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Prognostic value of LINE-1 retrotransposon expression and its subcellular localization in breast cancer.

Chen L, Dahlstrom JE, Chandra A, Board P, Rangasamy D - Breast Cancer Res. Treat. (2012)

Bottom Line: The majority of invasive cancers were found to express both ORF1p and ORF2p in the cytoplasm, while nuclear expression was also seen in a subclass of those invasive cancers in the range of 28-31 %.Tumors with high nuclear expression of ORF1p and ORF2p were more significantly associated with lymph node metastasis (p = 0.001) and the worst patient survival (p < 0.0001) than those with cytoplasmic expression.Our observation shows altered expression patterns of ORF1p and ORF2p within invasive cancers, which are related to differences in overall patient survival.

View Article: PubMed Central - PubMed

Affiliation: John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia.

ABSTRACT
Long interspersed nuclear element 1 (L1) belongs to a family of retrotransposons. Expression of the normally repressed L1 retrotransposons has been shown to induce genome instability by creating DNA double-stranded breaks and chromosomal rearrangements through the process of retrotransposition. At present, little is known about the expression of L1-encoded ORF1p and ORF2p which are indispensable for its retrotransposition activity. Given its potentially harmful effects on the genome, we investigated the implications of both ORF1p and ORF2p expression and their subcellular localization in a range of breast cancer cell lines and breast tumor tissues including 15 normal breast tissues, 25 fibroadenomas, 25 ductal carcinomas in situ (DCIS), and 95 invasive cancers. Clinicopathologic parameters and survival outcomes were investigated in association with the cytoplasmic and nuclear expression of ORF1p and ORF2p using univariate and multivariate analysis. High cytoplasmic expression of ORF1p and ORF2p was seen in DCIS tumors, but they were not related with survival outcome. The majority of invasive cancers were found to express both ORF1p and ORF2p in the cytoplasm, while nuclear expression was also seen in a subclass of those invasive cancers in the range of 28-31 %. Tumors with high nuclear expression of ORF1p and ORF2p were more significantly associated with lymph node metastasis (p = 0.001) and the worst patient survival (p < 0.0001) than those with cytoplasmic expression. This is the first study examining the effects of both ORF1p and ORF2p expression in breast cancer tissues. Our observation shows altered expression patterns of ORF1p and ORF2p within invasive cancers, which are related to differences in overall patient survival. The differing patterns of both cytoplasmic and nuclear ORF1p and ORF2p expression indicate that further studies of the biology and function of L1 retrotransposons are required in breast cancer.

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Effects of subcellular localizations on overall patient survival. Kaplan–Meier analysis performed based on the presence of nuclear or cytoplasmic ORF1p and ORF2p. A Nuclear localization of both ORF1p and ORF2p exhibited a significant difference in the overall survival of patients with invasive cancers. B Cytoplasmic localization of ORF1p and ORF2p showed no difference in patients' survival. p value was calculated by log-rank test
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Fig5: Effects of subcellular localizations on overall patient survival. Kaplan–Meier analysis performed based on the presence of nuclear or cytoplasmic ORF1p and ORF2p. A Nuclear localization of both ORF1p and ORF2p exhibited a significant difference in the overall survival of patients with invasive cancers. B Cytoplasmic localization of ORF1p and ORF2p showed no difference in patients' survival. p value was calculated by log-rank test

Mentions: In the breast, it has been recently reported that nuclear, but not cytoplasmic ORF1p, is associated with genomic instability of tumors, which are characterized by aggressive behavior and poor outcome [25]. In agreement with this study, no correlation between survival of the patients with DCIS tumors and cytoplasmic expression of ORF1p and ORF2p were observed. There were no breast cancer-related deaths in patients with DCIS tumors. In the case of invasive cancers, 21 % of patients (20 of 95) died with breast cancer. The mean follow-up time for the patients with invasive cancers was 10.7 years (range 1–14 years). When the localization of the protein was considered, the 10-year survival was 50–51.8 % for overall nuclear expression of ORF1p and ORF2p, while cytoplasmic expression was 75–75.4 %. Analysis of the prognostic significance of expression using the Kaplan–Meier survival curves showed that nuclear expression of ORF1p and ORF2p significantly affected patient outcome (p < 0.0001), but not the cytoplasmic expression (Fig. 5). Although nuclear expression of ORF1p and ORF2p was significantly associated with ER- and PR-positive invasive cancers in univariate analysis, the significance of ER and PR disappeared on Cox-regression multivariate analysis. In Cox-regression analysis, nuclear expression of both ORF1p and ORF2p was significantly associated with poor patient outcomes (p = 0.027, p = 0.027, respectively), while cytoplasmic expression was not (Table 4). In patients with high nuclear ORF1p and ORF2p expression, there was a strong trend for lymph node metastasis (p = 0.001).Fig. 5


Prognostic value of LINE-1 retrotransposon expression and its subcellular localization in breast cancer.

