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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

Basal levels of RARα, RARβ, and RARγ mRNA splicing variants in mammary tumorsTotal RNA was extracted from the tissue slices deriving from the surgical specimens of breast cancer patients used in Fig3 before any treatment with DMSO or ATRA. RNA was subjected to RT–PCR analysis to determine the basal expression of the indicated RAR splicing variants.Each value represents the mean ± SD of two replicate measurements. The table shows the statistical significance of the indicated comparisons. *Significantly different (P-value < 0.05, Student's t-test). **Significantly different (P-value < 0.01, Student's t-test).The plots illustrate the average expression levels of the indicated mRNAs (mean ± SD of two replicates) in tumor samples classified as ATRA-sensitive (Sens) and ATRA-resistant (Res) according to the response of Ki67. *Significantly different (P-value < 0.05, Student's t-test).
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fig07: Basal levels of RARα, RARβ, and RARγ mRNA splicing variants in mammary tumorsTotal RNA was extracted from the tissue slices deriving from the surgical specimens of breast cancer patients used in Fig3 before any treatment with DMSO or ATRA. RNA was subjected to RT–PCR analysis to determine the basal expression of the indicated RAR splicing variants.Each value represents the mean ± SD of two replicate measurements. The table shows the statistical significance of the indicated comparisons. *Significantly different (P-value < 0.05, Student's t-test). **Significantly different (P-value < 0.01, Student's t-test).The plots illustrate the average expression levels of the indicated mRNAs (mean ± SD of two replicates) in tumor samples classified as ATRA-sensitive (Sens) and ATRA-resistant (Res) according to the response of Ki67. *Significantly different (P-value < 0.05, Student's t-test).

Mentions: The profiles of expression of the RAR splicing variants were defined in the primary tumors used to evaluate ATRA sensitivity (see Fig3). In all the specimens considered, RARα3 and RARα2 are the most abundant RARα mRNAs and have a similar level of expression (Fig7A), which is different from what is observed in the cell lines. Across all the samples, RARβ1 is more abundant than RARβ2, although RARβ1 levels are at least one order of magnitude lower than the RARα3/RARα2 counterparts. In the case of the RARγ variants, RARγ1 and RARγ2 show intermediate levels of expression relative to RARα3/RARα2 and RARβ1/RARβ2. RARγ2 in primary tumors is more abundant than expected from the cell-line results, while RARγ3 is by far the least abundant species. The expression of RARα3/RARα1, RARα3/RARα2, RARα3/RARα4, RARα2/RARα4, RARγ1/RARγ2, RARγ1/RARγ3, and RARγ2/RARγ3 across the tumor samples is highly correlated (Supplementary Fig S8).


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)

Basal levels of RARα, RARβ, and RARγ mRNA splicing variants in mammary tumorsTotal RNA was extracted from the tissue slices deriving from the surgical specimens of breast cancer patients used in Fig3 before any treatment with DMSO or ATRA. RNA was subjected to RT–PCR analysis to determine the basal expression of the indicated RAR splicing variants.Each value represents the mean ± SD of two replicate measurements. The table shows the statistical significance of the indicated comparisons. *Significantly different (P-value < 0.05, Student's t-test). **Significantly different (P-value < 0.01, Student's t-test).The plots illustrate the average expression levels of the indicated mRNAs (mean ± SD of two replicates) in tumor samples classified as ATRA-sensitive (Sens) and ATRA-resistant (Res) according to the response of Ki67. *Significantly different (P-value < 0.05, Student's t-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4520659&req=5

fig07: Basal levels of RARα, RARβ, and RARγ mRNA splicing variants in mammary tumorsTotal RNA was extracted from the tissue slices deriving from the surgical specimens of breast cancer patients used in Fig3 before any treatment with DMSO or ATRA. RNA was subjected to RT–PCR analysis to determine the basal expression of the indicated RAR splicing variants.Each value represents the mean ± SD of two replicate measurements. The table shows the statistical significance of the indicated comparisons. *Significantly different (P-value < 0.05, Student's t-test). **Significantly different (P-value < 0.01, Student's t-test).The plots illustrate the average expression levels of the indicated mRNAs (mean ± SD of two replicates) in tumor samples classified as ATRA-sensitive (Sens) and ATRA-resistant (Res) according to the response of Ki67. *Significantly different (P-value < 0.05, Student's t-test).
Mentions: The profiles of expression of the RAR splicing variants were defined in the primary tumors used to evaluate ATRA sensitivity (see Fig3). In all the specimens considered, RARα3 and RARα2 are the most abundant RARα mRNAs and have a similar level of expression (Fig7A), which is different from what is observed in the cell lines. Across all the samples, RARβ1 is more abundant than RARβ2, although RARβ1 levels are at least one order of magnitude lower than the RARα3/RARα2 counterparts. In the case of the RARγ variants, RARγ1 and RARγ2 show intermediate levels of expression relative to RARα3/RARα2 and RARβ1/RARβ2. RARγ2 in primary tumors is more abundant than expected from the cell-line results, while RARγ3 is by far the least abundant species. The expression of RARα3/RARα1, RARα3/RARα2, RARα3/RARα4, RARα2/RARα4, RARγ1/RARγ2, RARγ1/RARγ3, and RARγ2/RARγ3 across the tumor samples is highly correlated (Supplementary Fig S8).

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