Why is a cell like a clock?Because both cycle through a sequence of repetitive events. Thetimepiece hands turn from one hour to the next through one day afteranother; the cell through the stages of division and chromosome share-out to its progeny cells.The face of a clock or watch is usually parsed into 12- or 24-hoursegments. A cell cycles through four segments:y In G1 (the first "gap)" phase of division, it uncoils its DNA andsynthesizes RNA and protein;y In S phase it synthesizes the nuclear DNA to equip its two daughtercells;y Next, G2, (the second gap phase) is a brief interval before.y M phase, (mitosis) in which the cell pinches into two, each with itschromosome-containing nucleus.The main spring that drives and regulates this cell-cycling process hasrecently been identified as a family of three phase G1 proteins aptlynamed cell cyclins. When one of them, cyclin D1, mutates, it's like theclock's mainspring slipping out of its cogwheel control, and drivingrunaway, non-stop cell division _ i.e., cancer.This concept is neat, plausible and controversial. To test cyclin D1'soncogenic culpability, scientists at Massachusetts General Hospital inBoston enlisted rodents. Their paper in last Thursday's Nature reports"Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenicmice."One of its authors, endocrine oncologist Andrew Arnold, hadpreviously fingered cyclin D1 as a candidate oncogene. Theirexperiment's bottom line, the Nature paper said, "adds weight to thecandidacy of cyclin D1 as a key breast oncogene.""There have been eight or nine papers by people trying to show that inthe last two years," the report's principal author, research pediatricianEmmett Schmidt, told BioWorld Today. He added, "I guess oursended up in Nature because it was the clearest demonstration thatcyclin D1 could cause cancer."To reach this conclusion, he and his co-authors created a line oftransgenic mice into whose fertilized embryonic nuclei they hadinjected cDNA encoding human cyclin D1, plus mouse mammarytumor virus long terminal repeat (MMTV-LTR) sequences.That add-on enhancer targeted the D1 gene to the future femaleanimals' breast tissue. Schmidt noted that this breast-focused strategy isidentical with that by which sheep, goats and cows are being madetransgenic, to yield high-value pharmaceutical proteins in their milk.In Schmidt's transgenic mice, the experiment yielded murinemammary tissue laced with human cyclin D1. "When the mice growup, he said, "there's too much of this gene in their breast tissue." Attwo-month intervals, Schmidt's team tracked the abnormal over-growthof still non-malignant cells. "Then after about 15 months," hecontinued, "when you look at the outcome, a high proportion of themice have developed breast cancer."So far, eight of 12 transgenic mice have incurred breast cancer, andothers may yet develop tumors.This discovery of over-expressed cyclin D1 levels in breast cancer,"Schmidt added, "is important. You can use it as a tool to decide whatpatients are at high risk of not surviving their breast cancers."Test Identifies Women Who May Have Poor OutcomeMassachusetts General researchers are now making progress towarddeveloping this test as a prognostic indicator, "to identify women whowill have a poor outcome," based on the presence of the cyclin D1gene in their tumor cells. So," Schmidt said, "the cancers that developin these mice can very well be a useful tester model."He observed that "Somewhere around 15 to 50 percent of breastcancers are associated with abnormally high levels of this particularprotein. That's why we tested it in mice for its ability to cause cancer."In a striking parallel to the human condition, the transgenic animalsdeveloped mammary tissue disturbances that correlated with their age,number of pregnancies and level of the D1 gene expression.Some companies are developing specific anti-tumor agents targetedtoward this oncogene. Schmidt cited, by way of example, Mitotix, Inc.,a new biotechnology firm in Cambridge, Mass., which is developinginhibitors of cell division and growth.At a more basic level, he said, "You can potentially use the mice to askwhat it is the gene does to regulate abnormal growth." n

-- David N. Leff Science Editor

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