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Cellular and molecular determinants of all-trans retinoic acid sensitivity in breast cancer: Luminal phenotype and RARα expression.

Centritto F, Paroni G, Bolis M, Garattini SK, Kurosaki M, Barzago MM, Zanetti A, Fisher JN, Scott MF, Pattini L, Lupi M, Ubezio P, Piccotti F, Zambelli A, Rizzo P, Gianni' M, Fratelli M, Terao M, Garattini E - EMBO Mol Med (2015)

Bottom Line: Luminal and ER(+) (estrogen-receptor-positive) cell lines are generally sensitive to ATRA, while refractoriness/low sensitivity is associated with a Basal phenotype and HER2 positivity.Pathway-oriented analysis of the constitutive gene-expression profiles in the cell lines identifies RARα as the member of the retinoid pathway directly associated with a Luminal phenotype, estrogen positivity and ATRA sensitivity.All this is paralleled by similar effects on ATRA-dependent inhibition of cell motility, indicating that RARα may mediate also ATRA anti-metastatic effects.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.

No MeSH data available.


Related in: MedlinePlus

ATRA-dependent perturbations of the transcriptome in primary tumorsTissue slices corresponding to the indicated patients were treated with vehicle (DMSO) or ATRA (0.1 μM) for 48 h. Whole-genome gene expression studies were performed on the extracted total RNA using a microarray platform.The heat-map shows the genes significantly up- or down-regulated by ATRA (P < 0.005, paired t-test) in either Luminal-A and -B (Lum) or triple-negative (TN) tumors, and the results are expressed as the log2 ratio observed between the ATRA and vehicle-treated samples.A Venn diagram of the genes up- or down-regulated by ATRA in TN and Lum tumors is shown. The number of genes commonly or selectively regulated in TN and Lum tumors is indicated.The heat-map shows the regulation patterns of the retinoid-dependent genes significantly modulated by ATRA (P < 0.001) in either TN or Lum tumors. The symbols highlighted in red represent the five genes differentially and significantly regulated by ATRA in Lum versus TN tumors.The panel shows the estrogen-receptor (ESR1) pathway, which is significantly enriched for genes regulated by ATRA in Lum tumors. The green arrows indicate up-regulatory or stimulating interactions, while the red arrows indicate down-regulatory or inhibitory interactions. The gray arrows indicate unknown types of interactions. The red and blue dots above the protein symbols indicate the effect of ATRA in Lum tumors (red = up-regulation; blue = down-regulation).
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fig12: ATRA-dependent perturbations of the transcriptome in primary tumorsTissue slices corresponding to the indicated patients were treated with vehicle (DMSO) or ATRA (0.1 μM) for 48 h. Whole-genome gene expression studies were performed on the extracted total RNA using a microarray platform.The heat-map shows the genes significantly up- or down-regulated by ATRA (P < 0.005, paired t-test) in either Luminal-A and -B (Lum) or triple-negative (TN) tumors, and the results are expressed as the log2 ratio observed between the ATRA and vehicle-treated samples.A Venn diagram of the genes up- or down-regulated by ATRA in TN and Lum tumors is shown. The number of genes commonly or selectively regulated in TN and Lum tumors is indicated.The heat-map shows the regulation patterns of the retinoid-dependent genes significantly modulated by ATRA (P < 0.001) in either TN or Lum tumors. The symbols highlighted in red represent the five genes differentially and significantly regulated by ATRA in Lum versus TN tumors.The panel shows the estrogen-receptor (ESR1) pathway, which is significantly enriched for genes regulated by ATRA in Lum tumors. The green arrows indicate up-regulatory or stimulating interactions, while the red arrows indicate down-regulatory or inhibitory interactions. The gray arrows indicate unknown types of interactions. The red and blue dots above the protein symbols indicate the effect of ATRA in Lum tumors (red = up-regulation; blue = down-regulation).

Mentions: ATRA exerts major quantitative effects on the transcriptomes not only of Luminal/ER+ tumors, but also of TN cancers (Fig12A and Supplementary Table S5). Cluster analysis of the regulated transcripts results in a clear separation between Luminal/ER+ and TN tumors on the basis of the genomic responses to ATRA. It is interesting to notice that cluster analysis groups together the three Ki67-unresponsive Luminal/ER+ cases (Patients No. 41, 55 and 61). A total of 1,702 genes are significantly regulated by ATRA (P < 0.005, paired t-test) in either TN or Luminal/ER+ tumors. Approximately 20% of the genes (up-regulated genes = 198; down-regulated genes = 134) are similarly modulated by ATRA in both the Luminal/ER+ and TN cases (Fig2B).


