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Oncogenic miR-181a/b affect the DNA damage response in aggressive breast cancer.

Bisso A, Faleschini M, Zampa F, Capaci V, De Santa J, Santarpia L, Piazza S, Cappelletti V, Daidone M, Agami R, Del Sal G - Cell Cycle (2013)

Bottom Line: Breast cancer is a heterogeneous tumor type characterized by a complex spectrum of molecular aberrations, resulting in a diverse array of malignant features and clinical outcomes.Among other alterations, aberrant expression of microRNAs has been found in breast cancer and other human tumors, where they act as either oncogenes or tumor suppressors by virtue of their ability to finely modulate gene expression at the post-transcriptional level.These evidences suggest that monitoring the expression of miR-181a/b could be helpful in tailoring more effective treatments based on inhibition of PARP1 in breast and other tumor types.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio Nazionale CIB, AREA Science Park, Trieste, Italy.

ABSTRACT
Breast cancer is a heterogeneous tumor type characterized by a complex spectrum of molecular aberrations, resulting in a diverse array of malignant features and clinical outcomes. Deciphering the molecular mechanisms that fuel breast cancer development and act as determinants of aggressiveness is a primary need to improve patient management. Among other alterations, aberrant expression of microRNAs has been found in breast cancer and other human tumors, where they act as either oncogenes or tumor suppressors by virtue of their ability to finely modulate gene expression at the post-transcriptional level. In this study, we describe a new role for miR-181a/b as negative regulators of the DNA damage response in breast cancer, impacting on the expression and activity of the stress-sensor kinase ataxia telangiectasia mutated (ATM). We report that miR-181a and miR-181b were overexpressed in more aggressive breast cancers, and their expression correlates inversely with ATM levels. Moreover we demonstrate that deregulated expression of miR-181a/b determines the sensitivity of triple-negative breast cancer cells to the poly-ADP-ribose-polymerase1 (PARP1) inhibition. These evidences suggest that monitoring the expression of miR-181a/b could be helpful in tailoring more effective treatments based on inhibition of PARP1 in breast and other tumor types.

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Figure 1. miR-181a/b expression levels correlate with breast cancer aggressiveness. (A) Plot of miR-181a and miR-181b expression (ΔΔCt) according to tumor grade (grade 1 tumors n = 17, grade 2 n = 60, grade 3 n = 27). miR-181a and miR-181b levels were evaluated by RT-qPCR and normalized to the expression of U6B RNA (see “Materials and Methods” for details). p < 10−7 (miR-181a) and p < 10−8 (miR-181b), Anova test on linear regression models. (B) Plot of miR-181a and miR-181b expression (ΔΔCt) according to Ki67 staining evaluated by IHC. p < 10−09 for both miR-181a and miR-181b, Anova test on linear regression models. (C) miR-181a/b expression was classified as high or low relative to the average value of expression in all samples. Percentage of miR-181a/b high or low expression within grade 1 or grade 3 tumors is reported. p = 0.0014 for miR-181a and p = 4.2 × 10−6 for miR-181b, Pearson’s Chi-square test. (D) Kaplan-Meier survival curves of disease free survival (DFS) of breast cancer patients classified according to the expression miR-181b, LogRank test, p = 0.0066, n = 123) (E) Mosaic plot showing the distribution of tumors with high (blue bars), medium (green bars) or low (red bars) miR-181b levels, assessed by comparing miRNA abundance in breast tumor samples that developed (relapse) or not (disease-free) a metastasis within 5 y after diagnosis. p-value (p < 0.05, Pearson’s Chi-square test) was calculated comparing “low” vs “high” miR-181b expression (see “Materials and Methods” for details).
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Figure 1: Figure 1. miR-181a/b expression levels correlate with breast cancer aggressiveness. (A) Plot of miR-181a and miR-181b expression (ΔΔCt) according to tumor grade (grade 1 tumors n = 17, grade 2 n = 60, grade 3 n = 27). miR-181a and miR-181b levels were evaluated by RT-qPCR and normalized to the expression of U6B RNA (see “Materials and Methods” for details). p < 10−7 (miR-181a) and p < 10−8 (miR-181b), Anova test on linear regression models. (B) Plot of miR-181a and miR-181b expression (ΔΔCt) according to Ki67 staining evaluated by IHC. p < 10−09 for both miR-181a and miR-181b, Anova test on linear regression models. (C) miR-181a/b expression was classified as high or low relative to the average value of expression in all samples. Percentage of miR-181a/b high or low expression within grade 1 or grade 3 tumors is reported. p = 0.0014 for miR-181a and p = 4.2 × 10−6 for miR-181b, Pearson’s Chi-square test. (D) Kaplan-Meier survival curves of disease free survival (DFS) of breast cancer patients classified according to the expression miR-181b, LogRank test, p = 0.0066, n = 123) (E) Mosaic plot showing the distribution of tumors with high (blue bars), medium (green bars) or low (red bars) miR-181b levels, assessed by comparing miRNA abundance in breast tumor samples that developed (relapse) or not (disease-free) a metastasis within 5 y after diagnosis. p-value (p < 0.05, Pearson’s Chi-square test) was calculated comparing “low” vs “high” miR-181b expression (see “Materials and Methods” for details).