Chen L, Dahlstrom JE, Chandra A, Board P, Rangasamy D - Breast Cancer Res. Treat. (2012)

Effects of subcellular localizations on overall patient survival. Kaplan–Meier analysis performed based on the presence of nuclear or cytoplasmic ORF1p and ORF2p. A Nuclear localization of both ORF1p and ORF2p exhibited a significant difference in the overall survival of patients with invasive cancers. B Cytoplasmic localization of ORF1p and ORF2p showed no difference in patients' survival. p value was calculated by log-rank test
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3473189&req=5

Fig5: Effects of subcellular localizations on overall patient survival. Kaplan–Meier analysis performed based on the presence of nuclear or cytoplasmic ORF1p and ORF2p. A Nuclear localization of both ORF1p and ORF2p exhibited a significant difference in the overall survival of patients with invasive cancers. B Cytoplasmic localization of ORF1p and ORF2p showed no difference in patients' survival. p value was calculated by log-rank test
Mentions: In the breast, it has been recently reported that nuclear, but not cytoplasmic ORF1p, is associated with genomic instability of tumors, which are characterized by aggressive behavior and poor outcome [25]. In agreement with this study, no correlation between survival of the patients with DCIS tumors and cytoplasmic expression of ORF1p and ORF2p were observed. There were no breast cancer-related deaths in patients with DCIS tumors. In the case of invasive cancers, 21 % of patients (20 of 95) died with breast cancer. The mean follow-up time for the patients with invasive cancers was 10.7 years (range 1–14 years). When the localization of the protein was considered, the 10-year survival was 50–51.8 % for overall nuclear expression of ORF1p and ORF2p, while cytoplasmic expression was 75–75.4 %. Analysis of the prognostic significance of expression using the Kaplan–Meier survival curves showed that nuclear expression of ORF1p and ORF2p significantly affected patient outcome (p < 0.0001), but not the cytoplasmic expression (Fig. 5). Although nuclear expression of ORF1p and ORF2p was significantly associated with ER- and PR-positive invasive cancers in univariate analysis, the significance of ER and PR disappeared on Cox-regression multivariate analysis. In Cox-regression analysis, nuclear expression of both ORF1p and ORF2p was significantly associated with poor patient outcomes (p = 0.027, p = 0.027, respectively), while cytoplasmic expression was not (Table 4). In patients with high nuclear ORF1p and ORF2p expression, there was a strong trend for lymph node metastasis (p = 0.001).Fig. 5

Bottom Line: The majority of invasive cancers were found to express both ORF1p and ORF2p in the cytoplasm, while nuclear expression was also seen in a subclass of those invasive cancers in the range of 28-31 %.Tumors with high nuclear expression of ORF1p and ORF2p were more significantly associated with lymph node metastasis (p = 0.001) and the worst patient survival (p < 0.0001) than those with cytoplasmic expression.Our observation shows altered expression patterns of ORF1p and ORF2p within invasive cancers, which are related to differences in overall patient survival.

View Article: PubMed Central - PubMed

Affiliation: John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia.

ABSTRACT
Long interspersed nuclear element 1 (L1) belongs to a family of retrotransposons. Expression of the normally repressed L1 retrotransposons has been shown to induce genome instability by creating DNA double-stranded breaks and chromosomal rearrangements through the process of retrotransposition. At present, little is known about the expression of L1-encoded ORF1p and ORF2p which are indispensable for its retrotransposition activity. Given its potentially harmful effects on the genome, we investigated the implications of both ORF1p and ORF2p expression and their subcellular localization in a range of breast cancer cell lines and breast tumor tissues including 15 normal breast tissues, 25 fibroadenomas, 25 ductal carcinomas in situ (DCIS), and 95 invasive cancers. Clinicopathologic parameters and survival outcomes were investigated in association with the cytoplasmic and nuclear expression of ORF1p and ORF2p using univariate and multivariate analysis. High cytoplasmic expression of ORF1p and ORF2p was seen in DCIS tumors, but they were not related with survival outcome. The majority of invasive cancers were found to express both ORF1p and ORF2p in the cytoplasm, while nuclear expression was also seen in a subclass of those invasive cancers in the range of 28-31 %. Tumors with high nuclear expression of ORF1p and ORF2p were more significantly associated with lymph node metastasis (p = 0.001) and the worst patient survival (p < 0.0001) than those with cytoplasmic expression. This is the first study examining the effects of both ORF1p and ORF2p expression in breast cancer tissues. Our observation shows altered expression patterns of ORF1p and ORF2p within invasive cancers, which are related to differences in overall patient survival. The differing patterns of both cytoplasmic and nuclear ORF1p and ORF2p expression indicate that further studies of the biology and function of L1 retrotransposons are required in breast cancer.

Show MeSH
Related in: MedlinePlus