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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

Effects of RAR agonists on the growth of Luminal and Basal breast cancer cell linesThe indicated Luminal and Basal cell lines were challenged with increasing concentrations of ATRA, the RARα agonist, AM580, the RARβ agonist, UVI2003, and the RARγ agonist, BMS961, for 6 days. The complement of RAR-variant transcripts expressed in each cell line is shown in the left bar graphs (mean ± SD of two replicate measurements). The growth curves (sulforhodamine assay) of the cell lines are illustrated by the right linear plots. The results are expressed in % values relative to the corresponding control dishes treated with vehicle alone (right graphs). Each result is the mean ± SD of five replicate wells. ATRA sc = ATRA score.
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fig09: Effects of RAR agonists on the growth of Luminal and Basal breast cancer cell linesThe indicated Luminal and Basal cell lines were challenged with increasing concentrations of ATRA, the RARα agonist, AM580, the RARβ agonist, UVI2003, and the RARγ agonist, BMS961, for 6 days. The complement of RAR-variant transcripts expressed in each cell line is shown in the left bar graphs (mean ± SD of two replicate measurements). The growth curves (sulforhodamine assay) of the cell lines are illustrated by the right linear plots. The results are expressed in % values relative to the corresponding control dishes treated with vehicle alone (right graphs). Each result is the mean ± SD of five replicate wells. ATRA sc = ATRA score.

Mentions: The functional role of RARα in the anti-proliferative action of ATRA was evaluated in Luminal and Basal cell lines with different ATRA scores and RAR-variant expression profiles (Fig9) with a pharmacological approach, using the validated (Supplementary Fig S9) AM580 RARα agonist (Gianni et al, 1996), the UVI2003 RARβ agonist (Alvarez et al, 2014), and the BMS961 RARAγ agonist (Gianni et al, 1993). The cell lines were challenged with increasing concentrations of ATRA, AM580, UVI2003, and BMS961 for 3 (data not shown) and 6 days prior to evaluation of cell growth. In the ATRA-sensitive Luminal lines, AM580 is the only agonist which inhibits growth in a dose-dependent manner. In ER+/HER2−HCC-1428 cells, AM580 is more effective than ATRA, while the opposite is true in the ER−/HER2−EVSAT counterpart. In the remaining Luminal lines, AM580 and ATRA show similar efficacy. AM580 is also the sole agonist inhibiting the growth of the retinoid-sensitive Basal cell lines, HCC-1599, MDA-MB157, and HCC-1954. In these cellular contexts, no significant difference in the anti-proliferative activity of AM580 and ATRA is noticeable. AM580, UVI2003, BMS961, and ATRA are equally ineffective in retinoid-resistant HCC-38 cells.


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)

Effects of RAR agonists on the growth of Luminal and Basal breast cancer cell linesThe indicated Luminal and Basal cell lines were challenged with increasing concentrations of ATRA, the RARα agonist, AM580, the RARβ agonist, UVI2003, and the RARγ agonist, BMS961, for 6 days. The complement of RAR-variant transcripts expressed in each cell line is shown in the left bar graphs (mean ± SD of two replicate measurements). The growth curves (sulforhodamine assay) of the cell lines are illustrated by the right linear plots. The results are expressed in % values relative to the corresponding control dishes treated with vehicle alone (right graphs). Each result is the mean ± SD of five replicate wells. ATRA sc = ATRA score.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig09: Effects of RAR agonists on the growth of Luminal and Basal breast cancer cell linesThe indicated Luminal and Basal cell lines were challenged with increasing concentrations of ATRA, the RARα agonist, AM580, the RARβ agonist, UVI2003, and the RARγ agonist, BMS961, for 6 days. The complement of RAR-variant transcripts expressed in each cell line is shown in the left bar graphs (mean ± SD of two replicate measurements). The growth curves (sulforhodamine assay) of the cell lines are illustrated by the right linear plots. The results are expressed in % values relative to the corresponding control dishes treated with vehicle alone (right graphs). Each result is the mean ± SD of five replicate wells. ATRA sc = ATRA score.
Mentions: The functional role of RARα in the anti-proliferative action of ATRA was evaluated in Luminal and Basal cell lines with different ATRA scores and RAR-variant expression profiles (Fig9) with a pharmacological approach, using the validated (Supplementary Fig S9) AM580 RARα agonist (Gianni et al, 1996), the UVI2003 RARβ agonist (Alvarez et al, 2014), and the BMS961 RARAγ agonist (Gianni et al, 1993). The cell lines were challenged with increasing concentrations of ATRA, AM580, UVI2003, and BMS961 for 3 (data not shown) and 6 days prior to evaluation of cell growth. In the ATRA-sensitive Luminal lines, AM580 is the only agonist which inhibits growth in a dose-dependent manner. In ER+/HER2−HCC-1428 cells, AM580 is more effective than ATRA, while the opposite is true in the ER−/HER2−EVSAT counterpart. In the remaining Luminal lines, AM580 and ATRA show similar efficacy. AM580 is also the sole agonist inhibiting the growth of the retinoid-sensitive Basal cell lines, HCC-1599, MDA-MB157, and HCC-1954. In these cellular contexts, no significant difference in the anti-proliferative activity of AM580 and ATRA is noticeable. AM580, UVI2003, BMS961, and ATRA are equally ineffective in retinoid-resistant HCC-38 cells.

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