ABSTRACT
OBJECTIVES: Carcinogenesis is a multistep process involving the accumulation of genetic and molecular abnormalities. It has been suggested that there is a relationship between telomere attrition in the early stages of carcinogenesis and activation of the DNA damage response machinery. We explored telomere length modification and damage response pathway activation at 3 steps of breast carcinogenesis. METHODS: We carried out a retrospective immunohistochemical analysis of pathway ataxia telangiectasia mutated (p-ATM) (series 1981) and gamma-H2AX (series 139) levels in normal breast, preneoplastic lesions, and invasive carcinoma. Fluorescent in situ hybridization was used to analyze telomere length at each stage. RESULTS: ATM was activated in 45% of normal tissue samples, 70% of preneoplastic lesions, and 14% of breast carcinomas. The increase in ATM activation, between normal tissues and preneoplasia, was not significant (P = 0.095), whereas, ATM repression between preneoplasia and cancer was significant (P = 0.0023). Telomeres in preneoplastic lesions were more frequently shorter than those in normal tissues (P = 0.0116). Finally, telomere lengths were long in 38.9% and very short in 38.9% of breast carcinomas (P = 0.0087 for comparisons with preneoplastic lesions). CONCLUSIONS: This study suggests that a major defect in DNA repair occurs between preneoplasia and breast cancer. This defect is associated with changes in telomere length between the preneoplastic and the cancer stage.
