Telomere Shortening Occurs in Subsets of Normal Breast Epithelium as well as in Situ and Invasive Carcinoma

Abstract

In the setting of inactivated DNA damage-sensitive checkpoints, critically shortened telomeres promote chromosomal instability and the types of widespread cytogenetic alterations that characterize most human carcinomas. Using a direct telomere fluorescence in situ hybridization technique, we analyzed 114 invasive breast carcinomas, 29 carcinoma in situ lesions, 10 benign proliferative lesions, and different normal epithelial components of the male and female breast. We found marked telomere shortening in the majority (52.5%) of invasive carcinomas; smaller subsets of invasive carcinoma demonstrated moderate telomere shortening (17.5%) or normal telomere lengths (21%), while a small subgroup (5%) contained elongated telomeres. Strikingly, the majority (78%) of ductal carcinoma in situ demonstrated markedly or moderately shortened telomeres. Surprisingly, unlike all other normal epithelia studied to date, moderate telomere shortening was observed in benign secretory cells in approximately 50% of histologically-normal terminal duct lobular units (from which most breast cancer is thought to arise), while such shortening was not seen in myoepithelial cells or normal large lactiferous ducts of the female breast or male breast ducts (from which breast cancer infrequently arises). We postulate that such shortening is the result of hormonally driven, physiological proliferation, and may delineate a population of epithelial cells at risk for subsequent malignant transformation.

Gene expression abnormalities in histologically normal breast epithelium of breast cancer patients

“…Recently, abnormalities have been appreciated in histologically normal breast epithelium. These abnormalities include allelic imbalance or loss of heterozygosity, [1][2][3][4][5][6][7][8] aberrant methylation of p16 INK4 9 and of RASSF1A, 10 cytogenetic changes, 11,12 telomere shortening, 13 loss of IGF2 imprinting, 14 aberrant response to estrogen, 15 loss of RARb expression, 16 aberrant phosporylation of p38, 17 upregulation of EZH2. 18 Some of these abnormalities have been detected in normal-appearing tissue adjacent to the tumor, and others have been found at a distance from it.…”

Evaluation of Genomic Instability as an Early Event in the Progression of Breast Cancer

“…This finding parallels our previous studies in tumors of the prostate and their matched TA-HN tissues, 28 and is in agreement with the work of previous investigators who reported that genetic alterations, including telomere attrition and loss of heterozygosity, occur in histologically normal tissues adjacent to breast tumors. [34][35][36][37][38][41][42][43][44] In these previous studies, the sites of telomere attrition, loss of heterozygosity, and AI were physically distant from one another and from the tumors, albeit in most cases at undefined distances from the corresponding tumor lesions. 24,[42][43][44] In contrast, and to our knowledge, the findings in cohort 1 represent the first study in breast cancers that analyzes genomic instability at defined distances (1 cm and 5 cm) from the visible tumor margins.…”

“…[34][35][36][37][38][41][42][43][44] In these previous studies, the sites of telomere attrition, loss of heterozygosity, and AI were physically distant from one another and from the tumors, albeit in most cases at undefined distances from the corresponding tumor lesions. 24,[42][43][44] In contrast, and to our knowledge, the findings in cohort 1 represent the first study in breast cancers that analyzes genomic instability at defined distances (1 cm and 5 cm) from the visible tumor margins. Consequently, this study reveals that genomic instability in tumor adjacent, histologically normal breast tissues is a function of distance from the tumor lesion, showing decreasing extent of genomic instability with increasing distance from the tumor margin.…”

“…29,30 Recently, Meeker and colleagues observed that telomere length abnormalities are early and frequent events in the malignant transformation of several types of cancer, including breast. 27,31,32 In addition, telomere attrition and other measures of genomic instability, such as allelic imbalance and loss of heterozygosity, demonstrate that genomic instability occurs within atypical breast hyperplasias, [33][34][35] histologically normal tissue proximal to breast tumors, [36][37][38][39][40][41][42] and, in some instances, breast tissue from women with benign breast disease. 43 Loss of heterozygosity and allelic imbalance have also been found in the stromal compartment of cancer-associated breast tissues.…”

Three-Dimensional Telomere Dynamics in Follicular Thyroid Cancer

“…These results suggest early focal appearance of thyrocytes with abnormal telomere phenotypes which may contribute to FTC in the Thrb PV/PV mouse model. Precancerous stages and cancer can both present with telomere shortening (38,39), and FISH-based detection of shorter telomeres in histological specimens was shown to be an early event in human prostate, pancreas, bladder, large intestine, esophagus, oral cavity, and uterine cervix cancer development (39)(40)(41). However, shorter telomeres are not always associated with cancer but have also been described in breast ductal carcinoma in situ and in normal breast secretory cells (38).…”