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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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Differential expression of ORF1p and ORF2p. Boxplots represent the comparison of histoscores between cytoplasmic and nuclear expression of ORF1p and ORF2p in breast tumors. This revealed a significant increase in the nuclear expression of both ORF1p and ORF2p in invasive cancers compared with DCIS
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Fig4: Differential expression of ORF1p and ORF2p. Boxplots represent the comparison of histoscores between cytoplasmic and nuclear expression of ORF1p and ORF2p in breast tumors. This revealed a significant increase in the nuclear expression of both ORF1p and ORF2p in invasive cancers compared with DCIS

Mentions: In breast tumor samples, the staining intensity and the percentage of cells expressing cytoplasmic and nuclear staining were determined separately using a weighted histocore method [21]. Expression of ORF1p and ORF2p was both categorized into three groups: (i) cytoplasmic expression, weak <29 %, moderate 30–59 %, and high expression >60 %; (ii) nuclear expression, weak < 29 %, moderate 30–59 %, and high > 60 % (Fig. 4). In DCIS tumors (n = 25), 88 % and 84 % displayed expression that ranged from weak to high for ORF1p and ORF2p, respectively. There was no significant difference between the pattern of staining between low and high grade DCIS. Notably, both ORF1p and ORF2p exhibited high cytoplasmic expression in 76 % (19 of 25) and 80 % (20 of 25) of cases, respectively. None of the patients with DCIS displayed high nuclear expression. In contrast, 59 % and 60 % of invasive cancers (n = 95) showed cytoplasmic and/or nuclear expression for ORF1p and ORF2p, respectively. Notably, 28 % (27 of 95) and 32 % (30 of 95) of those invasive cancers showed high nuclear expression for both ORF1p and ORF2p and the cytoplasmic staining, respectively, which ranged from weak to moderate was also found in those cases. No significant correlation was observed between the nuclear expression and histologic grades although patients with high nuclear expression of ORF1p and ORF2p showed higher mitotic counts and higher nuclear pleomorphism than patients with cytoplasmic expression. The association between nuclear and cytoplasmic expression was significant for both ORF1p and ORF2p (p = 0.0001). Together, these data suggest that L1 retrotransposons are differentially expressed in breast tumors, with the highest expression seen in the cytoplasm of DCIS, whereas the invasive cancers showed expression ranging from weak to high in both the cytoplasm and nucleus of the malignant cells.Fig. 4


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)

Differential expression of ORF1p and ORF2p. Boxplots represent the comparison of histoscores between cytoplasmic and nuclear expression of ORF1p and ORF2p in breast tumors. This revealed a significant increase in the nuclear expression of both ORF1p and ORF2p in invasive cancers compared with DCIS
© Copyright Policy
Related In: Results  -  Collection

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

Fig4: Differential expression of ORF1p and ORF2p. Boxplots represent the comparison of histoscores between cytoplasmic and nuclear expression of ORF1p and ORF2p in breast tumors. This revealed a significant increase in the nuclear expression of both ORF1p and ORF2p in invasive cancers compared with DCIS
Mentions: In breast tumor samples, the staining intensity and the percentage of cells expressing cytoplasmic and nuclear staining were determined separately using a weighted histocore method [21]. Expression of ORF1p and ORF2p was both categorized into three groups: (i) cytoplasmic expression, weak <29 %, moderate 30–59 %, and high expression >60 %; (ii) nuclear expression, weak < 29 %, moderate 30–59 %, and high > 60 % (Fig. 4). In DCIS tumors (n = 25), 88 % and 84 % displayed expression that ranged from weak to high for ORF1p and ORF2p, respectively. There was no significant difference between the pattern of staining between low and high grade DCIS. Notably, both ORF1p and ORF2p exhibited high cytoplasmic expression in 76 % (19 of 25) and 80 % (20 of 25) of cases, respectively. None of the patients with DCIS displayed high nuclear expression. In contrast, 59 % and 60 % of invasive cancers (n = 95) showed cytoplasmic and/or nuclear expression for ORF1p and ORF2p, respectively. Notably, 28 % (27 of 95) and 32 % (30 of 95) of those invasive cancers showed high nuclear expression for both ORF1p and ORF2p and the cytoplasmic staining, respectively, which ranged from weak to moderate was also found in those cases. No significant correlation was observed between the nuclear expression and histologic grades although patients with high nuclear expression of ORF1p and ORF2p showed higher mitotic counts and higher nuclear pleomorphism than patients with cytoplasmic expression. The association between nuclear and cytoplasmic expression was significant for both ORF1p and ORF2p (p = 0.0001). Together, these data suggest that L1 retrotransposons are differentially expressed in breast tumors, with the highest expression seen in the cytoplasm of DCIS, whereas the invasive cancers showed expression ranging from weak to high in both the cytoplasm and nucleus of the malignant cells.Fig. 4

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