The discovery that a second cell marker, CXCR4, is over-expressed by aggressive HER2-positive breast cancers explains why these tumors typically metastasize to the lungs, liver, and bone, according to an article in the November issue of Cancer Cell.

The researchers found that surface markers on lung, liver, and bone tissue match up with the receptor that is over-expressed, CXCR4, causing an attraction between free tumor cells and these tissues. This molecular match for an observed clinical behavior may make this form of breast cancer, which affects up to 30 percent of patients, open to new treatment. Currently, the vast majority of women who die from HER2-positive breast cancer have developed metastatic disease in their lung, liver, and/or bones.

"It has always been a puzzle as to why, when HER2-positive cancer cells circulate throughout the body looking for a new home, they preferentially travel to these organs," said the study's lead investigator, Mien-Chie Hung, PhD. "We now have explained it biochemically, and hope that this leads to strategies that prevent such metastasis."

CXCR4 is a chemokine receptor protein found in abundance on HER2-positive breast cancer cells. Under normal conditions, chemokines primarily accelerate inflammatory responses by attracting circulating white blood cells that have a corresponding chemokine receptor. Researchers had previously found that some diseases, including HIV and cancer, use the same chemical attraction to invade the body.

In the current work, The M. D. Anderson Cancer Center team specifically found breast cancer that over-expresses HER2 protein also ramps up production of CXCR4. HER2-positive breast cancer cells that float free of the tumor are studded with excess CXCR4 receptors, which are attracted to a chemokine known as stromal cell-derived factor-1a, or SDF-1a. In other words, the strong attraction causes HER2-positive breast cancer cells to leave the blood and lymphatic systems and migrate to organs with large amounts of these chemokines, where the cancer cells then settle and grow.

"HER2 turns on, and then magnifies, the ability of these cancer cells to zero in on organs that release this chemical signal," said Hung. "That explains why HER2 breast cancers can so easily induce metastasis."

The researchers specifically identified the pathway by which HER2 switches on CXCR4 production. They then conducted a set of cell and animal studies to test their findings. Examining human breast tumor tissues, they found a significant correlation between HER2 and CXCR4 expression, and they also observed that CXCR4 expression was associated with a poor overall survival rate in patients with breast cancer.

In lab and animal studies, Hung and his group then showed that when they blocked CXCR4 expression in tumors by using a special RNA molecule, the cancer became less invasive.

"Our data establish a molecular mechanism whereby HER2-overexpressing cancer cells home in on specific organs and provide crucial evidence of a functional link between the HER2 and CXCR4 signaling pathways," said Hung.

Clinically, the discovery may help physicians predict how HER2-positive breast cancer will likely metastasize. The finding also "provides strong support for the notion that an agent that can block CXCR4 could have anticancer potential," concluded Hung. Efforts are now under way to develop such a drug to treat cancer.