Telomeric instability and reduced proliferative potential in ovarian surface epithelial cells from women with a family history of ovarian cancer

Objective. Increased telomeric instability in normal ovarian surface epithe lium may contribute to ovarian carcinogenesis in women from families with a high frequency of breast/ovarian cancer. To test this hypothesis, we compa red proliferative potential, mean telomeric length, and telomerase activity in SV-40 large T-antigen transfected cell lines derived from normal ovaria n surface epithelium of women with and without a familial history of breast /ovarian cancer. Methods. Telomeric instability was examined in SV-40 large T-antigen transf ected cell lines of normal ovarian surface epithelium from patients with (F HIOSE, N = 5) and without (NFHIOSE, N = 11) a history of familial breast/ov arian cancer, The duration and total attainable number of population doubli ngs, mean telomeric length, rate of telomeric loss, and telomerase activity were determined by cell counts, Southern blot analysis, and PCR ELISA. Results. FHIOSE cells attained fewer population doublings than NFHIOSE cell s and doubled at approximately half the rate of NFHIOSE cells, indicating a reduced proliferative capacity in FHIOSE cells. While telomerase activity was not detected in FHIOSE or NFHIOSE cell lines, mean telomeric lengths in FHIOSE were generally 1 kb shorter than in NFHIOSE cells and the rate of t elomeric loss as a function of population doublings was up to threefold gre ater in FHIOSE cells, Conclusions. Increased telomeric instability and reduced growth potential s uggest greater proximity to replicative senescence in ovarian surface epith elium from women with a familial history of breast/ ovarian cancer. Consequ ently, an accumulation of genetic aberrations due to accelerated cellular a ging may contribute to the enhanced susceptibility for malignant transforma tion and earlier onset in heritable ovarian cancer. (C) 1999 Academic Press .