Telomere shortening occurs in subsets of normal breast epithelium as well as in situ and invasive carcinoma - PubMed (original) (raw)

Comparative Study

Telomere shortening occurs in subsets of normal breast epithelium as well as in situ and invasive carcinoma

Alan K Meeker et al. Am J Pathol. 2004 Mar.

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.

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Figures

Figure 1

Figure 1

H&E staining (A, C, E) and TELI-FISH (B, D, F) analysis of telomere length in normal breast TDLU. A and B: Note that the secretory cells (negative with the green actin stain, facing the lumen) have comparable intensity of telomere signals as the ME cells (actin-positive). C and D: Note that the secretory cells in this TDLU have far less intense telomere signals that the ME cells. E and F: Note the variation in telomere signals among the secretory cells in this TDLU.

Figure 2

Figure 2

Quantitation of telomere lengths in normal TDLU. Mean DAPI-normalized telomere signal intensities were determined by digital image analysis for 10 to 20 randomly selected luminal and ME cells. Cases 1 to 4 were judged by visual inspection to have comparable telomere lengths between the two cell types, while telomeres appeared markedly shorter in the luminal cells of cases 5 and 6. (* P value <0.01, ** P value <0.00000001).

Figure 3

Figure 3

TELI-FISH analysis of telomere length in normal lactiferous duct. Note that the luminal cells (negative with the green actin stain, facing the lumen) have comparable intensity of telomere signals as the ME cells (actin-positive). Inset: H&E-stained adjacent section.

Figure 4

Figure 4

TELI-FISH analysis of telomere length in DCIS. Note that the luminal DCIS cells (negative with the green actin stain, facing the lumen) have virtually no telomere signal, in comparison to the ME cells (actin-positive). Inset: H&E-stained adjacent section.

Figure 5

Figure 5

TELI-FISH analysis of telomere length in invasive ductal carcinoma (IDC). Two examples of high-grade IDC are shown. A: This IDC has virtually undetectable telomere signals. Note the actin-positive pericytes of the capillary at the upper right of the figure, which, along with the benign endothelial cells, have intact telomere signals and hence serve as an internal control. B: This IDC has extremely bright telomere signals. Note the entrapped normal acini within the lesion, which are actin-positive. In this case, the tumor telomere signals are so strong that, at this setting, the normal acini and stromal telomere signals present are not visible in the image. Insets: adjacent H&E sections.

Figure 6

Figure 6

Anaphase bridges in DAPI-stained IDC and DCIS. A: Normal anaphase in an IDC with normal length telomeres. B: Normal anaphase in a DCIS with normal length telomeres. C: Anaphase bridge in an IDC with abnormally short telomeres. D: Anaphase bridge in a DCIS with abnormally short telomeres.

Figure 7

Figure 7

PNA probe accessibility controls. Serial tissue sections were hybridized with either telomere-specific PNA probe (A,C,E) or centromere-specific PNA probe (B,D,F). A and B: Normal breast TDLU. C and D: DCIS. E and F: Invasive carcinoma. Note the diminished telomere signals in these examples of normal luminal cells, DCIS and IDC, as compared to the robust centromere signals in these same cells.

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