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Opposite Effects of CRABP1 and CRABP2 Homologs on Proliferation of Breast Cancer Cells and Their Sensitivity to Retinoic Acid

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Abstract

Resistance of tumor cells to retinoic acid (RA), a promising therapeutic agent, is the major factor limiting the use of RA in clinical practice. The mechanisms of resistance to RA are still poorly understood. Cellular Retinoic Acid Binding Proteins, CRABP1 and CRABP2, are essential mediators of RA signaling, but role of the two CRABP homologs in regulating cellular sensitivity to RA has not been well studied. In addition, the effects of CRABP1 and CRABP2 on cell proliferation have not been compared. Here, using a broad panel of breast cancer cell lines with different levels of RA sensitivity/resistance, we show for the first time that in the RA-sensitive cells, CRABP1 expression is restricted by methylation, and protein levels are highly variable. In the moderately-RA-resistant cell lines, high level of CRABP1 is observed both at the mRNA and protein levels, unchanged by inhibition of DNA methylation. The cell lines with maximum resistance to RA are characterized by complete repression of CRABP1 expression realized at transcriptional and posttranscriptional levels, and exogenous expression of each of the CRABP homologs has no effect on the studied characteristics. CRABP1 and CRABP2 proteins have opposing effects on proliferation and sensitivity to RA. In particular, CRABP1 stimulates and CRABP2 reduces proliferation and resistance to RA in the initially RA-sensitive cells, while in the more resistant cells the role of each homolog in both of these parameters is reversed. Overall, we have shown for the first time that CRABP proteins exert different effects on the growth and sensitivity to RA of breast cancer cells (stimulation, suppression, or no effect) depending on the baseline level of RA-sensitivity, with the effects of CRABP1 and CRABP2 homologs on the studied properties always being opposite.

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Abbreviations

BC:

breast cancer

ATRA:

all-trans retinoic acid

CRABP1 and CRABP2:

cellular retinoic acid binding protein 1 and 2

DAC:

5-Aza-2′-deoxycytidine

RA:

retinoic acid

RAR:

retinoic acid receptor

TSA:

trichostatin A

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Funding

This study was financially supported by the Russian Science Foundation (grant no. 22-15-00373).

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Authors and Affiliations

  1. Federal State Budgetary Institution “N. N. Blokhin National Medical Research Center of Oncology” of the Ministry of Health of the Russian Federation, 115522, Moscow, Russia

    Adel D. Enikeev, Pavel M. Abramov, Danila S. Elkin, Andrey V. Komelkov, Anastasiya A. Beliaeva & Elena M. Tchevkina

  2. Pirogov Russian National Research Medical University, 117997, Moscow, Russia

    Darya M. Silantieva

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  1. Adel D. Enikeev
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  2. Pavel M. Abramov
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  3. Danila S. Elkin
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  4. Andrey V. Komelkov
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  5. Anastasiya A. Beliaeva
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Contributions

A.D.E. conducting experiments, analysis of the literature, writing the paper; P.M.A., D.S.E., A.V.K., A.A.B., and D.M.S. conducting experiments, E.M.Tch. design of the study, analysis of the results, editing of the manuscript.

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Correspondence to Elena M. Tchevkina.

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Enikeev, A.D., Abramov, P.M., Elkin, D.S. et al. Opposite Effects of CRABP1 and CRABP2 Homologs on Proliferation of Breast Cancer Cells and Their Sensitivity to Retinoic Acid. Biochemistry Moscow 88, 2107–2124 (2023). https://doi.org/10.1134/S0006297923120131

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