Mentions: To identify miRNAs that may be deregulated in breast cancer, we performed a survey of public breast cancer data sets for miRNA expression. This search highlighted that miR-181b is frequently overexpressed in tumor samples included in three different breast cancer collections (Fig.  S1).24-26 To validate this data, we investigated the expression of miR-181b and of its sibling miR-181a (originated from the same polycristronic transcripts) in a panel of 104 snap-frozen primary breast cancers and eight normal tissue counterparts (104 BC data set, Table S1). As shown in Figure 1A, higher levels of miR-181a/b were detected in tumor samples as compared with normal tissue, and, importantly, their expression levels correlated positively with tumor aggressiveness, with grade 3 (G3) tumors showing highest expression of the two miRNAs with respect to grade 1 (G1) and 2 (G2) tumors (Fig. 1A) as well as with proliferation index, as judged by KI67 protein expression (Fig. 1B). In particular, in G3 tumors, high levels of miR-181a/b were detected in 67% (miR-181a) and 70% (miR-181b) of cases, while in G1 samples, only 18% of them showed high levels of expression for miR-181a and 29% of them for miR-181b (Fig. 1C).


Oncogenic miR-181a/b affect the DNA damage response in aggressive breast cancer.

Bisso A, Faleschini M, Zampa F, Capaci V, De Santa J, Santarpia L, Piazza S, Cappelletti V, Daidone M, Agami R, Del Sal G - Cell Cycle (2013)

