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. 2010 Feb;1(2):115-24.
doi: 10.1177/1947601909360812.

Association of nuclear localization of a long interspersed nuclear element-1 protein in breast tumors with poor prognostic outcomes

Chris R Harris  1 , Robin Normart, Qifeng Yang, Elizabeth Stevenson, Bruce G Haffty, Shridar Ganesan, Carlos Cordon-Cardo, Arnold J Levine, Laura H Tang
Affiliations

Association of nuclear localization of a long interspersed nuclear element-1 protein in breast tumors with poor prognostic outcomes

Chris R Harris et al. Genes Cancer. 2010 Feb.

Abstract

Within healthy human somatic cells, retrotransposition by long interspersed nuclear element-1 (also known as LINE-1 or L1) is thought to be held in check by a variety of mechanisms, including DNA methylation and RNAi. The expression of L1-ORF1 protein, which is rarely found in normal tissue, was assayed using antibodies with a variety of clinical cancer specimens and cancer cell lines. L1-ORF1p expression was detected in nearly all breast tumors that the authors examined, and the protein was also present in a high percentage of ileal carcinoids, bladder, and pancreatic neuroendocrine tumors, as well as in a smaller percentage of prostate and colorectal tumors. Tumors generally demonstrated cytoplasmic L1-ORF1p; however, in several breast cancers, L1-ORF1p was nuclear. Patients with breast tumors displaying nuclear L1-ORF1p had a greater incidence of both local recurrence and distal metastases and also showed poorer overall survival when compared with patients with tumors displaying cytoplasmic L1-ORF1p. These data suggest that expression of L1-ORF1p is widespread in many cancers and that redistribution from cytoplasm to nucleus could be a poor prognostic indicator during breast cancer. High expression and nuclear localization of L1-ORF1p may result in a higher rate of L1 retrotransposition, which could increase genomic instability.

Keywords: breast cancers; line expression; line movement.

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Conflict of interest statement

The authors declared no potential conflicts of interest with respect to the authorship and/or publication of this article.

Figures

Figure 1.
Figure 1.
Western blot and immunofluorescence experiments using anti-L1-ORF1p sera. (A) and (B) Protein extracts were prepared from human cell lines or from normal or cancerous human tissue prior to separation by SDS-PAGE and Western blotting. In (A), extracts were from cell lines Tera-2, NTera2/D1,NCI-H727, and BON1. In (B), lanes 1 and 2 are extracts from normal adjacent tissue and breast tumor from patient “A”; lanes 3 and 4 are from normal adjacent tissue and breast tumor from patient “B”; lanes 5-10 are from normal uterine, spleen, ileal, lung, colon, and pancreatic tissue, respectively; lane 11 contains no protein extract; and lane 12 contains molecular weight markers. (C) and (D) Immunofluorescence experiments using lung cell line H460 (C) or colon cell line H1299 (D). In (C), nucleolin is used to image nucleoli, and L1-ORF1p appears to locate in the cytoplasm and nucleoli of the H460 cell line. In (D), PCNA antisera were used as these can stain nuclei but not nucleoli in HCT116 (data not shown), and the L1-ORF1 protein appears to localize in both nuclei and nucleoli but not in the cytoplasm of this cell line.
Figure 2.
Figure 2.
Cytoplasmic localization of L1-ORF1p in human tumors. The following tissues were stained with L1-ORF1p antisera: (A) Healthy prostate, colon, kidney, and spleen samples, none of which stain significantly for L1-ORF1p, thus revealing the specificity of the L1-ORF1p antisera; (B) tumors originating from human bladder tissue, with the first panel displaying a tumor that does not stain for L1-ORF1p and the other two panels staining strongly for cytoplasmic L1-ORF1p; (C) two prostate tumors, in which the left panel does not stain but the right panel stains for cytoplasmic L1-ORF1p; (D) two colorectal tumors, the first of which does not stain for L1-ORF1p whereas the other stains for cytoplasmic L1-ORF1p.
Figure 3.
Figure 3.
Nuclear localization of L1-ORF1p in selected human tumors. (A) two different pancreatic neuroendocrine tumors stained with L1-ORF1p antisera, showing nuclear (left panel) and cytoplasmic localization of the protein; (B) two different ileal carcinoid tumors, showing nuclear (left panel) and cytoplasmic localization of L1-ORF1p; (C) three different breast tumors, showing nuclear (left and middle panels) and cytoplasmic localization of L1-ORF1p.
Figure 4.
Figure 4.
Potential clinical impact of nuclear L1-ORF1p on breast cancer. (A) overall patient survival according to presence of nuclear or cytoplasmic L1-ORF1p; (B) incidence of local recurrence of primary breast tumor according to presence of nuclear or cytoplasmic L1-ORF1p; (C) incidence of formation of distal metastases according to presence of nuclear or cytoplasmic L1-ORF1p. Each curve shows statistical significance as determined by p values, which were generated by log-rank test.
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