Shorter telomeres in luminal B, HER-2 and triple-negative breast cancer subtypes

Abstract

Telomeres are nucleoprotein structures that protect chromosome ends from degradation and recombination. Cancers often have critically shortened telomeres, contributing to genomic instability. Many of these tumors activate telomerase to stabilize telomeric ends and achieve a capacity for unlimited replication. Telomere shortening has been reported in in situ and invasive carcinomas, including breast, and has been associated with disease recurrence after surgical resection. However, previous studies have not evaluated breast cancer subtypes. The objective of this study was to evaluate telomere lengths in different subtypes of breast cancer. Breast carcinomas (n=103) identified between 2001 and 2010 from patients seen at the Johns Hopkins Hospital were categorized into luminal A (n=18), luminal B (n=28), HER-2-positive (n=20) and triple-negative carcinomas (n=37) based on tumor characteristics. Telomere lengths were assessed directly at the single cell level by fluorescence in situ hybridization, and patient groups were compared using Fisher's exact tests. ER-negative status (P=0.022), PR-negative status (P=0.008), HER-2-positive status (P=0.023) and p53-positive status (P=0.022) were associated with shorter telomere length. A larger proportion of luminal A cancers had normal or long telomere lengths as compared with luminal B cases (P=0.002), HER-2-positive cases (P=0.011) or triple-negative cases (P=0.0003). Luminal B, HER-2-positive and triple-negative cases did not differ significantly. Telomere length was shorter in more aggressive subtypes, such as luminal B, HER-2-positive and triple-negative tumors, suggesting that tumor telomere length may have utility as a prognostic and/or risk marker for breast cancer.

Figure 1

Telomere length analysis by FISH in breast adenocarcinomas. Three representative examples of cases showing short, normal or long telomere lengths in cancer cells are shown. (a) This case shows strikingly diminished telomere signals in tumor cells as compared to the surrounding benign stroma and in an adjacent terminal ductal lobular unit with myoepithelial (*) and luminal (**) cells. (b) This case displays comparable telomere intensities in tumor cells with those observed in the surrounding benign stroma. (c) In this case, cancer cells show extremely bright telomere signals in cancer cells when compared with the surrounding benign stroma. In all the images, the DNA is stained with DAPI (blue) and telomere DNA is stained with the Cy3-labeled telomere-specific peptide nucleic acid probe (red). It is noteworthy that the centromere DNA, stained with the FITC-labeled centromere-specific peptide nucleic acid probe, has been omitted from the image to emphasize the differences in telomere lengths. In all panels, the arrows point to cancer cells and the arrowheads point to benign stromal cells. Original magnification, × 400.

Figure 2

Proportion of cases with short telomeres among different subtypes of breast cancer. P-values were determined using two-sided Fisher’s exact tests.