Concurrent deregulation of gelsolin and cyclin D1 in the majority of humanand rodent breast cancers

Decreased gelsolin and increased cyclin D1 are among the most common defect s found in human and rodent breast cancers. Our purpose was to determine th e frequency of concurrence of these 2 alterations in this malignancy. Our r esults demonstrate that gelsolin protein and mRNA were significantly reduce d in 80-100% of rodent mammary carcinomas that developed spontaneously, fol lowing oncogene introduction, or after treatment with viral, chemical or ho rmonal agents, The reduction in gelsolin most likely occurs during the tran sition from preneoplasia to carcinoma because hyperplasias had normal level s of gelsolin whereas microtumors had reduced expression. Southern analysis revealed no major mutations in the gelsolin gene of tumors with low expres sion. Cyclin D1 mRNA was increased in 50-100% of these rodent mammary tumor s, although the cyclin D1 gene was not amplified. By nuclear runon assay, d ownregulation of gelsolin in both human and mouse mammary cancer cells invo lved diminished transcription and, conversely, human breast cancer cells ex pressing high levels of cyclin D1 had increased initiation of cyclin D1 tra nscription compared with cyclin D1 low expressors. Thus, alteration in the rate of transcription appears to be an important factor underlying the dysf unction of these genes. According to our data, concurrent deregulation of g elsolin and cyclin D1 is highly prevalent among breast cancers of humans an d rodents, with both defects present in 89% of the neoplasms analyzed in th is study, In fact, most tumors in every rodent model of mammary tumorigenes is examined had the 2 alterations, (C) 1999 Wiley-Liss, Inc.