Study finds HER2-positive breast cancer invades organs due to fatal chemical attraction

11/10/04

HOUSTON - Researchers at The University of Texas M. D. Anderson Cancer Center have solved the mystery of why an aggressive form of HER2-positive breast cancer travels readily to a few key organs - lungs, liver and bone -where it then establishes new tumors. They say this finding may lead to strategies to block that deadly spread.

The study, published in the November issue of Cancer Cell, describes a lethal attraction between signals found on HER2-positive breast cancer cells and those on the surface of the organs -a magnetism that explains why this form of breast cancer, which affects up to 30 percent of patients, can be so invasive. The vast majority of women who die from HER2-positive breast cancer had developed secondary tumors in their lung, liver and 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," says the study's lead author, Mien-Chie Hung, Ph.D., a professor and chair of the Department of Molecular & Cellular Oncology. "We now have explained it biochemically, and hope that this leads to strategies that prevent such metastasis."

Their discovery focuses on the relationship between HER2 and chemokine receptor proteins on breast cancer cells. Chemokines are a large family of proteins primarily known to speed inflammatory responses by drawing them to circulating white blood cells that have a corresponding chemokine receptor. Researchers have found that some diseases, including HIV and cancer, use this same chemical attraction to invade the body.

Although scientists already had discovered that the chemokine receptor CXCR4 was involved in the movement of certain forms of breast cancer to target organs, they did not know how CXCR4 did that for HER2-postive breast cancer until now.

The M. D. Anderson team specifically found breast cancer that overexpress HER2 proteins also ramp up production of CXCR4. HER2-positive breast cancer cells that float free of the tumor are studded with excess CXCR4 receptors, which are previously known to be attracted to a chemokine produced by the target organs known as stromal cell-derived factor-1a, or SDF-1a. In other words, SDF-1a sends out a homing signal to hundreds of CXCR4 receptors on HER2 breast cancer cells. This 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," says 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 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," says 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," says Hung. Efforts are now under way to develop such a drug to treat cancer, he adds.

The work was funded by grants from the National Institutes of Health, the National Breast Cancer Research Foundation and the U.S. Army Breast Cancer Research Program. There were two "first" authors of the study: Yan Li, M.D., Ph.D., and Yong Pan, Ph.D. Other collaborators include Yongkun Wei, M.D., Ph.D.; Xiaoyun Cheng, M.D.; Binhua Zhou, M.D., Ph.D.; Ming Tan, M.D., Ph.D.; Xiaoyan Zhou, M.D.; Weiya Xia, M.D.; Gabriel Hortobagyi, M.D., and Dihua Yu, M.D. Ph.D. Dr. Li was a graduate student in the Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston.

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