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Short telomeres are frequent in hereditary breast tumors and are associated with high tumor grade

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Abstract

Telomere shortening is a common event involved in malignant transformation. Critically short telomeres may trigger chromosomal aberrations and produce genomic instability leading to cancer development. Therefore, telomere shortening is a frequent molecular alteration in early stages of many epithelial tumors and in breast cancer correlates with stage and prognosis. A better understanding of the involvement of short telomeres in tumors may have a significant impact on patient management and the design of more specific treatments. To understand the role of telomere length (TL) in breast cancer etiology we measured the length of individual telomere signals in single cells by using quantitative telomere in situ hybridization in paraffin-embedded tissue from hereditary and sporadic breast cancers. A total of 104 tumor tissue samples from 75 familial breast tumors (BRCA1, n = 14; BRCA2, n = 13; non-BRCA1/2, n = 48) and 29 sporadic tumors were analyzed. Assessment of telomere signal intensity allowed estimation of the mean TL and related variables, such as percentage of critically short telomeres and percentage of cells with short telomeres. These data were correlated with the immunohistochemical expression of molecular breast cancer markers. Hereditary BRCA1, BRCA2, and non-BRCA1/2 tumors were characterized by shorter TL comparing to sporadic tumors. Considering all tumors, tumor grade was a strong risk factor determining the proportion of short telomeres or short telomere cells. Moreover, some histopathological features appeared to be differentially associated to hereditary or sporadic subgroups. Short telomeres correlated with ER-negative tumors in sporadic cases but not in familial cases, whereas a high level of apoptosis was associated with shorter telomeres in hereditary BRCA1 and BRCA2 tumors. In addition, TL helped to define a subset of non-BRCA1/2 tumors with short telomeres associated with increased expression of antiapoptotic proteins. These findings highlight the potential interest of TL measurements as markers of aggressiveness in breast cancer.

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Acknowledgments

We thank all members of the Human Genetics Group and the Immunohistochemistry Unit of the Spanish National Cancer Research Centre for their help in obtaining and analyzing the results. This work was funded by Spanish Ministry of Economy and Competitiveness PI08/1120 and PI12/00070 projects, and the Asociación Española contra el Cancer (AECC). Research in the Blasco lab is funded by the Spanish Ministry of Economy and Competitiveness Projects SAF2008-05384 and CSD2007-00017, the Madrid Regional Government Project S2010/BMD-2303 (ReCaRe), the European Union FP7 Project FHEALTH-2010-259749 (EuroBATS), the European Research Council (ERC) Project GA#232854 (TEL STEM CELL), the Körber European Science Award from the Körber Foundation, the Preclinical Research Award from Fundación Lilly (Spain), Fundación Botín (Spain), and the AXA Research Fund.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Human Genetics Group, Spanish National Cancer Research Centre (CNIO) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

    Beatriz Martinez-Delgado, Miljana Tanic, Kira Yanowsky, Alicia Barroso & Javier Benitez

  2. Genetics Unit, Instituto de Investigación en Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Carretera Majadahonda-Pozuelo Km 2.200, Majadahonda, 28220, Madrid, Spain

    Beatriz Martinez-Delgado

  3. Telomeres and Telomerase Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    Mercedes Gallardo & Maria A. Blasco

  4. Hereditary Endocrine Tumors Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    Lucia Inglada-Perez

  5. Pathology Department, Fundación Jimenez Díaz, Madrid, Spain

    Maria Rodriguez-Pinilla

  6. Histopathology Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    Marta Cañamero

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  1. Beatriz Martinez-Delgado
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  2. Mercedes Gallardo
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  3. Miljana Tanic
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  4. Kira Yanowsky
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  5. Lucia Inglada-Perez
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  8. Marta Cañamero
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  9. Maria A. Blasco
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Correspondence to Beatriz Martinez-Delgado.

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Beatriz Martinez-Delgado and Mercedes Gallardo have contributed equally to this work.

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Martinez-Delgado, B., Gallardo, M., Tanic, M. et al. Short telomeres are frequent in hereditary breast tumors and are associated with high tumor grade. Breast Cancer Res Treat 141, 231–242 (2013). https://doi.org/10.1007/s10549-013-2696-6

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