Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: Implications for tumorigenesis

The high frequency of loss of heterozygosity (LOH) in epithelial cells of m ammary ductal carcinoma in situ (DCIS) and IDC is a well known phenomenon, whereas the genetic abnormalities in the mammary stroma and its influence o n the epithelial component have not been sufficiently studied. Using the PC R, we examined DNA extracts From microdissected stromal and epithelial tiss ues of 11 breast samples containing DCIS, including five cases associated w ith IDC, In each case, the mesenchymal tissue consisting of normal-appearin g stroma at a distance from DCIS and IDC or stroma close to either DCIS or IDC was manually microdissected. Epithelial cells from morphologically clea r-cut normal ducts and lobules, DCIS, and IDC were also microdissected. Twe lve polymorphic DNA markers were tested to identify possible genetic altera tions in the mesenchymal and epithelial cells on chromosomes 2p, 3p, 11q, 1 6q, and 17q, Samples from bilateral reduction mammoplasty from 10 women wit hout any clinical, radiological, or pathological abnormalities were also se lected as a control (reduction mammoplasty group). Whereas most cases (8/11 , 73%) displayed at least one identical LOH in both epithelial and mesenchy mal components, LOH at several loci was noted exclusively in stromal cells. The most frequent genetic alterations in the mesenchymal cells were at chr omosomes 17q24,16q23.1-24,2, 3q14.2, and 11q21-23,2, in 87.5, 62, 60, and 4 5% of informative cases, respectively. The LOH frequency in the stroma clos e to cancer ranged from 10 to 66.5% for DCIS and from 20 to 75% of informat ive cases for IDC. Furthermore, 10 of the 12 polymorphic markers revealed L OH in the stroma at a distance, ranging from 11 to 57% of informative cases . None of the control cases (women without any breast disease) revealed LOH either in the epithelial or in the stromal components. Our findings strong ly support the concept of stromal-epithelial interaction in the development and progression of mammary neoplasia, Furthermore, this study suggests tha t genetic alterations in the stromal cells may precede genotypic changes in the epithelial cells. At least in some cases, the mammary stroma in DCIS o r IDC apparently represents a neoplastic interactive component rather than a reactive response to the carcinoma. The frequent allelic loss (LOH) in th e mammary stroma, identified in our study, may explain some of the fibrobla stic abnormalities previously observed in patients with breast carcinoma or a variety of cancer-associated hereditary diseases. We conclude that the m ammary stroma may play a key role in inducing neoplastic transformation of epithelial cells, recapitulating its role in normal mammary duct developmen t.