow out of control because molecules involved in normal growth control "go haywire." Normal growth control in healthy breast cells looks like this: small signalling molecules called growth factors attach to antenna-like molecules called growth factor receptors on the outside of breast cells. These antenna molecules span the cell membrane. When a signal molecule attaches to the part outside the cell, the molecule transmits the signal to the part that sits inside the cell. There, it passes the signal on to a series of signal transducer molecules that work like a relay team, carrying the signal deeper inside the cell and eventually into the nucleus, the home of the cell's genes. When the signal arrives inside the nucleus, it "tells" still more molecules to turn on genes that produce proteins involved in cell growth. With these proteins active, the cell grows and divides.

For breast cells, Epidermal Growth Factor, or EGF, is a key growth factor. EGF targets a family of four similar growth factor receptors (antennae) called HER1, HER2, HER3 and HER4. In the often confusing world of molecule naming, proteins often have more than one name. HER1 is more often called EGFR (Epidermal Growth Factor Receptor). HER, by the way, stands for Human Epidermal growth factor Receptor. And HER2 is also called HER2/neu as well as ErbB2. Sorry. Not much we can do about that...

Finally, let's paint a clearer picture of how HER2 and its family members work. In a word, they work in pairs. When EGF attached to a HER family member, it doesn't cause the growth signal to be transmitted into the cell instantly. Instead, EGF binding cause HER receptors of all four types to want to link up with one another. It could be two HER2s. Or it could be other pairings like a HER2 with a HER3 (see diagram). When pairing occurs, it changes the shape of both of the paired HER molecules, and this causes each HER molecule to activate it's companion inside the cell. It's these activated, paired HERs that transmit signal to the relay team of signal transducer molecules.

Next: What goes wrong with HER2 in breast cancer?

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