title: The alternative lengthening of telomeres phenotype in breast carcinoma is associated with HER-2 overexpression.
abstract: Approximately 10-15% of human cancers do not show evidence of telomerase activity, and a subset of these maintain telomere lengths by a recombination-based mechanism termed alternative lengthening of telomeres (ALT). The ALT phenotype, relatively common in certain sarcomas and germ cell tumors, is very rare in carcinomas. In this study we describe evidence for the ALT phenotype in molecular subclasses of breast carcinoma, specifically a subset of cancers with HER-2 overexpression. Tissue microarrays were created from 71 invasive ductal carcinomas of the breast categorized into subclasses, and telomere lengths were directly assessed using fluorescence in situ hybridization with combined promyelocytic leukemia (PML) protein immunofluorescence. The ALT phenotype was identified in 3 of 21 HER-2-positive cases, but in none of the other 50 cases (P=0.023). This is the first direct observation of this mechanism of telomere maintenance in breast carcinoma unrelated to Li-Fraumeni syndrome. The correlation of the ALT phenotype with HER-2 positivity, both of which involve abnormal DNA amplification, suggests a possible common underlying mechanism. This telomere phenotype confers a poor prognosis in some cancers; two of the three cases in our study showed rapid tumor progression, possibly suggesting that it may adversely affect outcome in breast carcinoma as well. As cancers using the ALT pathway are predicted to be resistant to therapies based on telomerase inhibition, these results may have therapeutic consequences.
authors.affiliation: Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: Andrea Proctor
authors.initials: AP
authors.lastname: Subhawong
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Heaphy
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.forename: Yuko
authors.initials: Y
authors.lastname: Konishi
authors.forename: Nina
authors.initials: N
authors.lastname: Kouprina
authors.forename: Hind
authors.initials: H
authors.lastname: Nassar
authors.forename: Russell
authors.initials: R
authors.lastname: Vang
authors.forename: Alan K
authors.initials: AK
authors.lastname: Meeker
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D005784:Gene Amplification / Q000235:genetics; D018628:Gene Dosage / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D016615:Telomere / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone