Genes found to play a role in breast cancer's spread to the brain

[Soccermom2006]

http://www.eurekalert.org/pub_releas...-gft050109.php
"New research led by investigators at Memorial Sloan-Kettering Cancer Center (MSKCC) identifies three genes that specifically mediate the metastasis, or spread, of breast cancer to the brain and illuminates the mechanisms by which this spread occurs. The study was published online today in Nature.
According to the study, COX2 and HB-EGF — genes that induce cancer cell mobility and invasiveness — were found to be genetic mediators in the spread of breast cancer to the brain. A third gene, ST6GALNAC5, was shown to provide cancer cells with the capability of exiting the blood circulation and passing through the blood-brain barrier to enter the brain tissue.
"Our research sheds light on the role these genes play in determining how breast tumor cells break free and, once mobile, how they decide where to attack," said Joan Massagué, PhD, Chair of the Cancer Biology and Genetics Program at MSKCC and a Howard Hughes Medical Institute investigator.
Breast cancer metastasis to the brain typically occurs years after removal of a breast tumor, suggesting that disseminated cancer cells initially lack the specialized functions needed to overtake the dense network of capillaries that constitute the blood-brain barrier. This barrier prevents the entry of circulating cells and regulates the transport of molecules into the brain tissue. To generate brain metastasis, circulating cancer cells must, therefore, be able to pass through the blood-brain barrier and interact with the brain microenvironment.
In the study, Dr. Massagué and his colleagues isolated cancer cells that preferentially targeted the brain from patients with advanced disease. By combining this approach with gene expression profiling, additional testing in mouse model systems, and analysis of a body of clinical data, the investigators identified certain genes and functions that selectively mediate cancer cell passage through the blood-brain barrier.
The authors observed that ST6GALNAC5, an enzyme that is normally active only in brain tissue, causes a chemical reaction that creates a coating on the surface of breast cancer cells that enhances their ability to breach the blood-brain barrier. Their findings show that breast cancer cells use this brain-specific cell-coating enzyme as a means of infiltrating the brain.
"Our results draw attention to the role of the cell surface coating as a previously unrecognized participant in brain metastasis, and to the possibility of using drugs to disrupt its interactions," said Dr. Massagué. "Further study is necessary to explore the role of these genes in brain metastasis and their interest as therapeutic targets."
The study authors also noted that COX2 and HB-EGF, which prime breast cancer cells for entrance into the brain, had previously been found to be involved in breast cancer's spread to the lung. This suggests a partial sharing of genetic mediators of metastasis to both the brain and lung and may explain the association of brain and lung relapse in women with breast cancer.

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Metastasis is responsible for the majority of all cancer deaths and occurs when tumor cells acquire the ability to escape their original location and invade healthy tissue and organs elsewhere in the body. According to the National Cancer Institute, 170,000 new cases of cancer metastasis to the brain are diagnosed each year in the United States alone. The incidence of brain metastases is rising as a result of their resistance to treatments that are effective against cancer spread to other sites"

[Rich66]

Nature. 2009 Jun 18;459(7249):1005-9. Epub 2009 May 6.
Genes that mediate breast cancer metastasis to the brain.

Bos PD, Zhang XH, Nadal C, Shu W, Gomis RR, Nguyen DX, Minn AJ, van de Vijver MJ, Gerald WL, Foekens JA, Massagué J.
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
The molecular basis for breast cancer metastasis to the brain is largely unknown. Brain relapse typically occurs years after the removal of a breast tumour, suggesting that disseminated cancer cells must acquire specialized functions to take over this organ. Here we show that breast cancer metastasis to the brain involves mediators of extravasation through non-fenestrated capillaries, complemented by specific enhancers of blood-brain barrier crossing and brain colonization. We isolated cells that preferentially infiltrate the brain from patients with advanced disease. Gene expression analysis of these cells and of clinical samples, coupled with functional analysis, identified the cyclooxygenase COX2 (also known as PTGS2), the epidermal growth factor receptor (EGFR) ligand HBEGF, and the alpha2,6-sialyltransferase ST6GALNAC5 as mediators of cancer cell passage through the blood-brain barrier. EGFR ligands and COX2 were previously linked to breast cancer infiltration of the lungs, but not the bones or liver, suggesting a sharing of these mediators in cerebral and pulmonary metastases. In contrast, ST6GALNAC5 specifically mediates brain metastasis. Normally restricted to the brain, the expression of ST6GALNAC5 in breast cancer cells enhances their adhesion to brain endothelial cells and their passage through the blood-brain barrier. This co-option of a brain sialyltransferase highlights the role of cell-surface glycosylation in organ-specific metastatic interactions.

PMID: 19421193 [PubMed - indexed for MEDLINE]