The researchers found that women with a certain hereditary deformity syndrome run a nearly twenty times higher risk of contracting breast cancer than expected.
Several research teams around the world have long been searching for new hereditary breast cancer genes, but thus far few have been found.
"Our findings are extremely important, providing new knowledge of hereditary cancer genes and how they can cause breast cancer. The discovery also makes it possible to uncover breast cancer in women who have a predisposition for Saethre-Chotzen malformation syndrome," says Goran Stenman.
By detailed mapping of families with Saethre-Chotzen syndrome, the Goteborg scientists have now found that women with this syndrome have an elevated risk of contracting breast cancer. Saethre-Chotzen is a syndrome that primarily involves malformations of the skull, face, hands, and feet. The syndrome is caused by mutations in a gene called TWIST1.
"Our findings show that women with this syndrome run a nearly twenty times greater risk of contracting breast cancer than expected. Moreover, many of the women were young when they were affected by breast cancer," says Goran Stenman.
The findings of the study show that women with this syndrome should be receive early mammograms in order to discover breast cancer at an early stage.
"We have already started to use this new knowledge in our work with patients and now recommend regular mammograms for young women with this syndrome. Several early cases of breast cancer have already been uncovered with mammography," says Pelle Sahlin, chief physician at the Plastic Surgery Clinic.
The scientists are now going to perform various experiments to chart the mechanism of how TWIST1 increases the risk of breast cancer. Studies are also under way to find out what proportion of cases of hereditary breast cancer are caused by mutations in the TWIST1 gene.
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Shekhar MPV, Santner S, Carolin KA, Tait L. Direct involvement of breast tumor fibroblasts in the modulation of tamoxifen sensitivity. Am J Pathol 2007 170:1546,1560.
Using breast cancer cells, researchers have demonstrated that cancer phenotype can be reversibly altered by manipulations other than genetic means. Breast cancer cells grown in 3-D culture can be induced to form normal breast duct-like structures, as opposed to dense cell masses, by activating or inhibiting specific signaling pathways, including antibody binding to the extracellular matrix protein fibronectin.
In addition, cancer cell DNA, which has been shown previously to resist enzymatic digestion, could be rendered accessible to enzyme digestion following reversion of its 3-D growth phenotype. Importantly, such reversion of breast cancer cells could be overturned by removing the reversion stimuli, resulting in a return to cancerous growth and resistance to enzymatic DNA digestion.
These data underscore the plasticity displayed by cancer cells: even after a cell adopts a cancerous phenotype, it can be manipulated to regain ,normal, 3-D structure, growth, and DNA organization (ie, enzyme accessibility). The intimate link between cellular growth phenotype and susceptibility to enzymatic DNA digestion suggests that analysis of DNA accessibility may have future diagnostic implications.
Research was overseen by Dr. Andrew J. Maniotis at the University of Illinois at Chicago, Chicago, Illinois, and supported by the Department of Energy, the National Institutes of Health, and the Norwegian Cancer Society.
Sandal T, Valyi-Nagy K, Spencer VA, Folberg R, Bissell MJ, Maniotis AJ. Epigenetic reversion of breast carcinoma phenotype is accompanied by changes in DNA sequestration as measured by AluI restriction enzyme. Am J Pathol 2007 170:1739,1749.
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