Telomere shortening occurs early during breast tumorigenesis: a cause of chromosome destabilization underlying malignant transformation?

Chromosomal instability appears early during breast carcinogenesis and is considered a major driving force in malignant transformation. While current evidence suggests that centrosomal and mitotic checkpoint defects may, in large part, account for numerical chromosomal abnormalities, the mechanisms underlying structural chromosomal abnormalities remain largely unknown. Telomeres stabilize and protect chromosomal termini, but shorten due to cell division and oxidative damage. Moderate telomere shortening signals a tumor suppressive growth arrest in normal cells. Critically short telomeres, in the setting of abrogated DNA damage checkpoints, cause chromosomal instability due to end-to-end chromosomal fusions, subsequent breakage, and rearrangement, resulting in an increased cancer incidence in animal models. Recent results from high resolution in situ telomere length assessment in human breast tissues indicate that significant telomere shortening is prevalent in preinvasive breast lesions (DCIS), as well as focal areas of histologically normal epithelium from which breast carcinoma is thought to arise. Telomere shortening is therefore a strong candidate for the cause of structural chromosome defects that contribute to breast cancer development.