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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

Associations between components of the retinoid pathway and breast cancer phenotypeAssociations between the expression of the indicated members of the retinoid pathway in the TCGA gene-expression database are shown. Mammary tumors are classified into Luminal-A, Luminal-B, HER2-like, Normal-like, and Basal according to the PAM50 fingerprint. The average expression levels and the corresponding SD values of the indicated members of the retinoid pathway are shown by the upper box plots. For each member of the retinoid pathway, significant differences between the indicated groups of tumors are shown in the lower table. Significant P-values for the indicated comparisons (Student's t-test) are shown in red.
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fig05: Associations between components of the retinoid pathway and breast cancer phenotypeAssociations between the expression of the indicated members of the retinoid pathway in the TCGA gene-expression database are shown. Mammary tumors are classified into Luminal-A, Luminal-B, HER2-like, Normal-like, and Basal according to the PAM50 fingerprint. The average expression levels and the corresponding SD values of the indicated members of the retinoid pathway are shown by the upper box plots. For each member of the retinoid pathway, significant differences between the indicated groups of tumors are shown in the lower table. Significant P-values for the indicated comparisons (Student's t-test) are shown in red.

Mentions: To evaluate whether the expression patterns of retinoid receptors/binding proteins in cell lines recapitulate the situation in mammary tumors, we analyzed the TCGA RNA-seq dataset consisting of over 1,000 breast tumors classified into Luminal-A, Luminal-B, HER2-like, Normal-like and Basal according to PAM50. Consistent with the cell-line data, Basal tumors synthesize the smallest amounts of RARα, RXRα, and RXRγ and the highest levels of FABP5 (Fig5A and B). The analysis unmasks associations which are not evident in cell lines, that is, direct correlations between RARβ/RXRβ/CRABP1/PPARβ/δ expression and the Basal phenotype. Given the poor responsiveness of Basal cell lines to the retinoid (Fig1B), these results support the notion that FABP5 and PPARβ/δ are negative determinants of ATRA sensitivity (Balmer & Blomhoff, 2002; Kannan-Thulasiraman et al, 2010). As for RARβ, its expression does not seem to be important for ATRA anti-tumor activity in breast cancer (Connolly et al, 2013). In conclusion, our data demonstrate that RARα is the only receptor with a high level of expression in the cellular phenotypes predicted to be responsive to ATRA.


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)

Associations between components of the retinoid pathway and breast cancer phenotypeAssociations between the expression of the indicated members of the retinoid pathway in the TCGA gene-expression database are shown. Mammary tumors are classified into Luminal-A, Luminal-B, HER2-like, Normal-like, and Basal according to the PAM50 fingerprint. The average expression levels and the corresponding SD values of the indicated members of the retinoid pathway are shown by the upper box plots. For each member of the retinoid pathway, significant differences between the indicated groups of tumors are shown in the lower table. Significant P-values for the indicated comparisons (Student's t-test) are shown in red.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig05: Associations between components of the retinoid pathway and breast cancer phenotypeAssociations between the expression of the indicated members of the retinoid pathway in the TCGA gene-expression database are shown. Mammary tumors are classified into Luminal-A, Luminal-B, HER2-like, Normal-like, and Basal according to the PAM50 fingerprint. The average expression levels and the corresponding SD values of the indicated members of the retinoid pathway are shown by the upper box plots. For each member of the retinoid pathway, significant differences between the indicated groups of tumors are shown in the lower table. Significant P-values for the indicated comparisons (Student's t-test) are shown in red.
Mentions: To evaluate whether the expression patterns of retinoid receptors/binding proteins in cell lines recapitulate the situation in mammary tumors, we analyzed the TCGA RNA-seq dataset consisting of over 1,000 breast tumors classified into Luminal-A, Luminal-B, HER2-like, Normal-like and Basal according to PAM50. Consistent with the cell-line data, Basal tumors synthesize the smallest amounts of RARα, RXRα, and RXRγ and the highest levels of FABP5 (Fig5A and B). The analysis unmasks associations which are not evident in cell lines, that is, direct correlations between RARβ/RXRβ/CRABP1/PPARβ/δ expression and the Basal phenotype. Given the poor responsiveness of Basal cell lines to the retinoid (Fig1B), these results support the notion that FABP5 and PPARβ/δ are negative determinants of ATRA sensitivity (Balmer & Blomhoff, 2002; Kannan-Thulasiraman et al, 2010). As for RARβ, its expression does not seem to be important for ATRA anti-tumor activity in breast cancer (Connolly et al, 2013). In conclusion, our data demonstrate that RARα is the only receptor with a high level of expression in the cellular phenotypes predicted to be responsive to ATRA.

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