Figure 1. miR-181a/b expression levels correlate with breast cancer aggressiveness. (A) Plot of miR-181a and miR-181b expression (ΔΔCt) according to tumor grade (grade 1 tumors n = 17, grade 2 n = 60, grade 3 n = 27). miR-181a and miR-181b levels were evaluated by RT-qPCR and normalized to the expression of U6B RNA (see “Materials and Methods” for details). p < 10−7 (miR-181a) and p < 10−8 (miR-181b), Anova test on linear regression models. (B) Plot of miR-181a and miR-181b expression (ΔΔCt) according to Ki67 staining evaluated by IHC. p < 10−09 for both miR-181a and miR-181b, Anova test on linear regression models. (C) miR-181a/b expression was classified as high or low relative to the average value of expression in all samples. Percentage of miR-181a/b high or low expression within grade 1 or grade 3 tumors is reported. p = 0.0014 for miR-181a and p = 4.2 × 10−6 for miR-181b, Pearson’s Chi-square test. (D) Kaplan-Meier survival curves of disease free survival (DFS) of breast cancer patients classified according to the expression miR-181b, LogRank test, p = 0.0066, n = 123) (E) Mosaic plot showing the distribution of tumors with high (blue bars), medium (green bars) or low (red bars) miR-181b levels, assessed by comparing miRNA abundance in breast tumor samples that developed (relapse) or not (disease-free) a metastasis within 5 y after diagnosis. p-value (p < 0.05, Pearson’s Chi-square test) was calculated comparing “low” vs “high” miR-181b expression (see “Materials and Methods” for details).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 1: Figure 1. miR-181a/b expression levels correlate with breast cancer aggressiveness. (A) Plot of miR-181a and miR-181b expression (ΔΔCt) according to tumor grade (grade 1 tumors n = 17, grade 2 n = 60, grade 3 n = 27). miR-181a and miR-181b levels were evaluated by RT-qPCR and normalized to the expression of U6B RNA (see “Materials and Methods” for details). p < 10−7 (miR-181a) and p < 10−8 (miR-181b), Anova test on linear regression models. (B) Plot of miR-181a and miR-181b expression (ΔΔCt) according to Ki67 staining evaluated by IHC. p < 10−09 for both miR-181a and miR-181b, Anova test on linear regression models. (C) miR-181a/b expression was classified as high or low relative to the average value of expression in all samples. Percentage of miR-181a/b high or low expression within grade 1 or grade 3 tumors is reported. p = 0.0014 for miR-181a and p = 4.2 × 10−6 for miR-181b, Pearson’s Chi-square test. (D) Kaplan-Meier survival curves of disease free survival (DFS) of breast cancer patients classified according to the expression miR-181b, LogRank test, p = 0.0066, n = 123) (E) Mosaic plot showing the distribution of tumors with high (blue bars), medium (green bars) or low (red bars) miR-181b levels, assessed by comparing miRNA abundance in breast tumor samples that developed (relapse) or not (disease-free) a metastasis within 5 y after diagnosis. p-value (p < 0.05, Pearson’s Chi-square test) was calculated comparing “low” vs “high” miR-181b expression (see “Materials and Methods” for details).
Mentions: To identify miRNAs that may be deregulated in breast cancer, we performed a survey of public breast cancer data sets for miRNA expression. This search highlighted that miR-181b is frequently overexpressed in tumor samples included in three different breast cancer collections (Fig.  S1).24-26 To validate this data, we investigated the expression of miR-181b and of its sibling miR-181a (originated from the same polycristronic transcripts) in a panel of 104 snap-frozen primary breast cancers and eight normal tissue counterparts (104 BC data set, Table S1). As shown in Figure 1A, higher levels of miR-181a/b were detected in tumor samples as compared with normal tissue, and, importantly, their expression levels correlated positively with tumor aggressiveness, with grade 3 (G3) tumors showing highest expression of the two miRNAs with respect to grade 1 (G1) and 2 (G2) tumors (Fig. 1A) as well as with proliferation index, as judged by KI67 protein expression (Fig. 1B). In particular, in G3 tumors, high levels of miR-181a/b were detected in 67% (miR-181a) and 70% (miR-181b) of cases, while in G1 samples, only 18% of them showed high levels of expression for miR-181a and 29% of them for miR-181b (Fig. 1C).

Bottom Line: Breast cancer is a heterogeneous tumor type characterized by a complex spectrum of molecular aberrations, resulting in a diverse array of malignant features and clinical outcomes.Among other alterations, aberrant expression of microRNAs has been found in breast cancer and other human tumors, where they act as either oncogenes or tumor suppressors by virtue of their ability to finely modulate gene expression at the post-transcriptional level.These evidences suggest that monitoring the expression of miR-181a/b could be helpful in tailoring more effective treatments based on inhibition of PARP1 in breast and other tumor types.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio Nazionale CIB, AREA Science Park, Trieste, Italy.

ABSTRACT
Breast cancer is a heterogeneous tumor type characterized by a complex spectrum of molecular aberrations, resulting in a diverse array of malignant features and clinical outcomes. Deciphering the molecular mechanisms that fuel breast cancer development and act as determinants of aggressiveness is a primary need to improve patient management. Among other alterations, aberrant expression of microRNAs has been found in breast cancer and other human tumors, where they act as either oncogenes or tumor suppressors by virtue of their ability to finely modulate gene expression at the post-transcriptional level. In this study, we describe a new role for miR-181a/b as negative regulators of the DNA damage response in breast cancer, impacting on the expression and activity of the stress-sensor kinase ataxia telangiectasia mutated (ATM). We report that miR-181a and miR-181b were overexpressed in more aggressive breast cancers, and their expression correlates inversely with ATM levels. Moreover we demonstrate that deregulated expression of miR-181a/b determines the sensitivity of triple-negative breast cancer cells to the poly-ADP-ribose-polymerase1 (PARP1) inhibition. These evidences suggest that monitoring the expression of miR-181a/b could be helpful in tailoring more effective treatments based on inhibition of PARP1 in breast and other tumor types.

Show MeSH
Related in: MedlinePlus