Cellular and molecular determinants of all-trans retinoic acid sensitivity in breast cancer: Luminal phenotype and RARα expression.

Centritto F, Paroni G, Bolis M, Garattini SK, Kurosaki M, Barzago MM, Zanetti A, Fisher JN, Scott MF, Pattini L, Lupi M, Ubezio P, Piccotti F, Zambelli A, Rizzo P, Gianni' M, Fratelli M, Terao M, Garattini E - EMBO Mol Med (2015)

ATRA-dependent perturbations of the transcriptome in primary tumorsTissue slices corresponding to the indicated patients were treated with vehicle (DMSO) or ATRA (0.1 μM) for 48 h. Whole-genome gene expression studies were performed on the extracted total RNA using a microarray platform.The heat-map shows the genes significantly up- or down-regulated by ATRA (P < 0.005, paired t-test) in either Luminal-A and -B (Lum) or triple-negative (TN) tumors, and the results are expressed as the log2 ratio observed between the ATRA and vehicle-treated samples.A Venn diagram of the genes up- or down-regulated by ATRA in TN and Lum tumors is shown. The number of genes commonly or selectively regulated in TN and Lum tumors is indicated.The heat-map shows the regulation patterns of the retinoid-dependent genes significantly modulated by ATRA (P < 0.001) in either TN or Lum tumors. The symbols highlighted in red represent the five genes differentially and significantly regulated by ATRA in Lum versus TN tumors.The panel shows the estrogen-receptor (ESR1) pathway, which is significantly enriched for genes regulated by ATRA in Lum tumors. The green arrows indicate up-regulatory or stimulating interactions, while the red arrows indicate down-regulatory or inhibitory interactions. The gray arrows indicate unknown types of interactions. The red and blue dots above the protein symbols indicate the effect of ATRA in Lum tumors (red = up-regulation; blue = down-regulation).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4520659&req=5

fig12: ATRA-dependent perturbations of the transcriptome in primary tumorsTissue slices corresponding to the indicated patients were treated with vehicle (DMSO) or ATRA (0.1 μM) for 48 h. Whole-genome gene expression studies were performed on the extracted total RNA using a microarray platform.The heat-map shows the genes significantly up- or down-regulated by ATRA (P < 0.005, paired t-test) in either Luminal-A and -B (Lum) or triple-negative (TN) tumors, and the results are expressed as the log2 ratio observed between the ATRA and vehicle-treated samples.A Venn diagram of the genes up- or down-regulated by ATRA in TN and Lum tumors is shown. The number of genes commonly or selectively regulated in TN and Lum tumors is indicated.The heat-map shows the regulation patterns of the retinoid-dependent genes significantly modulated by ATRA (P < 0.001) in either TN or Lum tumors. The symbols highlighted in red represent the five genes differentially and significantly regulated by ATRA in Lum versus TN tumors.The panel shows the estrogen-receptor (ESR1) pathway, which is significantly enriched for genes regulated by ATRA in Lum tumors. The green arrows indicate up-regulatory or stimulating interactions, while the red arrows indicate down-regulatory or inhibitory interactions. The gray arrows indicate unknown types of interactions. The red and blue dots above the protein symbols indicate the effect of ATRA in Lum tumors (red = up-regulation; blue = down-regulation).
Mentions: ATRA exerts major quantitative effects on the transcriptomes not only of Luminal/ER+ tumors, but also of TN cancers (Fig12A and Supplementary Table S5). Cluster analysis of the regulated transcripts results in a clear separation between Luminal/ER+ and TN tumors on the basis of the genomic responses to ATRA. It is interesting to notice that cluster analysis groups together the three Ki67-unresponsive Luminal/ER+ cases (Patients No. 41, 55 and 61). A total of 1,702 genes are significantly regulated by ATRA (P < 0.005, paired t-test) in either TN or Luminal/ER+ tumors. Approximately 20% of the genes (up-regulated genes = 198; down-regulated genes = 134) are similarly modulated by ATRA in both the Luminal/ER+ and TN cases (Fig2B).

Bottom Line: Luminal and ER(+) (estrogen-receptor-positive) cell lines are generally sensitive to ATRA, while refractoriness/low sensitivity is associated with a Basal phenotype and HER2 positivity.Pathway-oriented analysis of the constitutive gene-expression profiles in the cell lines identifies RARα as the member of the retinoid pathway directly associated with a Luminal phenotype, estrogen positivity and ATRA sensitivity.All this is paralleled by similar effects on ATRA-dependent inhibition of cell motility, indicating that RARα may mediate also ATRA anti-metastatic effects.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.

No MeSH data available.


Related in: MedlinePlus