Human Molecular Genetics, 2001, Vol. 10, No. 18 1907-1913
© 2001 Oxford University Press
Genetic model of multi-step breast carcinogenesis involving the epithelium and stroma: clues to tumour–microenvironment interactions
1Clinical Cancer Genetics and Human Cancer Genetics Programs, Comprehensive Cancer Centre, and Division of Human Genetics, Department of Internal Medicine, 2Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics and 3Center for Biostatistics, Comprehensive Cancer Centre, The Ohio State University, Columbus, OH 43210, USA, 4Department of Pathology, University of Manitoba Health Sciences Centre, Winnipeg, Manitoba R3E 0W3, Canada and 5CRC Human Cancer Genetics Research Group, University of Cambridge, Cambridge CB2 2QQ, UK
Although numerous studies have reported that high frequencies of loss of heterozygosity (LOH) at various chromosomal arms have been identified in breast cancer, differential LOH in the neoplastic epithelial and surrounding stromal compartments has not been well examined. Using laser capture microdissection, which enables separation of neoplastic epithelium from surrounding stroma, we microdissected each compartment of 41 sporadic invasive adenocarcinomas of the breast. Frequent LOH was identified in both neoplastic epithelial and/or stromal compartments, ranging from 25 to 69% in the neoplastic epithelial cells, and from 17 to 61% in the surrounding stromal cells, respectively. The great majority of markers showed a higher frequency of LOH in the neoplastic epithelial compartment than in the stroma, suggesting that LOH in neoplastic epithelial cells might precede LOH in surrounding stromal cells. Furthermore, we sought to examine pair-wise associations of particular genetic alterations in either epithelial or stromal compartments. Seventeen pairs of markers showed statistically significant associations. We also propose a genetic model of multi-step carcinogenesis for the breast involving the epithelial and stromal compartments and note that genetic alterations occur in the epithelial compartments as the earlier steps followed by LOH in the stromal compartments. Our study strongly suggests that interactions between breast epithelial and stromal compartments might play a critical role in breast carcinogenesis and several genetic alterations in both epithelial and stromal compartments are required for breast tumour growth and progression.
+ To whom correspondence should be addressed at: Human Cancer Genetics Program, The Ohio State University Comprehensive Cancer Centre, 420 West 12th Avenue, Room 690C TMRF, Columbus, OH 43210, USA. Tel: +1 614 292 2347; Fax: +1 614 688 3582; Email: eng-1{at}medctr.osu.edu
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