{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:22:29Z","timestamp":1790716949145,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2005,7,28]],"date-time":"2005-07-28T00:00:00Z","timestamp":1122508800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes Chromosomes &amp; Cancer"],"published-print":{"date-parts":[[2005,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The development of genomic instability is an important step toward generating the multiple genetic changes required for cancer. Telomere dysfunction is one of the factors that contribute to tumorigenesis. Telomeres shorten with each cell division in the absence of telomerase. Human mammary epithelial cells (HMECs) obtained from normal human tissue demonstrate two growth phases. After an initial phase of active growth, HMECs exhibit a growth plateau termed <jats:italic>selection<\/jats:italic>. However, some cells can emerge from this growth plateau by spontaneously losing expression of the p16<jats:sup>INK4a<\/jats:sup> protein. These post\u2010selection HMECs are capable of undergoing an additional 20\u201350 population doublings in culture. Continued proliferation of these post\u2010selection HMECs leads to further telomere erosion, loss of the capping function, and the appearance of end\u2010to\u2010end chromosome fusions that can enter bridge\u2010fusion\u2010breakage (BFB) cycles, generating massive chromosomal instability before terminating in a population growth plateau termed <jats:italic>agonescence<\/jats:italic>. We have found that the chromosome arms carrying the shortest telomeres are those involved in telomere\u2013telomere type rearrangements. In addition, we found that the risk of a particular chromosome being unstable differs between individuals. Most importantly, we identified sister chromatid fusion as a first event in generating genomic instability in HMECs. During post\u2010selection HMEC growth, double strand breaks are generated by both fused chromosomes as well as individual chromosomes with fused chromatids entering BFB cycles. These broken chromosome extremities are able to join other broken ends or eroded telomeres, producing massive chromosomal instability at the later passages of the cell culture. This article contains Supplementary Material available at <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.interscience.wiley.com\/jpages\/1045-2257\/suppmat\">http:\/\/www.interscience.wiley.com\/jpages\/1045\u20102257\/suppmat<\/jats:ext-link>. \u00a9 2005 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/gcc.20244","type":"journal-article","created":{"date-parts":[[2005,7,28]],"date-time":"2005-07-28T18:30:35Z","timestamp":1122575435000},"page":"339-350","source":"Crossref","is-referenced-by-count":56,"title":["Telomere dysfunction drives chromosomal instability in human mammary epithelial 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